Pentamidine-Induced Derangements of Glucose Homeostasis: Determinant roles of renal failure and drug accumulation: A study of 128 patients

Assan, R; Perronne, Christian; Assan, D; Chotard, L.; Mayaud, C; Matheron, Sophie; Zucman, David

doi:10.2337/diacare.18.1.47

Cited by 74 publications

(16 citation statements)

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“…Despite concerted efforts focusing on modifications of the dihydrofolate reductase and dihydropteroate inhibitor portions of TMP-SMZ and the diamidine structure of pentamidine, no compound with increased anti-Pneumocystis carinii properties without toxicity has emerged as a clinical drug (11). With the potential problem of emerging resistance to the sulfa component of TMP-SMZ (1,21,26), the significant failure rate of prophylactic pentamidine, and its limited spectrum (17) and associated toxicity (2), it is necessary to identify new therapies or modifications of existing compounds that provide increased efficacy with no toxicity to the host.…”

mentioning

confidence: 99%

Highly Active Anti- Pneumocystis carinii Compounds in a Library of Novel Piperazine-Linked Bisbenzamidines and Related Compounds

Cushion

Walzer

Collins

et al. 2004

Antimicrob Agents Chemother

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Trimethoprim-sulfamethoxazole and pentamidine isethionate have been used extensively for the prophylaxis and therapy of pneumonia caused by Pneumocystis jirovecii. Problems associated with toxicity and potential emerging resistance for both therapies necessitate the development of safe and effective analogs or new treatment strategies. In the present study, a library of 36 compounds was synthesized by using the pentamidine molecule as the parent compound modified by a 1,4-piperazinediyl moiety as the central linker to restrict conformation flexibility. The compounds were evaluated for anti-Pneumocystis carinii activity in a bioluminescent ATP-driven assay. Four of the compounds were highly active, with 50% inhibitory concentration (IC 50 ) values of <0.01 g/ml; four had very marked activity (IC 50 < 0.10 g/ml); ten had marked activity (IC 50 < 1.0 g/ml); nine had moderate activity (IC 50 < 10 g/ml); one had slight activity (IC 50 ‫؍‬ 34.1 g/ml); and the remaining eight did not demonstrate activity in this assay system. The high level of activity was specifically associated with an alkyl chain length of five to six carbons attached to one of the nitrogens of the bisamidinium groups. None of the highly active compounds and only one of the very marked compounds exhibited any toxicity when evaluated in three mammalian cell lines. The strategy of substitution of 1,4-piperazine-linked bisbenzamidines produced compounds with the highest level of activity observed in the ATP assay and holds great promise for the development of efficacious anti-P. carinii therapy.Despite advances in the treatment of human immunodeficiency virus infection, Pneumocystis jirovecii pneumonia remains a leading cause of opportunistic infection and mortality in human immunodeficiency virus-infected patients. Currently available anti-Pneumocystis drugs are limited by significant problems of efficacy, toxicity, and emerging resistance (14,21,37,38). No member of the genus Pneumocystis can be maintained continuously outside the mammalian lung. Thus, drug development, as well as other aspects of investigation of this organism family, has been hindered.The effective use of pentamidine isethionate for the treatment of human Pneumocystis pneumonia was first reported in 1958 (18), and the early experience with the drug was summarized in 1967 (19). Trimethoprim-sulfamethoxazole (TMP-SMZ) later became the therapy of choice for this pneumonia due to increased efficacy and reduced toxicity (16). Despite concerted efforts focusing on modifications of the dihydrofolate reductase and dihydropteroate inhibitor portions of TMP-SMZ and the diamidine structure of pentamidine, no compound with increased anti-Pneumocystis carinii properties without toxicity has emerged as a clinical drug (11). With the potential problem of emerging resistance to the sulfa component of TMP-SMZ (1, 21, 26), the significant failure rate of prophylactic pentamidine, and its limited spectrum (17) and associated toxicity (2), it is necessary to identify new therapies or modifications of ...

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mentioning

confidence: 99%

Highly Active Anti- Pneumocystis carinii Compounds in a Library of Novel Piperazine-Linked Bisbenzamidines and Related Compounds

Cushion

Walzer

Collins

et al. 2004

Antimicrob Agents Chemother

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“…Early, sudden, sever and fatal hypoglycemia preceding hyperglycemia has also been reported [47,112]. Hypoglycemia may be attributed to an early excessive insulin leakage from β-cells and the absence or poor response of β-cells to glucagon [46]. Pentamidine induced nephrotoxicity and kidney dysfunction may prolong insulin action and contribute to hypoglycemia [47].…”

Section: Pentamidinementioning

confidence: 99%

“…Intravenours and aerosolized pentamidine use has been associated altering glucose heamostasis [45]. Retrospective studies indicate 9%-32% of patients treated with pentamidine develop hyperglycemia; mean onset is approximately 52 days after initiating therapy [46]. Pentamidine induced hyperglycemia is attributed to either hyperamylasemia causing an increase in glucagon release or decreased insulin release, especially after a meal [47].…”

Section: Pentamidinementioning

confidence: 99%

“…Dysglycemic effects of pentamidine can be delayed. Hyperglycemia and DM, with or without preceding hypoglycemia, can occur up to several months after cessation of therapy [46,47]. Therefore, patients should be educated on signs and symptoms of both hyper-and hypoglycemia, as well as their management and the importance of regular BG monitoring [47].…”

Section: Pentamidinementioning

confidence: 99%

“…In vitro studies found that pentamidine induces irreversible β cell damage, secretory defect and necrosis precipitating the development of DM [48][49][50]. Risk factors associated with hyperglycemia include higher cumulative or single pentamidine dose and renal impairment [46]. Dysglycemic effects of pentamidine can be delayed.…”

Section: Pentamidinementioning

confidence: 99%

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Medications affecting glycemic control

Korayem¹

2017

Int Clin Med

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Immunoassays for pentamidine and related compounds: Development of a facile inhibitory ELISA suitable for clinical use

Reisner

Gray

Jones

et al. 2000

J. Clin. Lab. Anal.

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Aromatic dicationic drugs have a broad spectrum of activity against protozoal and fungal pathogens including Pneumocystis carinii, Leishmania mexicana amazonensis, Cryptosporidium parvum and Cryptococcus neoformans. Pentamidine serves as the exemplar for an extensive collection of newly synthesized related compounds, which have reduced toxicity and a wider range of target organisms. Assays of pentamidine and related compounds have depended on HPLC‐tandem mass spectrometry (HPLC‐TMS) for the quantitation and identification of drug and metabolites. Immunoassays for pentamidine would have many advantages over the HPLC methods including relative simplicity of assay format and required equipment, convenience in sample preparation and reduction in time and cost of assays. In this report we describe a simple ELISA based immunoassay for pentamidine and pentamidine‐like drugs with requisite sensitivity and specificity for use as a clinical assay (EC50 value of about 50 nanomolar). Immunogen was synthesized by coupling the hapten aminopentamidine to ovalbumin (chemically modified to provide an optimal number of –SH groups) using sulfo‐MBS. Maleic‐anhydride activated ELISA plates were covalently sensitized using the aminopentamidine hapten and used in an inhibitory ELISA assay format whereby the ability of analyte to suppress antibody binding to sensitized plate was measured. The assay detects primarily the phenolic amidine of pentamidine when in a para position and hence can also detect structurally related derivatives of pentamidine of potential interest as new therapeutic agents. J. Clin. Lab. Anal. 14:73–82, 2000. © 2000 Wiley‐Liss, Inc.

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Pentamidine-Induced Derangements of Glucose Homeostasis: Determinant roles of renal failure and drug accumulation: A study of 128 patients

Abstract: Pentamidine-induced dysglycemic accidents are primarily due to inappropriate insulin release and toxicity to the islet B-cells. Drug accumulation due to excessive doses, iterative courses, and/or renal impairment is the determining risk factor.

Cited by 74 publications

References 40 publications

Highly Active Anti- Pneumocystis carinii Compounds in a Library of Novel Piperazine-Linked Bisbenzamidines and Related Compounds

Highly Active Anti- Pneumocystis carinii Compounds in a Library of Novel Piperazine-Linked Bisbenzamidines and Related Compounds

Medications affecting glycemic control

Immunoassays for pentamidine and related compounds: Development of a facile inhibitory ELISA suitable for clinical use

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