Recombinant Human Erythropoietin for Patients with AIDS Treated with Zidovudine

Fischl, Margaret A.; Galpin, Jeffrey E.; Levine, James D.; Groopman, Jerome E.; Henry, David H.; Kennedy, Peter G. E.; Miles, Steven A.; Rôbbins, William J.; Starrett, Barbara; Zalusky, Ralph; Abels, Robert I.; Tsai, Huei C.; Rudnick, Seth A.

doi:10.1056/nejm199005243222103

Cited by 325 publications

(95 citation statements)

References 7 publications

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“…Examples include rheumatoid arthritis (Means 1994), cancer (Miller et al 1990;Spivak 1994), and AIDS (Fischl et al 1990). It is likely that inflammatory cytokines suppress Epo gene expression in these disorders.…”

Section: Underproduction Of Epomentioning

confidence: 99%

Erythropoietin

Bunn

2013

Cold Spring Harbor Perspectives in Medicine

206

171

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During the past century, few proteins have matched erythropoietin (Epo) in capturing the imagination of physiologists, molecular biologists, and, more recently, physicians and patients. Its appeal rests on its commanding role as the premier erythroid cytokine, the elegant mechanism underlying the regulation of its gene, and its remarkable impact as a therapeutic agent, arguably the most successful drug spawned by the revolution in recombinant DNA technology. This concise review will begin with a synopsis of the colorful history of this protein, culminating in its purification and molecular cloning. It then covers in more detail the contemporary understanding of Epo's physiology as well as its structure and interaction with its receptor. A major part of this article focuses on the regulation of the Epo gene and the discovery of HIF, a transcription factor that plays a cardinal role in molecular adaptation to hypoxia. In the concluding section, a synopsis of Epo's role in disorders of red blood cell production will be followed by an assessment of the remarkable impact of Epo therapy in the treatment of anemias, as well as concerns that provide a strong impetus for the development of even safer and more effective treatment.

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Section: Underproduction Of Epomentioning

confidence: 99%

Erythropoietin

Bunn

2013

Cold Spring Harbor Perspectives in Medicine

206

171

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“…Thus, it is now possible to manipulate erythropoiesis independently of endogenous erythropoietin production (Spivak, 1994). Recombinant erythropoietin (r-HuEPO) has previously been shown to increase the haematocrit and reduce the transfusion requirement in patients with end-stage renal disease undergoing haemodialysis (Esbach et al, 1989) and in AIDS patients treated with zidovudine (Fischl et al, 1990). In addition, there are now a number of reports on the use of r-HuEPO to correct anaemia in cancer patients (Platanias et al, 1991;Abels, 1992aAbels, ,b, 1993Miller et al, 1992;Case et al, 1993;Lavey and Dempsey, 1993;Ludwig et al, 1993Ludwig et al, , 1994Vijayakumar et al, 1993;Dusenbery et al, 1994;Leitgeh et al, 1994;deCampos et al, 1995).…”

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confidence: 99%

Effect of subcutaneous recombinant human erythropoetin in cancer patients receiving radiotherapy: final report of a randomized, open-labelled, phase II trial

Sweeney

Nicolae²,

Ignacio³

et al. 1998

Br J Cancer

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Summary The purpose of this study was to determine the safety, efficacy and impact on quality of life of recombinant human erythropoietin (r-HuEPO) for cancer patients undergoing radiotherapy (RT). An open-labelled randomized design was used, with patients randomized to either treatment or control arms. Patients in the treatment arm received r-HuEPO given by subcutaneous injection at a dose of 200 units kg-' day-' plus oral iron supplements (ferrous sulphate 325 mg p.o. t.i.d.). Entry was restricted to patients with carcinoma of the lung, uterine cervix, prostate or breast who presented for RT with anaemia parameters reflective of 'the anaemia of chronic disease'. Radiotherapy policies (portals, doses, fraction size, etc.) were determined by the site and stage of disease. Complete blood counts (CBCs) were obtained weekly. The target level of haemoglobin was 15 g dl-1 for men and 14 g dl-1 for women. Quality of life (QOL) was assessed weekly by using an analogue scale to judge energy, activities of daily living and overall quality of life. Forty-eight patients were entered in the study, 24 in the treatment arm and 24 in the control arm. The prerandomization demographic characteristics and mean laboratory values were comparable in both arms. The mean haemoglobin at completion was 13.6 g dl-1 for r-HuEPO-treated patients compared with 11.0 g dl-1 for control subjects (P= 0.0012). Patients who received r-HuEPO demonstrated a mean weekly haemoglobin increase of 0.41 g dl-1 compared with a decrease in mean haemoglobin level in controls for 6 of the 7 weeks of the study (mean weekly decrease of 0.073 g dl-'). Target levels of haemoglobin were achieved by 41.6% of r-HuEPO-treated patients compared with none of the control subjects. The mean platelet count declined in both arms of the study with RT but the decline from pretreatment was less rapid in r-HuEPO-treated patients (11.2% decrease) compared with controls (26.3% decrease) and was statistically significant during weeks 4-6. Toxicity was minor with only mild irritation at the injection site. Mean quality of life end points were superior in the treatment arm but not statistically significant. r-HuEPO had a beneficial effect on weekly haemoglobin levels in patients undergoing RT with response rates similar to other studies. There was also a less rapid decline in weekly platelet counts in r-HuEPO-treated patients compared with control subjects. Further studies are needed to address the optimum dose and scheduling as well as the impact of r-HuEPO on clinical outcomes.

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“…It was the first approved anti-HIV drug 1 and has been used for the treatment of AIDS, since the late 1980s. However, AZT therapy using conventional formulations is frequently associated with dose-dependent adverse reactions, mainly anemia and neutropenia 2,3 .…”

Section: Introductionmentioning

confidence: 99%

New sustained release of Zidovudine Matrix tablets − cytotoxicity toward Caco-2 cells

Santos¹,

Pina²,

Marques³

et al. 2012

Drug Development and Industrial Pharmacy

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Objective: The aim of this study was to adjust the zidovudine (AZT) release from solid tablets to an ideal profile, by developing matrices comprising swellable polymers with nonswellable ones.Methods: Directly compressed matrices comprised different ratios of hydroxypropylmethylcellulose K15M and K100M, ethylcellulose, and methacrylic acid (Eudragit® RS PO and Eudragit® RL PO) were prepared. Technological characterization and evaluation of the in vitro release behavior were carried out. Cell density and viability following drug exposure were evaluated by the SRB method, for the Caco-2 line, while cell morphology was assessed upon Trypan blue staining.Results: A specific formulation containing 5% of each excipient − HPMC K15M, HPMC K100M, Eudragit® RS PO, and Eudragit® RL PO − was found to yield the best release profile. Application of the Korsmeyer-Peppas model to the dissolution profile evidenced that a non-Fickian (anomalous) transport is involved in the drug release. Regarding the influence of the tablets' composition on the drug's cytotoxic effect toward the Caco-2 cell line, a reduction of cell biomass (0-15%) was verified for the distinct AZT formulations tested, F19 having displayed the highest cytotoxicity, after 24 and 48 h of incubation. Additionally, a high reversibility of the AZT effect was observed. Conclusions:The results showed that the simultaneous application of both hydrophilic and hydrophobic polymers can modulate the drug release process, leading to an improved efficacy and patient compliance. All AZT formulations studied were found to be cytotoxic against Caco-2 cells, F19 being the most effective one.

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Recombinant Human Erythropoietin for Patients with AIDS Treated with Zidovudine

Cited by 325 publications

References 7 publications

Erythropoietin

Erythropoietin

Effect of subcutaneous recombinant human erythropoetin in cancer patients receiving radiotherapy: final report of a randomized, open-labelled, phase II trial

New sustained release of Zidovudine Matrix tablets − cytotoxicity toward Caco-2 cells

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