Limited data suggest that concomitant therapy with pentostatin (4 mg/sq m every 2 weeks) and fludarabine (principally 10 mg/sq m daily for 4 days at 28 day intervals), a synthetic purine nucleoside, may be associated with severe and/or fatal pulmonary toxicity (eg, pneumonitis). In one study, 4 of 6 patients receiving the drugs concomitantly for treatment of refractory chronic lymphocytic leukemia reportedly developed such toxicity.
Although therapy with either pentostatin or allopurinol alone has been associated with the development of skin rash, limited evidence suggests that concomitant use of the drugs, compared with pentostatin therapy alone, in patients with refractory hairy cell leukemia is not associated with an increased incidence of rash. However, other toxicities, including abnormalities in renal or hepatic function, have been observed in a few patients receiving concomitant pentostatin and allopurinol. ... One patient reportedly developed a fatal hypersensitivity vasculitis while receiving pentostatin and allopurinol concurrently; however, a causal relationship to the drugs has not been established.
Pentostatin inhibits the degradation of vidarabine and enhances its cytotoxicity in cell culture and in animals with experimentally induced leukemia. In addition, limited data in patients with acute leukemia suggest that combined therapy with the drugs may be associated with increased plasma vidarabine concentrations and/or half-life and greater toxicity compared with pentostatin therapy alone. Although improvement and/or remission has been reported in a few patients with acute T cell lymphoblastic leukemia who received vidarabine and pentostatin concomitantly.
No specific antidote for pentostatin overdosage is known. Administration of pentostatin in dosages higher than those currently recommended (20-50 mg/sq m over 5 days as compared with 4 mg/sq m every other week, respectively) has been associated with severe renal, hepatic, pulmonary, and CNS toxicity, which was unpredictable and occasionally fatal. In case of overdosage, management should include discontinuance of the drug and initiation of supportive measures appropriate to the type of toxicity observed.
Plasma concentrations of pentostatin following direct iv injection of 0.25 mg/kg daily for 4 or 5 days in a limited number of patients with advanced, refractory cancer ranged from approximately 3.2-9.7 ng/ml. Plasma concentrations appear to increase linearly with dose; in a study in patients with leukemia, plasma pentostatin concentrations determined 1 hour after administration of 0.25 or 1 mg/kg of the drug as a 30 min iv infusion averaged approximately 0.4 or 1.26 ug/ml, respectively.
No apparent correlation has been documented between mean or absolute plasma adenosine or deoxyadenosine concentrations and therapeutic or toxic responses to pentostatin; however, limited data suggest that there may be a correlation between response to the drug and the ratio of deoxyadenosine triphosphate to adenosine triphosphate in lymphoblasts. In addition, increases in plasma deoxyadenosine reportedly parallel the accumulation of deoxyadenosine triphosphate in erythrocytes and lymphoblasts, and there appears to be a correlation between toxicity and the ratio of deoxyadenosine triphosphate to adenosine triphosphate in erythrocytes.
Studies in animals indicate that pentostatin distributes rapidly to all body tissues, but the extent of drug accumulation in different tissues appears to vary among species. Following intraperitoneal injection in mice, the highest concentrations of the drug were found in the kidneys, liver, and spleen. In dogs, pentostatin tissue concentrations following iv administration were proportional to tissue adenosine deaminase activity, with the highest concentrations in the lungs, spleen, pancreas, heart, liver, and jejunum. Pentostatin reportedly enters erythrocytes via a facilitated transport system common to other nucleosides or by simple diffusion; efflux of the drug from cells has not been characterized, although the time course of pentostatin's effects (eg, adenosine deaminase inhibition) varies among different types of cells (eg, lymphocytes, erythrocytes).
Limited data in animals and humans indicate that pentostatin distributes relatively poorly into CSF, with peak CSF concentrations averaging approximately 10% of concurrent plasma concentrations. In a 6 yr old leukemia patient receiving pentostatin 0.25 mg/kg daily for 3 successive days by direct iv injection, serum and CSF (via lumbar puncture) pentostatin concentrations 4 hr after the initial dose were approximately 147 and 19 ng/ml, respectively, using an enzyme-inhibition titration assay; one hour after the third dose, corresponding serum and CSF concentrations were approximately 241 and 35 ng/ml, respectively.
来源:Hazardous Substances Data Bank (HSDB)
文献信息
Compounds and pharmaceutical compositions for the treatment of liver disorders
申请人：Sommadossi Jean-Pierre
公开号：US20080261913A1
公开（公告）日：2008-10-23
Provided herein are compounds, compositions and methods for the treatment of liver disorders, including liver cancer and metabolic diseases, such as diabetes, hyperlipidemia, atherosclerosis, and obesity. Specifically, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-cancer agents.
[EN] COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF LIVER DISORDERS<br/>[FR] COMPOSES ET COMPOSITIONS PHARMACEUTIQUES DESTINES AU TRAITEMENT DES TROUBLES HEPATIQUES
申请人：IDENIX PHARMACEUTICALS INC
公开号：WO2008082602A2
公开（公告）日：2008-07-10
[EN] Provided herein are compounds, compositions and methods for the treatment of liver disorders, including liver cancer and metabolic diseases, such as diabetes, hyperlipidemia, atherosclerosis, and obesity. Specifically, compounds and compositions of nucleoside derivatives are disclosed, which can be administered either alone or in combination with other anti-cancer agents. [FR] L'invention concerne des composés, des compositions et des méthodes de traitement des troubles hépatiques, notamment du cancer du foie et des maladies métaboliques telles que le diabète, l'hyperlipidémie, l'athérosclérose et l'obésité. L'invention concerne en particulier des composés et des compositions de dérivés de nucléosides pouvant être administrés seuls ou associés à d'autres agents anticancéreux.
