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Author (up) Allen, S.L.; Lundberg, A.S. file  url
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  Title Amonafide: a potential role in treating acute myeloid leukemia Type Journal Article
  Year 2011 Publication Expert Opinion on Investigational Drugs Abbreviated Journal Expert Opin Investig Drugs  
  Volume 20 Issue 7 Pages 995-1003  
  Keywords Animals; Antineoplastic Agents--pharmacokinetics, therapeutic use; Clinical Trials as Topic--methods; DNA Topoisomerases, Type II--metabolism; Drug Resistance, Neoplasm; Enzyme Inhibitors--pharmacokinetics, therapeutic use; Humans; Leukemia, Myeloid, Acute--drug therapy, enzymology, mortality; Naphthalimides--pharmacokinetics, therapeutic use; Survival Rate--trends; Treatment Outcome  
  Abstract INTRODUCTION: Amonafide is a novel topoisomerase II (Topo II) inhibitor and DNA intercalator that induces apoptotic signaling by blocking the binding of Topo II to DNA. Amonafide retains cytotoxic activity even in the presence of P-glycoprotein (Pgp)-mediated multi-drug resistance (MDR), a major contributor to clinical treatment failure. AREAS COVERED: In vitro, Pgp-mediated transport (efflux) of amonafide from myeloblasts obtained from patients with secondary acute myeloid leukemia (sAML) was significantly less than efflux of daunorubicin. Amonafide has shown efficacy in patients with sAML, as well as in patients with poor prognostic characteristics such as older age and unfavorable cytogenetics, all associated with MDR. Improved antileukemic activity is observed when amonafide is given together with cytarabine, rather than as monotherapy, with a complete remission rate of approximately 40% in a recent Phase II trial in sAML. The efficacy of amonafide was maintained among poor-risk subsets of patients, including older patients and patients who had previous myelodysplastic syndrome or previous leukemogenic therapy. The safety profile was acceptable and manageable. EXPERT OPINION: Amonafide plus cytarabine may have clinical utility in patients with sAML and in other poor-risk subgroups of acute myeloid leukemia (AML). Ongoing trials will help define the role for amonafide in the treatment of poor-risk AML.  
  Call Number Serial 199  
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Author (up) Goa, K.L.; Barradell, L.B. file  doi
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  Title Fluconazole. An update of its pharmacodynamic and pharmacokinetic properties and therapeutic use in major superficial and systemic mycoses in immunocompromised patients Type Journal Article
  Year 1995 Publication Drugs Abbreviated Journal Drugs  
  Volume 50 Issue 4 Pages 658-690  
  Keywords AIDS-Related Opportunistic Infections/immunology/microbiology; Acquired Immunodeficiency Syndrome/immunology/microbiology; Animals; Antifungal Agents/*pharmacokinetics/*pharmacology; Child; Fluconazole/*pharmacokinetics/*pharmacology; HIV Infections/immunology/microbiology; Humans; *Immunocompromised Host; Mycoses/*drug therapy/*immunology/metabolism; Neoplasms/immunology/microbiology  
  Abstract Fluconazole is a triazole antifungal agent which is now an established part of therapy in patients with immune deficiencies. It is effective against oropharyngeal/oesophageal candidiasis (candidosis) when used orally once daily either as treatment or secondary prophylaxis in patients with AIDS or as treatment or primary prophylaxis in neutropenia associated with cancer therapy. Fluconazole also resolves symptoms in up to 60% of patients with cryptococcal meningitis and AIDS. However, in this infection its efficacy as treatment relative to that of amphotericin B is equivocal, and its major role is as the drug of choice for maintenance therapy following amphotericin B induction. In this regard, fluconazole has been proven superior to amphotericin B and to itraconazole 200 mg/day. Comparisons with other drugs used for the treatment of mucosal candidiasis in patients with AIDS show fluconazole to be superior to nystatin, similar to itraconazole and at least as effective as clotrimazole and ketoconazole; it was more so than the latter azole in 1 study. In patients undergoing chemotherapy or bone marrow transplantation, fluconazole as primary prophylaxis has produced greater clinical benefit than a clotrimazole regimen. The incidence of adverse events appears to be somewhat higher in patients with AIDS compared with HIV-negative cohorts, but the qualitative pattern of events is similar. The most frequent events are gastrointestinal complaints, headache and skin rash: rare exfoliative skin reactions and isolated instances of clinically overt hepatic dysfunction have occurred in patients with AIDS. Issues yet to be clarified include: the use of fluconazole in children with AIDS, in whom results have been promising; its efficacy against other fungal infections encountered in immunocompromised patients; whether the drug influences mortality, as has been suggested by one placebo-controlled trial in patients undergoing bone marrow transplant; and the appropriateness of its potential for use as primary prophylaxis against cryptococcal meningitis in patients with AIDS, where it shows efficacy but there is concern over increasing risk of development of secondary resistance. Notwithstanding these undefined aspects of its clinical profile, fluconazole is now confirmed as an important antifungal drug in the management of fungal infections in patients with immune deficiencies. In patients with AIDS it is the present drug of choice as maintenance therapy against cryptococcal meningitis and is a preferred agent for secondary prophylaxis against candidal infections; it is also a favoured agent for primary prophylaxis in patients at risk because of neutropenia associated with chemotherapy or bone marrow transplantation.  
  Call Number Serial 1128  
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Author (up) Valles, A.S.; Borroni, M.V.; Barrantes, F.J. file  url
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  Title Targeting brain alpha7 nicotinic acetylcholine receptors in Alzheimer's disease: rationale and current status Type Journal Article
  Year 2014 Publication CNS Drugs Abbreviated Journal CNS Drugs  
  Volume 28 Issue 11 Pages 975-987  
  Keywords Allosteric Regulation/*drug effects; Alzheimer Disease/*drug therapy/metabolism/pathology; Amyloid beta-Peptides/metabolism; Cholinesterase Inhibitors/administration & dosage/pharmacology/*therapeutic use; Cognition/drug effects; Humans; Neurofibrillary Tangles/drug effects/metabolism/pathology; Nicotinic Agonists/administration & dosage/pharmacology/*therapeutic use; alpha7 Nicotinic Acetylcholine Receptor/*agonists  
  Abstract Alzheimer's disease (AD) is the most common form of dementia among older persons. Pathognomonic hallmarks of the disease include the development of amyloid senile plaques and deposits of neurofibrillary tangles. These changes occur in the brain long before the clinical manifestations of AD (cognitive impairment in particular) become apparent. Nicotinic acetylcholine receptors (AChRs), particularly the alpha7 subtype, are highly expressed in brain regions relevant to cognitive and memory functions and involved in the processing of sensory information. There is strong evidence that implicates the participation of AChRs in AD. This review briefly introduces current strategies addressing the pathophysiologic findings (amyloid-beta-peptide plaques, neurofibrillary tangles) and then focuses on more recent efforts of pharmacologic intervention in AD, specifically targeted to the alpha7 AChR. Whereas cholinesterase inhibitors such as donepezil, galantamine, or rivastigmine, together with the non-competitive N-methyl-D-aspartate receptor antagonist memantine are at the forefront of present-day clinical intervention for AD, new insights into AChR molecular pharmacology are bringing other drugs, directed at AChRs, to center stage. Among these are the positive allosteric modulators that selectively target alpha7 AChRs and are aimed at unleashing the factors that hinder agonist-mediated, alpha7 AChR channel activation. This calls for more detailed knowledge of the distribution, functional properties, and involvement of AChRs in various signaling cascades-together with the corresponding abnormalities in all these properties-to be able to engineer strategies in drug design and evaluate the therapeutic possibilities of new compounds targeting this class of neurotransmitter receptors.  
  Call Number Serial 1884  
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