losartan-potassium and Drug-Related-Side-Effects-and-Adverse-Reactions

A myriad variety of therapeutic agents or chemical substances can induce either a transient or persistent increase in blood pressure, or interfere with the blood pressure-lowering effects of antihypertensive drugs. Some agents cause either sodium retention or extracellular volume expansion, or activate directly or indirectly the sympathetic nervous system. Other substances act directly on arteriolar smooth muscle or do not have a defined mechanism of action. Some medications that usually lower blood pressure may paradoxically increase blood pressure, or an increase in pressure may be encountered after their discontinuation. In general, drug-induced pressure increases are small and transient: however, severe hypertension involving encephalopathy, stroke, and irreversible renal failure have been reported. The deleterious effect of therapeutic agents is more pronounced in patients with preexisting hypertension, in those with renal failure, and in the elderly. Careful evaluation of a patient's drug regimen may identify chemically induced hypertension and obviate unnecessary evaluation and facilitate antihypertensive therapy. Once chemical-induced hypertension has been identified, discontinuation of the causative agent is recommended, although hypertension can often be managed by specific therapy and dose adjustment if continued use of the offending agent is mandatory. The present review summarizes the therapeutic agents or chemical substances that elevate blood pressure and their mechanisms of action.

Topics: Adrenal Cortex Hormones; Alcohol Drinking; Anti-HIV Agents; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Caffeine; Cocaine; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Glycyrrhiza; Gonadal Steroid Hormones; Humans; Hypertension; Immunosuppressive Agents; Vascular Endothelial Growth Factor A

Antibody-mediated pure red cell aplasia is a very rare but devastating condition affecting patients receiving treatment with erythropoiesis-stimulating agents. New cases continue to emerge, generally in clusters, consistent with an 'environmental' trigger to its pathogenesis. Defining the causes of antibody-mediated pure red cell aplasia is clearly of importance for patients with chronic kidney disease, but any developments in this area may also have relevance to other disease areas as therapeutic delivery of endogenous proteins rapidly increases. This review focuses on the current knowledge regarding the etiology of antibody-mediated pure red cell aplasia and the current approach to therapy.

Topics: Chemistry, Pharmaceutical; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Immune Tolerance; Protein Multimerization; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic; Time Factors

Identification of serious adverse drug reactions (sADRS) associated with commonly used drugs can elude detection for years. Reye's syndrome (RS), nephrogenic systemic fibrosis (NSF), and pure red cell aplasia (PRCA) among chronic kidney disease (CKD) patients were recognized in 1951, 2000, and 1998, respectively. Reports associating these syndromes with aspirin, gadodiamide, and epoetin, were published 29, 6, and 4 years later, respectively. We obtained primary information from clinicians who identified causes of these sADRs and reviewed factors contributing to delayed identification of these toxicities. Overall, 3,500 aspirin-associated RS cases in the United States, 1,605 gadolinium-associated NSF cases, and 181 epoetin-associated PRCA cases were reported. Delays in FDA regulation of over-the- counter medications and administration of aspirin to children contributed to development of RS. For NSF, in 1996, the Danish Medicine Agency approved high-dose gadodiamide administration to chronic kidney disease (CKD) patients undergoing MR scans. Overall, 88 % of Danish NSF cases were from two hospitals and 97 % of United States' NSF cases were from 60 hospitals. These hospitals frequently administered high-doses of gadodiamide to CKD patients. Another factor was the decision to administer linear chelated contrast agents versus lower risk macrocyclic chelated agents. For PRCA, increased use of subcutaneous epoetin formulations to CKD patients, in part due to convenience and cost-savings considerations, and a European regulatory requirement requiring removal of albumin as a stabilizer, led to toxicity. Overall, 81, 13, and 17 years elapsed between drug introduction into practice and identification of a causal relationship for aspirin, erythropoietin, and gadodiamide, respectively. A substantial decline in new cases of these sADRs occurred within two years of identification of the offending drug. Clinicians should be vigilant for sADRs, even for frequently-prescribed pharmaceuticals, particularly in settings where formulation or regulatory changes have occurred, or when over-the-counter, off-label, or pediatric use is common.

Topics: Aspirin; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Female; Gadolinium; Humans; Male; Nephrogenic Fibrosing Dermopathy; Prevalence; Prognosis; Red-Cell Aplasia, Pure; Reye Syndrome; Risk Assessment; South Carolina; Survival Rate

Hematopoietic growth factors (HGFs) continue to be the most widely prescribed class of medications for patients with myelodysplastic syndromes (MDS), despite the advent of disease-modifying therapies for MDS (eg, azacitidine, decitabine, and lenalidomide) and the current absence of an MDS-specific US Food and Drug Administration (FDA)-approved indication for any of the HGFs. Erythropoiesis-stimulating agents (ESAs: epoetin alfa, darbepoetin alfa), myeloid growth factors (MGFs: filgrastim, pegfilgrastim, sargramostim), and the newest group of HGFs, thrombopoiesis-stimulating agents (TSAs: romiplostim, eltrombopag), can increase peripheral blood counts in some patients, and may ameliorate some of the signs and symptoms of MDS-associated bone marrow failure. Although HGFs are generally considered "supportive care" measures, recent data suggest that HGFs may alter the natural history of disease in MDS, either for better or worse. This review examines data on the safety and effectiveness of HGFs for patients with MDS.

Topics: Benzoates; Colony-Stimulating Factors; Darbepoetin alfa; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Filgrastim; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematinics; Humans; Hydrazines; Myelodysplastic Syndromes; Patient Selection; Polyethylene Glycols; Pyrazoles; Receptors, Fc; Recombinant Fusion Proteins; Recombinant Proteins; Thrombopoietin

Several drugs can cause hypertension and/or blunt the effect of antihypertensive treatment. They can exacerbate a previously well controlled hypertension and/or render it resistant to therapy. Accordingly, drugs represent a common cause of resistance of hypertension to treatment. Identification of drug-related hypertension can be achieved with a thorough medical history targeted to ascertain concurrent therapies that are prescribed for conditions other than cardiovascular diseases. This can avoid prescribing a more aggressive antihypertensive treatment and may prevent embarking in costly and sometimes invasive diagnostic procedures. Drugs that commonly raise blood pressure include NSAIDs, steroids, oestroprogestinic agents, immunosuppressants, erythropoietin, inhibitors of angiogenesis, anti-HIV agents, and also some high-density lipoprotein-raising agents. As withdrawal of the offending drug is often impracticable, knowledge of the mechanism(s) by which each drug exerts its pressor effects may help selecting the most effective treatment. Purpose of this review is to examine the most common causes of resistant hypertension that are due to drugs or abuse of substances along with their underlying pathophysiological mechanisms. The strategy for selecting the most appropriate treatment and the reasons for 'a call of action' of research in this area are also examined.

Topics: Angiogenesis Inhibitors; Anti-HIV Agents; Anti-Inflammatory Agents, Non-Steroidal; Anticholesteremic Agents; Antihypertensive Agents; Drug Antagonism; Drug Resistance; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Glucocorticoids; Humans; Hypertension; Immunosuppressive Agents; Treatment Failure

Disorders of coagulation are common adverse drug events encountered in critically ill patients and present a serious concern for intensive care unit (ICU) clinicians. Dosing strategies for medications used in the ICU are typically developed for use in noncritically ill patients and, therefore, do not account for the altered pharmacokinetic and pharmacodynamic properties encountered in the critically ill as well as the increased potential for drug-drug interactions, given the far greater number of medications ordered. This substantially increases the risk for coagulation-related adverse reactions, such as a bleeding or prothrombotic events. Although many medications used in the ICU have the potential to cause coagulation disorders, the exact incidence will vary based on the specific medication, dose, concomitant drug therapy, ICU setting, and patient-specific comorbidities. Clinicians must strongly consider these factors when evaluating the risk/benefit ratio for a particular therapy. This review surveys recent literature documenting the risk for adverse drug reactions specific to bleeding and/or clotting with commonly used medications in the ICU.

Topics: Anti-Infective Agents; Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Disorders; Blood Coagulation Factors; Colloids; Critical Care; Deamino Arginine Vasopressin; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Estrogens, Conjugated (USP); Factor VIIa; Fibrinolytic Agents; Fondaparinux; Hemostatics; Humans; Polysaccharides; Protein C; Recombinant Proteins; Thrombin; Thromboembolism; Vitamin K

Although numerous clinical trials have demonstrated the efficacy and tolerability of erythropoiesis-stimulating agents (ESAs) in patients with chemotherapy-induced anemia (CIA), results of some recent trials and one meta-analysis have suggested that ESAs may negatively impact survival and/or disease control in patients with cancer.. To assess the benefits and risks of ESAs in CIA, we conducted a pooled analysis of individual patient-level data from all randomized, double-blind, placebo-controlled trials in 2,122 patients with CIA receiving darbepoetin alfa (DA; n = 1,200) or placebo (n = 912).. DA did not increase mortality (hazard ratio = 0.97; 95% CI, 0.85 to 1.1) and had no effect on progression-free survival (hazard ratio = 0.93; 95% CI, 0.84 to 1.04) and disease progression (hazard ratio = 0.92; 95% CI, 0.82 to 1.03), but, as expected, increased the risk for thromboembolic events (hazard ratio = 1.57; 95% CI, 1.10 to 2.26). Overall and progression-free survival were not affected by baseline hemoglobin and seemed better in patients who achieved hemoglobin more than 12 or more than 13 g/dL. Transfusions and rates of hemoglobin increase (> 1 g/dL in 14 days; > 2 g/dL in 28 days) owing to transfusions were associated with an increased risk for death and disease progression in both treatment groups; in the absence of transfusions, rates of hemoglobin increase did not appear to increase the risk for adverse outcomes. Compared with placebo, DA significantly reduced the risk of receiving one or more transfusion.. There seemed to be no association between DA and risk of death or disease progression in this meta-analysis of individual patient data from DA studies conducted in CIA, the approved indication for ESAs in oncology.

Topics: Anemia; Antineoplastic Agents; Blood Transfusion, Autologous; Clinical Trials as Topic; Darbepoetin alfa; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Female; Hemoglobins; Humans; Male; Randomized Controlled Trials as Topic; Treatment Outcome

The purpose of this paper is to provide an overview of the current therapeutic options afforded to anemic chronic kidney disease (CKD) patients and the costs of these interventions.. Literature search of articles within Ovid MEDLINE between 1996 and 2007 that pertained to the treatment of anemia in chronic kidney disease patients.. Early detection and treatment of anemia associated with CKD has proven to provide positive cognitive and physical effects. Treatment options that increase iron storage and availability within the body and production of erythropoietin can assist in anemic CKD patients in achieving recommended levels of hemoglobin. Acknowledgement of the potential side effects associated with the medications selected to treat anemia can help in avoiding additional injury to the patient and thus reduce healthcare expenditure. A limitation of this review is that the search was performed within a single database.. Health care providers can play an active role in detecting anemia early and optimizing available treatment options. Future research on the effects of erythropoiesis-stimulating agents (ESA) on patients before they need dialysis, and a cost analysis between epoetin and darbepoetin alpha, would be beneficial.

Topics: Anemia; Darbepoetin alfa; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Health Care Costs; Hematinics; Humans; Iron; Practice Guidelines as Topic; Recombinant Proteins; Renal Insufficiency, Chronic

Since 1988, millions of patients have received epoetin products intravenously (IV) and subcutaneously. In 1998, epoetin-associated pure red cell aplasia (PRCA) was first reported and causation was attributed to formulations without human serum albumin (HSA), subcutaneous administration, and uncoated rubber stoppers.. Data on erythropoietin (EPO)-associated PRCA were obtained from the Food and Drug Administration (FDA), regulatory authorities in other countries, and the manufacturers of epoetin alfa, epoetin beta, and darbepoetin. The data included information on numbers of PRCA cases and estimated exposure-adjusted incidence rates by EPO product, anemia etiology, administration route, country of PRCA identification, and date reported.. In 1999, academicians in Paris identified 12 EPO-treated patients with antibody-mediated PRCA; 11 of these patients were on hemodialysis and had received subcutaneous Eprex (Johnson & Johnson). In 2002, authorities in Europe, Australia, Singapore, and Canada mandated Eprex by IV route to hemodialysis patients, and the relevant manufacturers added Teflon coating to prefilled syringes of Eprex; PRCA cases subsequently decreased by 90 percent. By 2003, 180 Eprex-associated PRCA cases were identified in Europe, Canada, Australia, and Asia, despite improvements in handling. Since 2002, FDA safety databases include information on 59 new cases of antibody-associated PRCA, primarily associated with subcutaneous epoetin alfa and darbepoetin that does not contain HSA.. Independent actions by regulatory authorities, manufacturers, and academic researchers identified significant numbers of PRCA cases between 1998 and 2003 and characterized the probable etiology. Today, antibody-mediated PRCA is an infrequent class toxicity occurring among some hemodialysis patients on EPOs.

Topics: Anemia; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

Biopharmaceuticals have revolutionized the treatment and management of many diseases. The advent of recombinant erythropoietins has greatly benefited patients with anemia related to chronic kidney disease and cancer, virtually eliminating the need for blood transfusions. Currently, the patents for many biopharmaceutical molecules have expired or are approaching expiration and a number of biosimilars manufacturers are aiming to claim part of the market share. Unlike the situation for synthetic "small molecule" drugs, identical copies of far more complex biopharmaceuticals cannot be produced. A biopharmaceutical can be 100 to 1000 times larger than a synthetic chemical drug, with extremely complex three-dimensional structure and biological functions which are often not completely understood. Due to their nature and complexity, these fascinating therapeutic molecules are products of highly controlled biological processes. This review takes a look at how biosimilars are fundamentally different from their originator products by examining the biopharmaceutical production process and how it can influence the structure and function of the final drug product.

Topics: Anemia; Animals; Biopharmaceutics; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Kidney Failure, Chronic; Molecular Structure; Protein Engineering; Protein Processing, Post-Translational; Recombinant Proteins

Anemia is common in patients treated with chemotherapy for both solid and hematologic malignancies, contributing to fatigue and diminished quality of life and exposing them to the inherent risks of red blood cell transfusions. Erythropoiesis-stimulating proteins have been shown to increase hemoglobin levels, reduce the need for transfusions, and improve quality of life. The current practice guidelines recommend treating moderate to severe chemotherapy-induced anemia with erythropoiesis-stimulating proteins, but the risk of transfusions may be less with earlier intervention at higher hemoglobin levels. A review of the literature suggests that treating mild chemotherapy-induced anemia with erythropoiesis-stimulating proteins reduces the risks of transfusions and the development of more-severe anemia. Weighing the clinical evidence together with other clinical and economic considerations should provide greater insight into the benefits of treating mild anemia in patients treated with chemotherapy.

Topics: Anemia; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoiesis; Erythropoietin; Humans; Neoplasms; Recombinant Proteins; Time Factors

This brief review is focused on the unwanted clinical effects mediated by antibodies against genetechnologically produced drugs. While many antibodies binding biotech-drugs may not be harmful, others may have deleterious clinical effects exposing patients to high risks. These antibodies can cause either lack of efficacy or hypersensitivity reactions. Examples for antibody-mediated lack of efficacy are inhibitors in hemophiliacs treated with Factor VIII, evidence of decreasing therapeutic efficacy of beta-interferons in MS-patients and pure red cell aplasia (PRCA) in patients with chronic renal failure treated with erythropoietin. Antibody-mediated hypersensitivity reactions have to be expected with all recombinant proteins. The mechanisms and causes of antibody production against biotech-drugs in patients are discussed.

Topics: Animals; Antibodies; Antibodies, Monoclonal; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Humans; Insulin; Interferons; Recombinant Proteins

Darbepoetin alfa (Aranesp), Nespo) is an amino acid substituted analog of human erythropoietin (EPO) that promotes erythrocyte survival, proliferation, and differentiation. Approved in Europe and the US for the treatment of anemia associated with chronic kidney disease (CKD), it is characterized by delayed clearance and a more prolonged elimination half-life than recombinant human erythropoietin (rhEPO; epoetin alfa and beta), permitting an extended interval between doses. Darbepoetin alfa is generally well tolerated, and clinical trials of 20-52 weeks' duration have demonstrated the efficacy of subcutaneous and intravenous administration at 1- or 2-week intervals in the initial treatment of anemia associated with CKD both in dialysis patients and in patients not yet on dialysis. Trials of up to 52 weeks' duration demonstrated that in the majority of patients with CKD, treatment with darbepoetin alfa at up to 4-week intervals maintained hemoglobin (Hb) levels established by prior erythropoietic treatment, while in patients undergoing dialysis, intravenous or subcutaneous darbepoetin alfa administered at 1- or 2-week intervals was noninferior to rhEPO administered once, twice, or three times per week in maintaining established Hb levels.

Topics: Anemia; Animals; Clinical Trials as Topic; Darbepoetin alfa; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Humans; Kidney Failure, Chronic; Treatment Outcome

Topics: Combined Modality Therapy; Comorbidity; Diet, Protein-Restricted; Diet, Sodium-Restricted; Disease Progression; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Humans; Hypertension; Kidney Diseases; Kidney Failure, Chronic; Kidney Function Tests; Prognosis; Renal Dialysis; Vasculitis; Water-Electrolyte Balance

To evaluate the safety and efficacy of epoetin alfa administered in extended-dosing intervals to a target hemoglobin (Hb) level not exceeding 12.0 g/dL for the treatment of anemia in subjects with chronic kidney disease (CKD) not on dialysis.. An open-label, randomized, multicenter, controlled study consisting of a 1-week screening phase and a 26-week open-label treatment phase.. Twenty-seven long term care (LTC) facilities in the United States.. Subjects with CKD who were not receiving dialysis, who had not received an erythropoiesis-stimulating agent for 8 weeks before screening, and whose Hb levels were lower than 11.0 g/dL at screening were eligible.. In the epoetin alfa group, subjects were administered 20,000 international units epoetin alfa subcutaneously every 2 weeks (Q2W). Dosing was based on the Hb concentration measurement obtained by HemoCue Hb201+System (Quest Diagnostics; Madison, NJ) at the time of the scheduled dose. When the Hb concentration was 11.0 to 11.5 g/dL on 2 consecutive biweekly measurements, the dose was doubled and administered on the day that the second consecutive measurement was obtained. The dosing interval was then extended to every 4 weeks (Q4W). Subjects in the standard of care (SOC) group received treatment for their anemia according to the practice of the LTC facility.. Study visits were every 2 weeks, at which time blood was drawn and used for efficacy analysis. Measurements included: the Hb concentration change from baseline to the end of the study; the proportion of subjects who achieved an Hb response (defined as 2 consecutive Hb measurements at least 1.0 g/dL greater than baseline or 2 consecutive Hb measurements ≥11.0 g/dL at any time during the study); the time to the Hb response; the proportion of subjects who received a transfusion and the number of units of transfused; the proportion of epoetin alfa-treated subjects converting to Q4W dosing; and the proportion of subjects who converted to Q4W dosing and remained on Q4W dosing through the end of the study.. A total of 157 subjects were randomized: 118 subjects to the epoetin alfa group and 39 to the SOC group. The mean change in Hb was significantly greater in the epoetin alfa group (0.9 g/dL) compared with the SOC group (0.3 g/dL) (P = .006). A significantly greater percentage of subjects achieved a Hb response in the epoetin alfa group (85.1%) compared with the SOC group (53.8%) (P < .001). The time to achieve a Hb response was significantly shorter in the epoetin alfa group (41 days) than in the SOC group (114 days) (P < .0001). There were no transfusions in the SOC group, whereas 4 subjects (3.5%) required transfusions in the epoetin alfa group. Of the 114 subjects receiving epoetin alfa, 33 (28.9%) subjects were converted to Q4W dosing, and all subjects who converted were able to be maintained on this schedule.. The administration of epoetin alfa in extended-dosing intervals of Q2W followed by Q4W was safe and effective in the treatment of anemia in subjects with CKD who reside in LTC facilities.

Topics: Aged; Aged, 80 and over; Anemia; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Long-Term Care; Male; Outcome Assessment, Health Care; Recombinant Proteins; Residential Facilities; United States

Fatigue is frequent in cancer patients undergoing chemotherapy. Erythropoietins (EPO) have shown well-documented effects on these patients, and administered in pharmacological doses, may reduce the need for transfusion of blood cells and improve quality of life (QoL). An explorative, descriptive, non-randomised intervention study using semi-structured interviews was conducted with the aim to gain an insight into the effects and experiences associated with EPO treatment in combination with a structured 6-week physical exercise intervention. Sixteen cancer patients with evidence of disease, who had received at least one cycle chemotherapy, participated. Participants received 500 μg Darbepoetin Alfa (DA) every 3 weeks during the intervention. Four typologies of patients were identified with regard to DA effects. The interviews revealed that eleven patients experienced some kind of immediate improvement in cognitive and emotional functioning, and subjective daily well-being. Furthermore physical improvement and changes in QoL outcomes showed no significant differences between the study group and a reference group. A significant increase in the hemoglobin concentration (7.14-7.87 mmol/L, P<0.05) was found in the study group. The future use of EPO in cancer patients is hampered by the reported negative influence of EPO on the prognosis in some diagnoses and should be based on randomized studies.

Topics: Adolescent; Adult; Aged; Darbepoetin alfa; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Exercise Therapy; Fatigue; Female; Hematinics; Humans; Male; Middle Aged; Neoplasms; Treatment Outcome; Young Adult

Forty-eight patients with early myelodysplastic syndrome (MDS) without excess of blasts, with average initial serum ferritin levels of 2739.5 μg/L (range 825-11287 μg/L), were treated with deferiprone (L1) in a daily dose of 40-90 mg/kg. Median duration of chelation treatment was 10.9 months (range 4-24 months). Chelation was effective (maintained or decreased iron stores) in 16 out of 22 patients (73%) with serum ferritin levels <2000 μg/L in contrast to only 12 out of 26 patients with serum ferritin levels >2000 μg/L. Combination of L1 with recombinant human erythropoietin (rHuEPO) (30-40 kU/week) resulted in effective chelation in five additional patients with serum ferritin levels >3000 μg/L. Incidence of adverse effects was comparable to that in thalassemic patients. Gastrointestinal symptoms represented the most frequent adverse effect of L1 therapy (37.5% of patients) that limited an effective escalation of the daily dose of the drug and led to discontinuation of the treatment for six patients. A decreased number of granulocytes was observed in five (13%) patients and agranulocytosis occurred in two patients (4%). Granulocyte counts were restored after cessation of L1 treatment and administration of granulocyte colony stimulating factor (G-CSF) in all but one patient. Administration of L1 in a daily dose of at least 75 mg/kg may represent an alternative approach in treatment of mild and moderate iron overload in MDS patients who cannot be treated with deferasirox (DFRA) or deferoxamine (DFO).

Topics: Adult; Aged; Aged, 80 and over; Agranulocytosis; Deferiprone; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Female; Ferritins; Gastrointestinal Diseases; Granulocyte Colony-Stimulating Factor; Humans; Iron Chelating Agents; Iron Overload; Male; Middle Aged; Myelodysplastic Syndromes; Pyridones; Recombinant Proteins; Treatment Outcome

Anemia is common among patients with chronic kidney disease (CKD). The introduction of erythropoietin treatment has changed anemia management, but the therapeutic hemoglobin (Hb) target is still under debate, and clinical evidence for its effect on cardiac functions and QOL is sparse.. A 16-week dose-response study and a 32-week follow-Up study were combined. After correcting anemia of less than 10 g/dl in pre-dialysis Japanese CKD patients, a higher Hb target (12-13 g/dl) by darbepoetin alfa (DPO) was compared with the conventional Hb target by epoetin alfa (EPO). Outcomes were anemia correction, management of the left ventricular mass index (LVMI) and QOL scores.. No significant difference was seen in Hb at baseline and week 16, but a significant difference was recorded at week 34 (12.34 +/- 0.93 g/dl for DPO and 10.43 +/- 0.90 g/dl for EPO). In both groups, LVMI decreased similarly until week 16, but the decrease of EPO was retarded, and a significant difference between LVMI was seen only in DPO at week 34 (100.7 +/- 16.6 g/m(2) for DPO and 110.9 +/- 25.2 g/m(2) for EPO). Relationships between Hb and LVMI change at week 34 were examined by stratifying Hb into four groups (Hb <10 g/dl, 10 g/dl < or = Hb <11 g/dl, 11 g/dl < or = Hb <12 g/dl and 12 g/dl < or = Hb), and a decrease of LVMI was prominent in the 12 g/dl < or = Hb group. Correction of anemia to 11 g/dl or more led to improved QOL scores. No safety difference was observed among the treatments.. Targeting a higher Hb around 12 g/dl was more beneficial than targeting conventional Hb in terms of reduction of LVMI and QOL. Further studies to determine the appropriate Hb target are necessary.

Topics: Adult; Aged; Asian People; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Heart Ventricles; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Japan; Kidney Failure, Chronic; Male; Middle Aged; Quality of Life; Recombinant Proteins

Erythropoietin (EPO) has been found to have anti-apoptotic and tissue protective effects on the myocardium. The aim of the present pilot study was to observe the safety and efficacy of EPO administration for patients with acute myocardial infarction (AMI).. Patients admitted with AMI had all undergone successful percutaneous coronary intervention (PCI). Patients were randomly assigned to 2 groups (control and EPO groups), and given 12,000 IU EPO iv or saline after PCI. The primary endpoints were the difference between the acute phase and chronic phase (6 months after the attack) regarding left ventricular function as measured on electrocardiogram-gated single-photon emission computed tomography. Thirty-six patients (control 16, EPO 20) were eligible for analysis. Left ventricular ejection fraction (LVEF) significantly increased in the EPO group (from 51.0+/-19.6% to 58.5+/-15.0%, P=0.0238), but not in the control group. Further analysis was separately undertaken in patients with occlusion in the left anterior descending artery (LAD) and others (non-LAD). LVEF was <50% in most patients in the LAD subgroup, and LVEF significantly increased in the EPO group (37.5+/-13.0 to 52.7+/-15.8, P=0.0049), but not in the control group. EPO administration did not trigger any adverse clinical events.. EPO administration is a promising treatment for AMI.

Topics: Aged; Angioplasty, Balloon, Coronary; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Female; Humans; Male; Middle Aged; Myocardial Infarction; Pilot Projects; Recombinant Proteins; Stroke Volume; Tomography, Emission-Computed, Single-Photon; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

Several studies have shown that darbepoetin alfa, an erythropoiesis-stimulating agent (ESA), can reduce transfusions and increase hemoglobin (Hb) levels in patients with chemotherapy-induced anemia (CIA). Recent safety concerns, however, have prompted changes to ESA product information. In the European Union and United States, ESA therapy initiation for CIA is now recommended at a Hb level < or = 10 g/dL. The present exploratory analysis examined how ESA initiation at this Hb level may impact patient care.. Data from a phase 3 randomized trial were retrospectively reanalyzed. CIA patients with nonmyeloid malignancies were randomized 1:1 to 500 mcg darbepoetin alfa every three weeks (Q3W) or 2.25 mcg/kg darbepoetin alfa weekly (QW) for 15 weeks. A previously published report from this trial showed Q3W dosing was non-inferior to QW dosing for reducing transfusions from week 5 to end-of-the-treatment period (EOTP). In the present analysis, outcomes were reanalyzed by baseline Hb <10 g/dL and > or = 10 g/dL. Endpoints included transfusion rates, Hb outcomes, and safety profiles.. This study reanalyzed 351 and 354 patients who initiated ESA therapy at a baseline Hb of <10 g/dL or > or = 10 g/dL, respectively. From week 5 to EOTP, the estimated Kaplan-Meier transfusion incidence (Q3W vs QW) was lower in the > or = 10 g/dL baseline-Hb group (14% vs 21%) compared with the <10 g/dL baseline-Hb group (36% vs 41%). By week 5, the > or = 10 g/dL baseline-Hb group, but not the <10 g/dL baseline-Hb group, achieved a mean Hb > or = 11 g/dL. The Kaplan-Meier estimate of percentage of patients (Q3W vs QW) who achieved Hb > or = 11 g/dL from week 1 to EOTP was 90% vs 85% in the > or = 10 g/dL baseline-Hb group and 54% vs 57% in the <10 g/dL baseline-Hb group. Both baseline-Hb groups maintained mean Hb levels <12 g/dL and had similar safety profiles, though more patients in the > or = 10 g/dL baseline-Hb group reached the threshold Hb of > or = 13 g/dL.. In this exploratory analysis, darbepoetin alfa Q3W and QW raised Hb levels and maintained mean Hb at <12 g/dL in both baseline-Hb groups. The > or = 10 g/dL baseline-Hb group had fewer transfusions and faster anemia correction. Additional studies should prospectively evaluate the relationship between Hb levels at ESA initiation and outcomes.. ClinicalTrials.gov Identifier NCT00118638.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Clinical Trials, Phase III as Topic; Darbepoetin alfa; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Retrospective Studies; Treatment Outcome; Young Adult

Numerous preclinical findings and a clinical pilot study suggest that recombinant human erythropoietin (EPO) provides neuroprotection that may be beneficial for the treatment of patients with ischemic stroke. Although EPO has been considered to be a safe and well-tolerated drug over 2 decades, recent studies have identified increased thromboembolic complications and/or mortality risks on EPO administration to patients with cancer or chronic kidney disease. Accordingly, the double-blind, placebo-controlled, randomized German Multicenter EPO Stroke Trial (Phase II/III; ClinicalTrials.gov Identifier: NCT00604630) was designed to evaluate efficacy and safety of EPO in stroke.. This clinical trial enrolled 522 patients with acute ischemic stroke in the middle cerebral artery territory (intent-to-treat population) with 460 patients treated as planned (per-protocol population). Within 6 hours of symptom onset, at 24 and 48 hours, EPO was infused intravenously (40,000 IU each). Systemic thrombolysis with recombinant tissue plasminogen activator was allowed and stratified for.. Unexpectedly, a very high number of patients received recombinant tissue plasminogen activator (63.4%). On analysis of total intent-to-treat and per-protocol populations, neither primary outcome Barthel Index on Day 90 (P=0.45) nor any of the other outcome parameters showed favorable effects of EPO. There was an overall death rate of 16.4% (n=42 of 256) in the EPO and 9.0% (n=24 of 266) in the placebo group (OR, 1.98; 95% CI, 1.16 to 3.38; P=0.01) without any particular mechanism of death unexpected after stroke.. Based on analysis of total intent-to-treat and per-protocol populations only, this is a negative trial that also raises safety concerns, particularly in patients receiving systemic thrombolysis.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Brain Ischemia; Double-Blind Method; Drug Administration Schedule; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Female; Humans; Infarction, Middle Cerebral Artery; Injections, Intravenous; Male; Middle Aged; Mortality; Neuroprotective Agents; Patient Selection; Placebo Effect; Recombinant Proteins; Stroke; Tissue Plasminogen Activator; Treatment Outcome; Young Adult

Epoetin alfa is an established treatment of anemia in patients with cancer who are receiving chemotherapy with or without radiation therapy. However, fewer data support its use in patients with cancer not currently receiving either therapy. This 16-week, open-label, nonrandomized, multicenter pilot study evaluated the clinical profile of epoetin alfa (40,000 U) administered weekly via subcutaneous injection in anemic patients with cancer not receiving chemotherapy or radiation therapy. The primary endpoint was the proportion of patients who achieved a minor (hemoglobin [Hgb] increase > or = 1-1.9 g/dL) or major (Hgb increase > or = 2 g/dL) hematologic response. The trial was temporarily suspended to amend the protocol to reflect updated package insert recommendations for target Hgb and dose adjustments. Of the 98 patients enrolled, 91 (mean age, 69.5 +/- 9.5 years; baseline Hgb level, 10.4 +/- 0.7 g/dL) were evaluated for efficacy in a modified intent-to-treat analysis. Nearly all patients (94.5% [86/91]) achieved a minor response, and the majority (80.2% [73/91]) achieved a major hematologic response at any time during the study. Mean Hgb levels increased steadily over the 12-week dosing period, with significant (P < 0.001) increases from baseline observed as early as week 2. Only one patient required a transfusion. Epoetin alfa was safe and well tolerated.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Neoplasms; Pilot Projects; Recombinant Proteins

This pilot study was conducted to evaluate the feasibility, activity, and safety of an induction dose of epoetin alpha in cancer patients with moderate or severe anemia who were receiving chemotherapy.. Thirty patients with solid tumors and hemoglobin (Hb) levels <11.0 g/dl were enrolled. Patients received single s.c. injections of epoetin alpha, 40 000 IU for three consecutive days, and were then observed for the following 30 days. The primary efficacy variable was the response rate (Hb increase > or=1 g/dl) at day 15. Secondary efficacy variables included the proportion of patients given blood transfusions between baseline and the end of study, the duration of response (Hb level > or=1 g/dl), and ability to maintain the planned chemotherapy dose (dose intensity).. At day 15, 23 of 30 (77%) patients had achieved increases in Hb levels of at least 1 g/dl. The mean Hb increase in responders was 2.0 g/dl [95% confidence interval (CI) = 1.7-2.3 g/dl]. The Hb increase was 2.3 +/- 0.7 g/dl in responders with baseline Hb levels <9.5 g/dl (median Hb value), and 1.7 +/- 0.6 g/dl in those with higher Hb levels (P = 0.012). The median duration of response was 6.1 weeks (95% CI = 1.6-10.6 weeks). Hematologic parameters were not significantly changed in nonresponders. Multivariate analysis detected no significant differences in Hb increase at day 15 on the basis of age, sex, weight, baseline Hb levels, type or stage of tumor, or treatment with platinum-based chemotherapy. No serious adverse event related to epoetin alpha treatment was observed.. We conclude that a higher initial dosing of epoetin alpha appears to be an efficient schedule for treating anemia in cancer patients undergoing chemotherapy, conferring higher response rates than those seen with standard doses. Further evaluation of these and other epoetin alpha dosage regimens is warranted.

Topics: Adult; Aged; Anemia; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hematopoiesis; Hemoglobins; Humans; Male; Middle Aged; Neoplasms; Recombinant Proteins

A thirty-seven year old male patient with heavily pretreated metastatic testicular carcinoma received escalating doses of recombinant human erythropoietin (EPO) before and throughout chemotherapy. Whereas previous chemotherapy regimens repeatedly caused anemic situations in this patient (hemoglobin (HB) 7.0 g/dl requiring multiple transfusions of red blood cells), EPO given as an i.v. bolus injection at escalating doses of 150 to 300 U/kg body weight (BW) twice/week, starting two weeks prior to the identical myelosuppressive treatment protocol, maintained HB at levels above 8.8 g/dl and thus obviated the need for erythrocyte transfusion. EPO was discontinued after 9 weeks of administration when the patient had achieved a hematocrit (HCT) of 41.1% and a HB of 12.7 g/dl. However, erythropoiesis continued to recover for the next 7 weeks reaching a HCT of 42.4% and a HB of 14.3 g/dl, although the next identical chemotherapy cycle had been given within this period. Along with the rise in HB, ferrokinetics changed significantly as measured by serum ferritin, which was reduced to one third at the end of EPO therapy after only 9 weeks (from 979 ng/ml to 320 ng/ml). No side effects due to EPO administration occurred. These data provide first evidence for efficacy of EPO in chemotherapy-induced anemia and may open new avenues for its clinical application.

Topics: Adult; Anemia; Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Humans; Iatrogenic Disease; Male

Our study aims to evaluate the effectiveness of intravenous erythropoietin (EPO) in patients with indirect traumatic optic neuropathy (TON), assess the side effects, and compare the visual function results among three groups of patients who had received different treatment options - EPO, steroids, and observation.. : Patients with indirect TON presenting to the neuro-ophthalmology clinic from August 2019 to March 2020, were assigned to three groups, with six patients in each group. In group 1, patients were recruited prospectively and received recombinant human erythropoietin, whereas, in groups 2 and 3, patients were recruited retrospectively and received intravenous methylprednisolone followed by oral steroids and multivitamins, respectively. Groups 1 and 2 included patients presenting within 2 weeks of trauma, whereas group 3 included those presenting beyond that. Best-corrected visual acuity, pupillary reaction, color vision, and visual fields following treatment were measured.. Initial visual acuity in the EPO group ranged from 20/80 to no perception of light (No PL). The mean initial BCVA (1.82 logMAR, standard deviation [SD] = 0.847) improved to 1.32, SD = 0.93 logMAR after treatment recorded at the third month (P = 0.0375), with no significant adverse effects. The initial BCVA of group 2 ranged from 20/120 to No PL. The mean initial BCVA (1.95, SD = 0.77 logMAR) improved to 1.45 logMAR, SD = 0.97 after treatment (P = 0.0435) but three patients had side effects of steroids. Initial visual acuity in Group 3 ranged from 20/40 to no PL. The mean initial BCVA (1.09 logMAR, SD = 1.10) worsened to 1.19 logMAR, SD = 1.06 after treatment after treatment (P = 0.0193). The improvement in BCVA when compared between the three groups was not significant.. Both erythropoietin and steroids are effective in the management of traumatic optic neuropathy. However, erythropoietin shows lesser or no side effects when compared to steroids.

Topics: Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Humans; Optic Nerve Injuries; Pilot Projects; Recombinant Proteins; Retrospective Studies; Steroids

Hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI) is a novel agent for the treatment of renal anemia. HIF-PHI increases endogenous erythropoietin production by inhibiting the degradation of an erythropoietin transcription factor. Although beneficial effects are expected from HIF-PHI, its novel mechanism raises concerns regarding the risk of potential adverse events. The cases of hypothyroidism, which had not been reported in clinical trials, were reported after the administration of roxadustat in a real-world setting. However, the effects of HIF-PHIs on thyroid function have not yet been fully evaluated. This study aimed to assess the clinical impact of HIF-PHIs on thyroid function using the Japanese Adverse Drug Event Report database, a spontaneous reporting system in Japan, because HIF-PHIs were made available in Japan before they were available in other countries. Although a disproportionality signal for hypothyroidism was detected with roxadustat (reporting odds ratio [ROR]:22.1, 95% confidence interval [CI]:18.3-26.7, no signals were detected with another HIF-PHI, daprodustat (ROR:1.3, 95%CI:0.3-5.4), and epoetin beta pegol (ROR:1.2, 95%CI:0.5-2.7). Signals of hypothyroidism due to roxadustat were also detected regardless of age or sex. Approximately 50% of hypothyroidism cases were reported within 50 days of starting roxadustat use. These results indicate that roxadustat use may be related to the development of hypothyroidism. The need for monitoring of thyroid function should be alerted during roxadustat administration regardless of age or sex.

Topics: Drug-Related Side Effects and Adverse Reactions; East Asian People; Erythropoietin; Humans; Hypothyroidism; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Renal Insufficiency, Chronic

Concerns have been expressed that large numbers of nonvalue-added reports have been accumulating in adverse drug reaction (ADR) databases, for example, via patient support programs. We performed an assessment of the impact of such reports, which we refer to as "precautionary reports," on safety signal detection in the Netherlands. The case narratives of ADR reports of three case products were screened with text-mining algorithms to identify those reports that lack a causal relationship with the suspected medicinal product. We demonstrate that precautionary reports impede the optimal use of the pharmacovigilance system by, on the one hand, masking safety signals and, on the other hand, creating spurious signals. The precautionary reporting bias and its suppressing effect on statistical signal detection results in an altered adverse event safety profile. The findings from this study highlight the need for a better alignment between regulatory authorities and marketing authorization holders regarding pharmacovigilance guidelines.

Topics: Adverse Drug Reaction Reporting Systems; Algorithms; Animals; Bias; Data Mining; Databases, Factual; Diphosphonates; Drug-Related Side Effects and Adverse Reactions; Endothelin Receptor Antagonists; Erythropoietin; Evidence-Based Medicine; Humans; Models, Animal; Models, Theoretical; Netherlands; Patient Safety; Reproducibility of Results; Risk Assessment; Translational Research, Biomedical

Oral mucositis (OM) represents a therapeutic challenge frequently encountered in cancer patients undergoing chemotherapy or radiotherapy. Erythropoietin (EPO) has anti-inflammatory, antioxidant, and wound-healing properties and therefore has important roles in the prevention and treatment of OM. In the current study, we developed a thermally sensitive mucoadhesive gel based on trimethyl chitosan (TMC) containing EPO for the treatment of OM. TMCs with various degrees of substitution (DS) were synthesized and mixed with β-glycerophosphate (GP) and characterized for gelation properties by means of rheological analysis. The effects of DS of TMCs and different concentrations of GP on gelation temperature and time were investigated. The mucoadhesive property of the mixtures was also assessed using cattle buccal mucosa. The optimized mixture was loaded with EPO and subjected to in vitro drug release, wash away, in vitro antimicrobial, and wound-healing tests. The effect of EPO-loaded formulation was also investigated in vivo in Sprague-Dawley rats with chemotherapy-induced mucositis. The best properties were obtained with the blend of TMC of 9.8% DS (5%) and GP (20%). EPO was released from the hydrogel during 8 h, and more than 30% of the drug still remained on the mucosa after 3 h of washing the buccal mucosa with phosphate buffer. TMC/GP mixture was characterized by antimicrobial properties. The EPO hydrogel demonstrated in vitro/in vivo wound-healing properties. Therefore, EPO-loaded hydrogel has the potential to be used in the treatment of OM and other oral or subcutaneous wounds.

Topics: Animals; Cattle; Chitosan; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Glycerophosphates; Humans; Hydrogels; Rats; Rats, Sprague-Dawley; Stomatitis; Temperature

Peginesatide (Omontys(®); Affymax, Inc., Cupertino, CA) was voluntarily withdrawn from the market less than a year after the product launch. Although clinical trials had demonstrated the drug to be safe and efficacious, 49 cases of anaphylaxis, including 7 fatalities, were reported not long after market introduction. Commercialization was initiated with a multiuse vial presentation, which differs in formulation from the single-use vial presentation used in phase 3 studies. Standard physical and chemical testing did not indicate any deviation from product specifications in either formulation. However, an analysis of subvisible particulates using nanoparticle tracking analysis and flow imaging revealed a significantly higher concentration of subvisible particles in the multiuse vial presentation linked to the hypersensitivity cases. Although it is unknown whether the elevated particulate content is causally related to these serious adverse events, this report illustrates the utility of characterizing subvisible particulates not captured by conventional light obscuration.

Topics: Cells, Cultured; Chemistry, Pharmaceutical; Clinical Trials, Phase III as Topic; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Humans; Nanoparticles; Particulate Matter; Peptides; Product Surveillance, Postmarketing

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests

The use of human recombinant erythropoietin (EPO) as a neuroprotective agent is limited due to its hematological side effects. An erythropoietin along with a low content of sialic acid (rhEPOb), similar to that produced in the brain during hypoxia, may be used as a neuroprotective agent without risk of thrombotic events. The objective of this investigation was to assess the toxicological potential of a nasal formulation with rhEPOb in acute, subacute and nasal irritation assays in rats. Healthy Wistar rats (Cenp:Wistar) were used for the assays. In an irritation test, animals received 15 μl of rhEPOb into the right nostril. Rats were sacrificed after 24 h and slides of the nasal mucosa tissues were examined. Control and treated groups showed signs of a minimal irritation consisting of week edema and vascular congestion in all animals. In the acute toxicity test, the dose of 47,143 UI/kg was administered by nasal route. Hematological patterns, body weight, relative organ weight, and organ integrity were not affected by single dosing with rhEPOb. In the subacute toxicity test, Wistar rats of both sexes received 6,600 UI/kg/day for 14 days. The toxicological endpoints examined included animal body weight, food consumption, hematological and biochemical patterns, selected tissue weights, and histopathological examinations. An increase of lymphocytes was observed in males that was considered to reflect an immune response to treatment. Histopathological examination of organs and tissues did not reveal treatment-induced changes. The administration of rhEPOb at daily doses of 6,600 UI/kg during 14 days did not produce hematological side effects. These results suggest that rhEPOb could offer the same neuroprotection as EPO, without hematological side effects.

Topics: Administration, Intranasal; Animals; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Female; Male; N-Acetylneuraminic Acid; Nasal Mucosa; Neuroprotective Agents; Rats; Rats, Wistar; Toxicity Tests, Acute; Toxicity Tests, Subacute

Topics: Adult; Aged; Aged, 80 and over; Anemia; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Humans; Middle Aged; Switzerland

Renal disease is commonly encountered by primary care physicians during their day-to-day visits with patients. Common renal disorders include hypertension, proteinuria, kidney stones, and chronic kidney disease. Despite their prevalence, many physicians may be unfamiliar with the diagnosis and initial treatment of these common renal disorders. Early recognition and intervention are important in slowing the progression of chronic kidney disease and preventing its complications. The evidence-based pearls in this article will help primary care physicians avoid common pitfalls in the recognition and treatment of such disorders and guide their decision to refer their patients to a specialist.

Topics: Aluminum; Anemia; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antacids; Blood Pressure; Blood Urea Nitrogen; Cardiovascular Diseases; Cathartics; Chronic Disease; Contraindications; Creatinine; Cyclosporine; Disease Progression; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Evidence-Based Medicine; Glomerular Filtration Rate; Humans; Hypertension; Immunosuppressive Agents; Kidney Diseases; Magnesium; Nephrolithiasis; Nephrology; Phosphates; Primary Health Care; Proteinuria; Recombinant Proteins; Referral and Consultation; Tacrolimus; Urinalysis

Topics: Child Development; Developmental Disabilities; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Infant, Premature; Male; Recombinant Proteins; Risk Assessment; Treatment Outcome; United States; United States Food and Drug Administration

Topics: Anemia; Drug and Narcotic Control; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Humans; Neoplasms; Receptors, Erythropoietin; United States; United States Food and Drug Administration

Topics: Anemia; Darbepoetin alfa; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Recombinant Proteins; United States; United States Food and Drug Administration

This analysis was conducted to compare the direct medical costs of treatment with darbepoetin alfa every 3 weeks (Q3W) and epoetin alfa every week (QW) in patients with chemotherapy-induced anaemia (CIA) from the payer's perspective.. An analysis was conducted from a US health plan perspective to compare the annual budget impact for CIA with darbepoetin alfa Q3W and epoetin alfa QW over a 16-week treatment period. Dosing regimens were obtained from registration clinical trials.. Mean doses, including dose adjustments, were 375.6 microg Q3W for darbepoetin alfa and 43,187 U QW for epoetin alfa. Costs of medical resources included drug acquisition and administration costs. The base case analysis resulted in a per-patient budget impact of $8,544 and $8,667 for darbepoetin alfa and epoetin alfa, respectively. Per member per month cost was $0.90 for darbepoetin alfa and $0.91 for epoetin alfa, based on an estimate of 2,735 CIA patients in a health plan population of 2.17 million. The analysis was most sensitive to drug dose, treatment period and drug price.. Results suggest that per-patient direct medical costs of CIA treatment, when initiated at labelled starting doses, are comparable for darbepoetin alfa Q3W and epoetin alfa QW.

Topics: Anemia; Budgets; Darbepoetin alfa; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Health Expenditures; Hematinics; Humans; Recombinant Proteins; Taxes; United States

To assess both the health-related quality of life (HR-QOL) and the economic value of erythropoietin treatment in chemotherapy-related anaemia using direct utility elicitation and discrete choice experiment (DCE) methods from a societal perspective in the UK.. The time trade-off (TTO) method was employed to obtain utility values suitable for the calculation of QALYs for no, mild, moderate and severe anaemia. Health-state descriptions were developed using the Functional Assessment of Cancer Therapy - Anaemia (FACT-AN) subscale and the EQ-5D questionnaires, and were validated by clinical experts and patients. In addition, a DCE was implemented to elicit preferences for various anaemia treatment scenarios. The DCE analysis comprised important aspects of treatment identified from a literature review and by consultation with expert clinicians and cancer patients. The DCE included cost as an attribute in order to elicit willingness-to-pay (WTP) values (pound, 2004 values). The two methods were applied in the same cross-sectional sample of 110 lay people. Face-to-face interviews were conducted between February and March 2004.. The mean utility scores were 0.86 (standard error [SE] 0.014) for the no-anaemia state, and 0.78 (SE 0.016), 0.61 (SE 0.020) and 0.48 (SE 0.020) for the mild, moderate and severe anaemia states, respectively. The DCE results revealed the following preferences as significant predictors of choice: higher level of relief from fatigue, lower duration of administration, subcutaneous/intravenous administration versus cannula injection, GP versus hospital location, lower risk of infection or allergic reactions and lower cost per month to the patient. Attribute levels were valued higher for recombinant erythropoietin than for blood transfusion; this is reflected in an incremental welfare value of 368 pounds (95% CI 318, 419).. The results highlight a societal view that the severity of chemotherapy-related anaemia will significantly affect cancer patients' HR-QOL. The DCE survey shows that the public value favourably the attributes of treatment with recombinant erythropoietin, and indicates a likely patient preference for treatment with recombinant erythropoietin over blood transfusion.

Topics: Adolescent; Adult; Aged; Anemia; Cost-Benefit Analysis; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Female; Humans; Male; Middle Aged; Quality of Life; Recombinant Proteins; Surveys and Questionnaires; United Kingdom

High-dose recombinant erythropoietin (rEpo) is neuroprotective in neonatal animal models of brain injury, but the long-term consequences of neonatal exposure have not been studied.. We hypothesized that multiple injections of high-dose rEpo during the neonatal period would be safe, and would improve neurologic outcomes after exposure to neonatal hypoxia or hypoxic-ischemic injury.. Three experimental groups of Sprague-Dawley rats were assessed: (1) normoxia, (2) hypoxia and (3) hypoxia-ischemia. Groups 1 and 2 were given 0, 2,500 or 5,000 U/kg rEpo subcutaneously for the first 5 days of life (P1-P5). Group 2 animals also underwent 2 h of hypoxia (8% O(2)) daily from P1-P3. Group 3 animals underwent right carotid artery ligation followed by hypoxia (8% O(2) x 90 min) on P7, followed by either vehicle or rEpo (2,500 U/kg subcutaneously QD x3). We evaluated short- and long-term physiologic and behavioral outcomes. Major organs were evaluated grossly and histologically.. rEpo treatment transiently raised hematocrit, prevented hypoxia-induced delays in geotaxis and growth, improved forelimb strength, promoted liver growth in males, lowered the adult platelet count, but did not alter other CBC indices or histology. rEpo prevented hypoxia-ischemia-induced learning impairment and substantia nigra neuron loss.. Repeated treatment of newborn rats with high-dose rEpo was safe under all conditions tested. rEpo treatment improved the development of hypoxia-exposed newborns and prevented the learning impairment and dopamine neuron loss due to unilateral hypoxic-ischemic brain injury.

Topics: Animals; Animals, Newborn; Avoidance Learning; Behavior, Animal; Brain; Dopamine; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Hematocrit; Hypoxia; Hypoxia-Ischemia, Brain; Liver; Models, Animal; Neurons; Neuroprotective Agents; Organ Size; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Weight Gain

Topics: Clinical Trials as Topic; Drug Industry; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Humans; Recombinant Proteins

Topics: Anemia; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Hematinics; Humans; Insurance, Health, Reimbursement; Practice Guidelines as Topic; Renal Dialysis; United States

Topics: Anemia; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Hematinics; Humans; Insurance, Health, Reimbursement; Renal Dialysis; United States

Topics: Anemia; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Hematinics; Hemoglobins; Humans; Practice Guidelines as Topic; Renal Dialysis; United States

Topics: Anemia; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Evidence-Based Medicine; Health Policy; Hematinics; Humans; Renal Insufficiency, Chronic; United States

The use of erythropoietic growth factors to treat chemotherapy-induced anemia (CIA) has been increasing as clinicians become more aware of the ability of these drugs to improve the quality of life of patients with cancer. The cost associated with erythropoietic growth factor therapy makes its appropriate use a practical issue for physicians and hospitals. Clinical practice guidelines can benefit physicians by increasing practice efficiency, reducing medical errors, increasing the quality of medical care, and decreasing reimbursement problems. The American Society of Clinical Oncology and the American Society of Hematology, the European Organisation for Research and Treatment of Cancer, and the National Comprehensive Cancer Network (NCCN) have all published guidelines for using erythropoietic growth factors to treat CIA, and this article reviews and summarizes those guidelines. Of the three guidelines for the use of erythropoietic growth factors in CIA, the NCCN guidelines are based on the most recent data. Current evidence indicates that erythropoietic growth factors can increase hemoglobin levels, reduce the need for red blood cell transfusions, and improve quality of life; the effect of erythropoietic therapy on outcomes in patients with CIA is still being investigated.

Topics: Anemia; Darbepoetin alfa; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Europe; Growth Substances; Hematinics; Humans; Recombinant Proteins; United States

(1) Current treatments for anaemia in patients receiving cancer chemotherapy include blood transfusion and epoetin alfa and beta. These epoetins correct anaemia in 40% to 65% of patients and reduce the number of patients who require transfusions during the second and third months of treatment by 12-35% in absolute terms. (2) Darbepoetin alfa is slightly more glycosylated than epoetin alfa and beta. It is no more effective than these two drugs in chronic renal failure. Darbepoetin alfa is now approved for the treatment of anaemia in patients who are receiving chemotherapy for non myeloid malignancies. (3) Two placebo-controlled dose-finding studies and two placebo-controlled trials involving nearly 1000 patients in total have shown that darbepoetin alfa decreases the number of transfused patients by 17-25% in absolute terms, and that it probably reduces fatigue. However, one-quarter of patients receiving darbepoetin were nonetheless transfused. (4) In the absence of reliable comparisons, there is no firm evidence that darbepoetin alfa is more effective than other epoetins. (5) According to relatively imprecise company reports, darbepoetin alfa increased the risk of thromboembolic events during clinical trials (6% versus 3%), including pulmonary embolism (1.3% versus 0%); the company also states that darbepoetin alfa does not increase the risk of arterial hypertension, a classical effect of epoetin that is mentioned in the summary of product characteristics (SPC). Placebo-controlled trials and dose-finding studies show no impact on the outcome of cancer, but follow-up is limited and a negative effect cannot be ruled out. The company states that no cases of erythroblastopenia have occurred among more than 70 000 treated patients. (6) According to the SPC, darbepoetin alfa can be given once a week. However, the optimal epoetin dosing schedule is unknown. Epoetin therapy takes several weeks to correct anaemia, whereas transfusion is immediately effective. (7) In practice, darbepoetin alfa seems a little easier to administer than epoetin alfa or beta, but the advantages and disadvantages of these drugs as compared with blood transfusion are not entirely clear.

Topics: Anemia; Blood Transfusion; Clinical Trials as Topic; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Humans; Recombinant Proteins; Treatment Outcome

Topics: Adenine; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Antihypertensive Agents; Antirheumatic Agents; Bone Resorption; Bosentan; Cephalosporins; Darbepoetin alfa; Diphosphonates; Drug Approval; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Heart Failure; Humans; Hypoglycemic Agents; Imidazoles; Indoles; Insulin; Insulin Aspart; Interleukin 1 Receptor Antagonist Protein; Natriuretic Agents; Natriuretic Peptide, Brain; Organophosphonates; Organophosphorus Compounds; Protein C; Recombinant Proteins; Serotonin Receptor Agonists; Sialoglycoproteins; Sulfonamides; Tenofovir; Tryptamines; Zoledronic Acid

Topics: Clinical Trials as Topic; Drug Industry; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Europe; Humans; Infusions, Intravenous; Prevalence; Recombinant Proteins; Red-Cell Aplasia, Pure; Risk Assessment

Treatment of metastatic melanoma with biochemotherapy results in the rapid onset of anemia, requiring blood transfusion in 9 of 13 (69%) patients. Prophylactic use of weekly subcutaneous recombinant epoetin alfa eliminated the need for transfusion in all but 1 of 21 (5%) patients.

Topics: Anemia; Blood Transfusion; Cost-Benefit Analysis; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Melanoma; Neoplasm Metastasis; Quality of Life; Recombinant Proteins

Topics: Anemia; Conflict of Interest; Death; Deception; Disclosure; DNA, Recombinant; Drug Industry; Drug-Related Side Effects and Adverse Reactions; Editorial Policies; Erythropoietin; Ethics Committees; Ethics Committees, Research; Financial Support; Hormones; Human Experimentation; Humans; Infant, Newborn; Infant, Premature; Information Dissemination; Information Services; Mortality; Peer Review; Placebos; Professional Misconduct; Publishing; Research Design; Research Personnel; Risk; Risk Assessment; United Kingdom