ABSTRACT
Introduction: We present a case report of hearing loss in a patient with Waldenstrom macroglobulinemia (WM) receiving treatment with bortezomib. Case Presentation: Our patient developed sudden bilateral sensorineural hearing loss after receiving three doses of bortezomib. His hearing loss was irreversible and resulted in a cochlear implant. Conclusion: Hearing loss secondary to bortezomib is a known, but very rare, side effect. Hearing loss secondary to WM is also rare and has been described in case reports.
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PURPOSE OF REVIEW: Treatment options for patients with acute lymphoblastic leukemia (ALL) beyond standard chemotherapy have grown significantly in recent years. In this review, we highlight new targeted therapies in ALL, with an emphasis on immunotherapy. RECENT FINDINGS: Major advances include antibody-based therapies, such as naked monoclonal antibodies, antibody-drug conjugates and bispecific T cell engaging (BiTE) antibodies, as well as adoptive cellular therapies such as chimeric antigen receptor (CAR) T cells. Apart from the above immunotherapeutic approaches, other targeted therapies are being employed in Philadelphia chromosome-positive (Ph+) ALL, Philadelphia-like (Ph-like) ALL, and T cell ALL. These new treatment strategies are changing the treatment landscape of ALL and challenging the current standard of care. Clinical trials will hopefully help determine how to best incorporate these novel therapies into existing treatment algorithms.
Subject(s)
Immunoconjugates/therapeutic use , Immunotherapy, Adoptive/methods , Humans , Immunotherapy, Adoptive/trends , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapyABSTRACT
Treatment options for older patients with acute myeloid leukemia (AML) range from supportive care alone to full-dose chemotherapy. Identifying factors that predict response to therapy may help increase efficacy and avoid toxicity. The phase II SWOG S0703 study investigated the use of hydroxyurea and azacitidine with gemtuzumab ozogamicin in the elderly AML population and found survival rates similar to those expected with standard AML regimens, with less toxicity. As part of this study, global DNA methylation along with promoter DNA methylation and expression analysis of six candidate genes (CDKN2A, CDKN2B, HIC1, RARB, CDH1 and APAF1) were determined before and during therapy to investigate whether very early changes are prognostic for clinical response. Global DNA methylation was not associated with a clinical response. Samples after 3 or 4 days of treatment with azacitidine showed significantly decreased CDKN2A promoter DNA methylation in patients achieving complete remission (CR) compared to those who did not. Samples from day 7 of treatment showed significantly decreased RARB, CDKN2B and CDH1 promoter DNA methylation in responders compared to nonresponders. Gene-specific DNA methylation analysis of peripheral blood samples may help early identification of those older AML patients most likely to benefit from demethylating agent therapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , DNA Methylation/genetics , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Aged , Aminoglycosides/administration & dosage , Aminoglycosides/adverse effects , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Azacitidine/administration & dosage , Azacitidine/adverse effects , Enzyme-Linked Immunosorbent Assay , Female , Gemtuzumab , Humans , Hydroxyurea/administration & dosage , Hydroxyurea/adverse effects , Male , Middle Aged , Prognosis , Promoter Regions, Genetic/genetics , Real-Time Polymerase Chain Reaction , Risk Factors , Transcriptome , Treatment OutcomeABSTRACT
BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to increase serum lithium concentrations. We sought to determine whether NSAIDs that selectively inhibit cyclooxygenase (COX) 2 also elevate serum lithium concentrations. METHOD: The U.S. Food and Drug Administration's Adverse Event Reporting System (AERS) database was searched in January 2003 for reports of interactions between lithium and rofecoxib or celecoxib, the selective COX-2 inhibitors marketed in the United States. Additionally, a literature search was performed using PubMed with the MeSH terms anti-inflammatory agents, nonsteroidal and lithium. Reports of interactions between NSAIDs and lithium were selected for review based on titles of retrieved citations. RESULTS: Eighteen cases of increased serum lithium concentrations after the addition of one of the COX-2 inhibitors to stable lithium therapy were retrieved from AERS, 13 with rofecoxib and 5 with celecoxib. Serum lithium concentration increases of up to 99% and 448% with concomitant celecoxib and rofecoxib use, respectively, were reported. Thirty-six English-language literature articles report interactions between lithium and various NSAIDs. Although some articles report no effect or decreased serum lithium concentrations with concomitant aspirin or sulindac, increased serum lithium concentration reports exist for aspirin, sulindac, and 14 other NSAIDs, including celecoxib and rofecoxib. CONCLUSION: Clinicians should consider NSAID use in the differential diagnosis of lithium toxicity, monitor patients' serum lithium concentrations during the initiation or discontinuation of NSAID therapy, and be aware that the selective COX-2 inhibitors can increase serum lithium concentrations leading to toxicity.
Subject(s)
Adverse Drug Reaction Reporting Systems/statistics & numerical data , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antimanic Agents/adverse effects , Antimanic Agents/blood , Cyclooxygenase Inhibitors/adverse effects , Cyclooxygenase Inhibitors/pharmacology , Lactones/adverse effects , Lactones/pharmacology , Lithium Carbonate/adverse effects , Lithium Carbonate/blood , Sulfonamides/adverse effects , Sulfonamides/pharmacology , Adult , Aged , Aged, 80 and over , Celecoxib , Drug Interactions , Female , Humans , Male , Middle Aged , Pyrazoles , Sulfones , United States , United States Food and Drug AdministrationABSTRACT
[reaction: see text] The application of microwave heating to a polymer-assisted solution-phase (PASP) synthesis technique has been utilized to develop a rapid and efficient protocol for the solution-phase synthesis of amides from either amine or carboxylic acid cores.
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OBJECTIVES: To gain a better understanding of the capacity of psychostimulant medications to induce adverse psychiatric reactions and determine the frequency of such reactions, we analyzed postmarketing surveillance data and clinical trial data for drugs, either approved or under development, for the treatment of attention-deficit/hyperactivity disorder. METHODS: The US Food and Drug Administration requested manufacturers of drugs approved for attention-deficit/hyperactivity disorder or with active clinical development programs for that indication to search their electronic clinical trial databases for cases of psychosis or mania using prespecified search terms. The manufacturers supplied descriptions of clinical trials, numbers of patients exposed to study drug, and duration of exposure to permit calculations of incidence rates. Independently, cases of psychosis or mania in children and adults for drugs used to treat attention-deficit/hyperactivity disorder from the Food and Drug Administration Adverse Event Reporting System safety database were analyzed. Manufacturers were asked to conduct similar analyses of their postmarketing surveillance databases. RESULTS: We analyzed data from 49 randomized, controlled clinical trials in the pediatric development programs for these products. A total of 11 psychosis/mania adverse events occurred during 743 person-years of double-blind treatment with these drugs, and no comparable adverse events occurred in a total of 420 person-years of placebo exposure in the same trials. The rate per 100 person-years in the pooled active drug group was 1.48. The analysis of spontaneous postmarketing reports yielded >800 reports of adverse events related to psychosis or mania. In approximately 90% of the cases, there was no reported history of a similar psychiatric condition. Hallucinations involving visual and/or tactile sensations of insects, snakes, or worms were common in cases in children. CONCLUSIONS: Patients and physicians should be aware that psychosis or mania arising during drug treatment of attention-deficit/hyperactivity disorder may represent adverse drug reactions.
Subject(s)
Attention Deficit Disorder with Hyperactivity/drug therapy , Hallucinations/chemically induced , Psychoses, Substance-Induced/etiology , Adverse Drug Reaction Reporting Systems , Child , Female , Humans , MaleABSTRACT
We report the synthesis of kinase targeted libraries based on the thienopyrazole scaffold. Several thienopyrazole analogs have been identified as submicromolar inhibitors of KDR.
Subject(s)
Chemistry, Pharmaceutical/methods , Drug Design , Enzyme Inhibitors/pharmacology , Phosphotransferases/chemistry , Pyrazoles/chemistry , Pyrazoles/chemical synthesis , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/chemistry , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Models, ChemicalABSTRACT
A series of 1,4-dihydroindeno[1,2-c]pyrazoles was prepared and evaluated for their enzymatic inhibition of KDR kinase. Computer modeling studies revealed the importance of attaching a basic side chain in predicting the binding mode of those compounds. Further investigation of structure-activity relationships led to 19, a lead compound with an acceptable selectivity profile, activity in whole cells, and good oral efficacy in an estradiol-induced murine uterine edema model of VEGF activity.
Subject(s)
Indenes/pharmacology , Pyrazoles/pharmacology , Administration, Oral , Animals , Chemistry, Pharmaceutical , Drug Design , Edema/pathology , Estradiol/pharmacology , Female , Indenes/chemistry , Inhibitory Concentration 50 , Mice , Models, Chemical , Models, Molecular , Pyrazoles/chemistry , Structure-Activity Relationship , Uterus/drug effects , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/chemistryABSTRACT
We report the discovery of a novel class of macrolide antibiotics that have improved antibacterial activity against Ery-resistant organisms.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Bacteria/drug effects , Erythromycin/pharmacology , Macrolides/chemical synthesis , Anti-Bacterial Agents/pharmacology , Bacteria/metabolism , Cell Membrane/metabolism , Drug Resistance , Drug Resistance, Bacterial , Macrolides/pharmacology , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
A narrow structure-activity relationship was established for the 4-aryl group in 4-aryl-pyridine glucagon antagonists, with only small substituents being well-tolerated, and only at the 3'- and 4'-positions. However, substitution with a 2'-hydroxy group gave a ca. 3-fold increase in activity (e.g., 4'-fluoro-2'-hydroxy analogue 33, IC50=190 nM). For efficient preparation of 2'-substituted phenylpyridines, a novel synthesis via pyrones and 4-methoxy-pyridines was developed.
Subject(s)
Glucagon/antagonists & inhibitors , Pyridines/chemical synthesis , Pyridines/pharmacology , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
SAR studies for novel non-imidazole containing H(3) receptor antagonists with high potency and selectivity for rat H(3) receptors are described. A high throughput screening lead, A-923, was further elaborated in a systematic manner to clarify a pharmacophore for this class of aryloxyalkyl piperazine based compounds.
Subject(s)
Histamine Antagonists/chemistry , Histamine Antagonists/pharmacology , Ketones/chemistry , Piperazines/chemistry , Receptors, Histamine H3/drug effects , Amines/chemistry , Animals , Binding, Competitive , Carbamates/chemistry , Cerebral Cortex/metabolism , Histamine Antagonists/metabolism , Humans , Kinetics , Ligands , Rats , Receptors, Histamine H1/metabolism , Receptors, Histamine H2/metabolism , Receptors, Histamine H3/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Structure-activity relationship studies on novel non-imidazole, D-amino acid containing ligands of histamine 3 receptors are presented. A-304121 is a D-alanine piperazine amide with high affinity at the rat H(3) receptor.
Subject(s)
Amino Acids/chemistry , Histamine Antagonists/chemistry , Histamine Antagonists/metabolism , Receptors, Histamine H3/metabolism , Acylation , Amino Acid Motifs , Amino Acids/metabolism , Animals , Binding, Competitive , Biological Availability , Cerebral Cortex/metabolism , Humans , Kinetics , Ligands , Piperazines/chemistry , Rats , Receptors, Histamine H1/metabolism , Receptors, Histamine H2/metabolism , Receptors, Histamine H3/drug effects , Structure-Activity RelationshipABSTRACT
Optimized substituent patterns in 4-aryl-pyridine glucagon receptor antagonists were merged to produce highly potent derivatives containing both a 3-[(1R)-hydroxyethyl] and a 2'-hydroxy group. Due to restricted rotation of the phenyl-pyridine bond, these analogues exist as four isomers. A diastereoselective methylcopper reaction was developed to facilitate the synthesis, and single isomers were isolated with activities in the range IC(50)=10-25 nM.