Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues

Blanche, Stéphane; Tardieu, Marc; Rustin, Pierre; Slama, Abdelhamid; Barret, Béatrice; Firtion, Ghislaine; Ciraru-Vigneron, N; Lacroix, Catherine; Rouzioux, Christine; Mandelbrot, Laurent; Desguerre, Isabelle; Rötig, Agnès; Mayaux, Marie-Jeanne; Delfraissy, Jean‐François

doi:10.1016/s0140-6736(99)07219-0

Cited by 604 publications

(312 citation statements)

References 24 publications

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“…Although not established for fludarabine, other nucleoside analogues, both anti-viral and cytotoxic, can undergo phosphorylation by the mitochondrial deoxyguanosine kinase resulting in impaired cellular energy metabolism. 15 As the cardiotoxicity we have observed with the combination of fludarabine and melphalan has not been seen with either agent used in isolation, despite widespread and prolonged usage, it is possible that the interaction of both agents is required for the toxic effect. There are emerging preclinical data that the combination of fludarabine and alkylating agents may impair the removal of DNA-alkylator adduct formation, 16 but the effect of this drug combination on other intracellular metabolic functions remains unexplored.…”

Section: Discussionmentioning

confidence: 92%

Acute left ventricular failure following melphalan and fludarabine conditioning

Ritchie

Seymour

Roberts

et al. 2001

Bone Marrow Transplant

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Summary:Cardiotoxicity has rarely been reported as a complication of melphalan or fludarabine administration as single agents. Recently, melphalan and fludarabine have been used in combination as non-myeloablative conditioning chemotherapy prior to allogeneic stem cell transplantation. We have observed the development of severe left ventricular failure in three of 21 patients treated with this combination. Cardiotoxicity in this context has not previously been reported and has implications for the assessment, monitoring and treatment of patients undergoing pre-transplant conditioning with melphalan and fludarabine. Bone Marrow Transplantation (2001) 28, 101-103. Keywords: emlphalan; fludarabine; BMT; cardiotoxity The alkylating agent melphalan, either alone or in combination with other agents such as busulphan and total body irradiation, has been widely used in myeloablative conditioning regimens prior to stem cell transplantation for diseases such as multiple myeloma, 1 non-Hodgkin lymphoma 2 and Hodgkin's disease. 3 The clinical utility of melphalan has recently been extended by the development of nonmyeloablative transplant regimens intended to exploit the graft-versus-tumour effect of allogeneic T cell chimerism whilst reducing the toxicities associated with myeloablative conditioning. 4 Non-myeloablative regimens have seen melphalan used in novel combinations with agents such as the purine analogue, fludarabine. 5 The application of these novel regimens is particularly attractive in patients considered too old for standard allografts.It is conceivable that these regimens may lead to unexpected toxicities due to the cumulative or synergistic effects of the individual drugs, particularly in an older patient population. Although cardiac dysfunction is well described with other alkylating agents such as cyclophosphamide, 6 single-agent melphalan has not been shown to affect cardiac contractility in prospective studies. also only been rarely associated with cardiac dysfunction, with a single report of non-fatal congestive heart failure in two of 27 patients treated for chronic lymphocytic leukaemia. 8 Conditioning regimens combining fludarabine and melphalan have been associated with veno-occlusive disease and mucosal toxicity, but development of cardiotoxicity had not been specifically assessed in earlier reports. 5,9 Recently, in an updated series, reduced-intensity conditioning with melphalan and purine analogues was associated with the development of Bearman grade 3-4 cardiotoxicity in four of 86 patients. 10 The clinical features of cardiotoxicity in this setting have not, however, been documented. We describe the development of severe left ventricular failure (LVF) in three of 21 patients undergoing non-myeloablative stem cell transplantation (NMSCT) following conditioning with these agents. Case reportsTwenty-one patients have undergone NMSCT following conditioning with melphalan and fludarabine at our institution for multiple myeloma (11), chronic lymphocytic leukaemia (3), chronic myeloid leukaemia (2),...

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Section: Discussionmentioning

confidence: 92%

Acute left ventricular failure following melphalan and fludarabine conditioning

Ritchie

Seymour

Roberts

et al. 2001

Bone Marrow Transplant

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“…4 However, AZT is not innocuous. [16][17][18][19] CDC currently recommends that children perinatally exposed to antiretrovirals should have long-term follow-up, including evaluation for late effects of these therapies, such as tumor onset, neurologic and neurodevelopmental deficits. 20,21 With an HIV seroprevalence among Hispanic mothers of 0.05% in our population, the number needed to screen would be more than 16,000 Hispanic gravidas to prevent a single case of perinatal transmission of HIV (based on a 25% baseline risk of vertical transmission and an optimal decrease to 8% with peripartum AZT).…”

Section: Discussionmentioning

confidence: 99%

High False-positive Rate of Human Immunodeficiency Virus Rapid Serum Screening in a Predominantly Hispanic Prenatal Population

et al. 2004

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“…The few studies on long‐term HAART exposure have focused on foetal and perinatal ARV effects 32, 33, 34, 35, 36, 37, but rarely on maternal‐related problems which may, in turn, affect children.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial toxicity and caspase activation in HIV pregnant women

Hernández

Morén

Catalán-García

et al. 2016

J Cellular Molecular Medi

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To assess the impact of HIV‐infection and highly active anti‐retroviral treatment in mitochondria and apoptotic activation of caspases during pregnancy and their association with adverse perinatal outcome. Changes of mitochondrial parameters and apoptotic caspase activation in maternal peripheral blood mononuclear cells were compared at first trimester of pregnancy and delivery in 27 HIV‐infected and ‐treated pregnant women versus 24 uninfected pregnant controls. We correlated immunovirological, therapeutic and perinatal outcome with experimental findings: mitochondrial DNA (mtDNA) content, mitochondrial protein synthesis, mitochondrial function and apoptotic caspase activation. The HIV pregnancies showed increased adverse perinatal outcome (OR: 4.81 [1.14–20.16]; P < 0.05) and decreased mtDNA content (42.66 ± 5.94%, P < 0.01) compared to controls, even higher in naïve participants. This depletion caused a correlated decrease in mitochondrial protein synthesis (12.82 ± 5.73%, P < 0.01) and function (20.50 ± 10.14%, P < 0.001), not observed in controls. Along pregnancy, apoptotic caspase‐3 activation increased 63.64 ± 45.45% in controls (P < 0.001) and 100.00 ± 47.37% in HIV‐pregnancies (P < 0.001), in correlation with longer exposure to nucleoside analogues. HIV‐infected women showed increased obstetric problems and declined genetic and functional mitochondrial parameters during pregnancy, especially those firstly exposed to anti‐retrovirals. The apoptotic activation of caspases along pregnancy is emphasized in HIV pregnancies promoted by nucleoside analogues. However, we could not demonstrate direct mitochondrial or apoptotic implication in adverse obstetric outcome probably because of the reduced sample size.

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Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues

Cited by 604 publications

References 24 publications

Acute left ventricular failure following melphalan and fludarabine conditioning

Acute left ventricular failure following melphalan and fludarabine conditioning

High False-positive Rate of Human Immunodeficiency Virus Rapid Serum Screening in a Predominantly Hispanic Prenatal Population

Mitochondrial toxicity and caspase activation in HIV pregnant women

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