Fatigue Related Directly To Chronic Hemolysis
in [Nutrition]
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From: ironjustice on 3 Aug 2008 22:29 On Jun 18, 9:47 am, "ironjust...(a)aol.com" <ironjust...(a)aol.com> wrote: fatigue and hemolysis << IMPROVEMENT IN FATIGUE WITH ECULIZUMAB TREATMENT OF PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) OCCURS INDEPENDENT OF CHANGES IN ANEMIA Authors A. Hill,1 P. Muus,2 U. Dührsen,3 G. Socié,4 A. Risitano,5 R. De Paz,6 E. Van den Neste,7 A. Zanella,8 J.S. Lai,9 P. Hillmen,10 R. Rother,11 D. Cella9 Address 1Teaching Hospitals NHS Foundation Trust, BRADFORD, UK; 2Radboud University, NIJMEGEN, Netherlands; 3University Essen, ESSEN, Germany; 4Hospital Saint Louis and INSERM, PARIS, France; 5Midiche Federico II University of Naple, NAPLES, Italy; 6Hospital De La Paz, MADRID, Spain; 7Ucl St. Luc, BRUSSELS, Belgium; 8Ospedale Maggiore di Milano, MILAN, Italy; 9Northwestern University and Evanston Northwestern Healthcare, EVANSTON, IL, USA; 10Leeds Teaching Hospitals NHS Trust, LEEDS, UK; 11Alexion Pharmaceuticals, Inc., CHESHIRE, CT, USA Abstract  Background. In patients with paroxysmal nocturnal hemoglobinuria (PNH), RBCs undergo chronic complement-mediated hemolysis resulting in serious sequelae including anemia, thrombosis, pain, dyspnea, poor quality of life and disabling fatigue. Fatigue levels in patients with PNH are similar to that experienced by anemic cancer patients, and treatment measures to improve anemia can improve fatigue in both disease settings. In PNH, however, fatigue is also related directly to chronic hemolysis. Aims. To elucidate the contribution of hemolysis versus anemia to the improvement in fatigue in eculizumab-treated PNH patients. Methods. Patient-reported fatigue was determined utilizing the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale and anemia and hemolysis were objectively recorded in the double-blind placebo controlled phase 3 TRIUMPH and the open label phase 3 SHEPHERD PNH studies. The effect of eculizumab treatment on fatigue in PNH patients was compared to changes in fatigue in anemic cancer patients who received EPO using the same fatigue questionnaire; patients were analyzed as 3 strata: >1 g/dL increase; no change; or a >1 g/dL decrease in hemoglobin during treatment. Effect sizes (ES) indicating large, moderate or small clinical improvements were assessed. Results. Treatment independent univariate analysis of PNH patients showed that intravascular hemolysis reduction (decreased lactate dehydrogenase levels) and anemia improvement (increased hemoglobin) were both significantly associated with fatigue improvement (odds ratio 1.11, p<0.001 and 1.29, p=0.005, respectively). Further, multivariate analysis indicated that hemolysis reduction was predictive of an improvement in fatigue independent of an improvement in anemia (1.07, p=0.028). Eculizumab treatment was associated with a significant improvement in fatigue by one week and the improvement has been sustained for over two years. The improvement in fatigue was larger (p=0.002) in eculizumab-treated anemic PNH patients compared to EPO- treated anemic cancer patients. Patients treated with eculizumab experienced a large improvement (ES:1.0) when the hemoglobin level increased, and a moderate fatigue improvement when hemoglobin showed no change (ES:0.72) or even decreased (ES:0.61). By contrast, patients treated with EPO experienced a small improvement in FACIT-Fatigue score only when hemoglobin level increased (ES:0.48); fatigue scores in EPO treated patients did not change meaningfully when hemoglobin levels did not change (ES:0.15) and actually showed worsening when hemoglobin levels decreased (ES:-0.33) during treatment (Table 1). Summary and conclusions. Taken together, these findings suggest that eculizumab-treated PNH patients experience a larger improvement in fatigue than EPO-treated cancer patients due to the improvement in hemolysis with eculizumab. Also, there is improvement in fatigue with eculizumab that is independent of any improvement in anemia. In contrast to the observations with EPO in which patients did not experience meaningful improvement in fatigue unless they also showed an improvement in anemia, meaningful improvements in fatigue were experienced with eculizumab by both those patients who had an improvement in anemia as well as by patients that had no improvement in anemia. Since improvement in fatigue with eculizumab is associated with relatively rapid reduction in hemolysis and occurs independent of change in anemia, eculizumab can benefit a broader PNH patient population than those who realize improvement in anemia. Who loves ya. Tom Jesus Was A Vegetarian! http://tinyurl.com/2r2nkh Man Is A Herbivore! http://tinyurl.com/a3cc3 DEAD PEOPLE WALKING http://tinyurl.com/zk9fk > http://www.medicalnewstoday.com/articles/111618.php > > Soliris,Hemolysisand Fatigue in PNH > > Fatigue levels in patients with PNH are often severe and similar to > those experienced by anemic cancer patients. Soliris previously has > been shown to reduce substantially the frequently disabling fatigue > associated with PNH. The data presented today provide additional > insight into the mechanism through which Soliris positively impacts > PNH-related fatigue. While treatments designed to improve anemia can > improve fatigue in both PNH and cancer, these data demonstrate that > fatigue in PNH is also related directly to chronichemolysisand can > be improved independent of correction of anemia. Soliris has also been > associated with other significant benefits in patients with PNH, > including reduction inhemolysisand reduction in thrombotic events > during treatment phase compared to the same period of time prior to > treatment (see SmPC on EMEA website). (5-7) > > In the presentation by Dr. Hill, data on 164 patients with PNH were > derived from two Phase 3 studies of Soliris as a treatment for PNH: > TRIUMPH, a six-month, double-blind, placebo-controlled study, and > SHEPHERD, a 12-month, open-label study. Data on anemic cancer patients > were obtained from a published report. (8) Patient-reported fatigue in > both groups of patients was determined utilizing the Functional > Assessment of Chronic Illness Therapy (FACIT) - Fatigue scale. Anemia > was measured by levels of hemoglobin, andhemolysiswas measured by > levels of lactate dehydrogenase (LDH). Key findings included the > following: > While intravascularhemolysisreduction (decreased LDH) and anemia > improvement (increased hemoglobin) were both significantly associated > with fatigue improvement (odds ratio 1.11, P<0.001 and 1.29, P=0.005, > respectively),hemolysisreduction was predictive of an improvement in > fatigue independent of an improvement in anemia in patients with PNH > (1.07, P=0.028). > > The improvement in fatigue was greater (P=0.002) in Soliris-treated > PNH patients compared to EPO-treated anemic cancer patients. > > When the magnitude of clinical impact was analyzed by using standard > descriptors for the Effect Size (ES) measurement of fatigue in both > groups, (9) > > PNH patients treated with Soliris experienced a large improvement in > fatigue, (ES: +1.0) when the hemoglobin level increased as compared to > anemic cancer patients treated with EPO who experienced only a small > improvement in fatigue (ES: +0.48) > Similarly, PNH patients treated with Soliris experienced a moderate > improvement in fatigue (ES:+0.72) when hemoglobin levels did not > improve compared to EPO-treated anemic cancer patients for whom > fatigue scores did not change meaningfully (ES:+0.15) when hemoglobin > levels did not improve. > Importantly Soliris-treated PNH patients still experienced a moderate > improvement in fatigue (ES: +0.61) even when hemoglobin levels > decreased, while EPO-treated anemic cancer patients experienced a > small worsening of fatigue (ES:-0.33) when hemoglobin levels > decreased. > The improvement in fatigue associated with Soliris therapy in clinical > trials was observed within the first week of treatment and has been > sustained for the duration of the clinical trials. (10) > > "As in cancer patients, fatigue in PNH patients is often severe enough > to make the ordinary activities of daily life impossible," said > Leonard Bell, M.D., Chief Executive Officer of Alexion. "This study > indicates that patients can experience life-changing improvements in > fatigue with long-term Soliris therapy regardless of changes in their > anemia. This, and the other compelling clinical benefits that Soliris > offers patients with PNH, are the basis for our commitment that every > patient who can benefit from Soliris should have access to it." > > About PNH > > PNH is a rare blood disease that affects an estimated 8,000 to 10,000 > people in North America and Europe and, using similar prevalence > estimates, potentially 1,000 - 2,000 patients in Japan.(11) Although > affecting all age groups, PNH often strikes people in the prime of > their lives, with an average age of onset in the early 30's. (12) > Approximately 10 percent of all patients first develop symptoms at 21 > years of age or younger. (4) PNH develops without warning and can > occur in men and women of all backgrounds and ages. PNH often goes > unrecognized, with delays in diagnosis often ranging from one to more > than 10 years. (3) The estimated median survival for PNH patients is > between 10 and 15 years from the time of diagnosis. (3,12) > > PNH has been identified more commonly among patients with disorders of > the bone marrow, including aplastic anemia (AA) and myelodysplastic > syndrome (MDS). (13,14,15,16) In patients with thrombosis of unknown > origin, PNH may be an underlying cause. (3,12) > > Prior to approval of Soliris, there were no therapies specifically > available for the treatment of PNH. PNH treatment was limited to > symptom management through periodic blood transfusions, non-specific > immunosuppressive therapy and, infrequently, bone marrow > transplantations - a procedure that carries considerable mortality > risk. (4,17) > > Who loves ya. > Tom > > Jesus Was A Vegetarian!http://tinyurl.com/2r2nkh > > Man Is A Herbivore!http://tinyurl.com/a3cc3 > > DEAD PEOPLE WALKINGhttp://tinyurl.com/zk9fk
From: ironjustice on 15 Aug 2008 23:06 On Aug 3, 7:29 pm, ironjustice <ironjust...(a)aol.com> wrote: hemolysis and fatigue << "May be explained by the very feature they all share, intravascular hemolysis" http://tinyurl.com/6gr5ww "We, therefore, propose that paroxysmal nocturnal hemoglobinuria, sickle cell, thalassemia, red cell membrane disorders, red cell enzymopathies, thrombotic thrombocytopenic purpura, malaria, cardiopulmonary bypass, transfusion of aged blood, and alloimmune hemolysis, may be explained by the very feature they all share, intravascular hemolysis. " Therefore .. iron excess .. because hemolytic anemia is iron loading. Who loves ya. Tom Jesus Was A Vegetarian! http://tinyurl.com/2r2nkh Man Is A Herbivore! http://tinyurl.com/a3cc3 DEAD PEOPLE WALKING http://tinyurl.com/zk9fk > On Jun 18, 9:47 am, "ironjust...(a)aol.com" <ironjust...(a)aol.com> wrote:fatigueandhemolysis<< > > IMPROVEMENT INFATIGUEWITH ECULIZUMAB TREATMENT OF PATIENTS WITH > PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) OCCURS INDEPENDENT OF > CHANGES IN ANEMIA > Authors  A. Hill,1 P. Muus,2 U. Dührsen,3 G. Socié,4 A. Risitano,5 R. > De Paz,6 E. Van den Neste,7 A. Zanella,8 J.S. Lai,9 P. Hillmen,10 R. > Rother,11 D. Cella9 > Address  1Teaching Hospitals NHS Foundation Trust, BRADFORD, UK; > 2Radboud University, NIJMEGEN, Netherlands; 3University Essen, ESSEN, > Germany; 4Hospital Saint Louis and INSERM, PARIS, France; 5Midiche > Federico II University of Naple, NAPLES, Italy; 6Hospital De La Paz, > MADRID, Spain; 7Ucl St. Luc, BRUSSELS, Belgium; 8Ospedale Maggiore di > Milano, MILAN, Italy; 9Northwestern University and Evanston > Northwestern Healthcare, EVANSTON, IL, USA; 10Leeds Teaching Hospitals > NHS Trust, LEEDS, UK; 11Alexion Pharmaceuticals, Inc., CHESHIRE, CT, > USA > > Abstract   > Background. > In patients with paroxysmal nocturnal hemoglobinuria (PNH), RBCs > undergo chronic complement-mediatedhemolysisresulting in serious > sequelae including anemia, thrombosis, pain, dyspnea, poor quality of > life and disablingfatigue.Fatiguelevels in patients with PNH are > similar to that experienced by anemic cancer patients, and treatment > measures to improve anemia can improvefatiguein both disease > settings. > In PNH, however,fatigueis also related directly to chronichemolysis. > Aims. > To elucidate the contribution ofhemolysisversus anemia to the > improvement infatiguein eculizumab-treated PNH patients. > Methods. > Patient-reportedfatiguewas determined utilizing the Functional > Assessment of Chronic Illness Therapy (FACIT)-Fatiguescale and anemia > andhemolysiswere objectively recorded in the double-blind placebo > controlled phase 3 TRIUMPH and the open label phase 3 SHEPHERD PNH > studies. The effect of eculizumab treatment onfatiguein PNH patients > was compared to changes infatiguein anemic cancer patients who > received EPO using the samefatiguequestionnaire; patients were > analyzed as 3 strata: >1 g/dL increase; no change; or a >1 g/dL > decrease in hemoglobin during treatment. Effect sizes (ES) indicating > large, moderate or small clinical improvements were assessed. > Results. > Treatment independent univariate analysis of PNH patients showed that > intravascularhemolysisreduction (decreased lactate dehydrogenase > levels) and anemia improvement (increased hemoglobin) were both > significantly associated withfatigueimprovement (odds ratio 1.11, > p<0.001 and 1.29, p=0.005, respectively). Further, multivariate > analysis indicated thathemolysisreduction was predictive of an > improvement infatigueindependent of an improvement in anemia (1.07, > p=0.028). Eculizumab treatment was associated with a significant > improvement infatigueby one week and the improvement has been > sustained for over two years. The improvement infatiguewas larger > (p=0.002) in eculizumab-treated anemic PNH patients compared to EPO- > treated anemic cancer patients. Patients treated with eculizumab > experienced a large improvement (ES:1.0) when the hemoglobin level > increased, and a moderatefatigueimprovement when hemoglobin showed > no change (ES:0.72) or even decreased (ES:0.61). By contrast, patients > treated with EPO experienced a small improvement in FACIT-Fatigue > score only when hemoglobin level increased (ES:0.48);fatiguescores > in EPO treated patients did not change meaningfully when hemoglobin > levels did not change (ES:0.15) and actually showed worsening when > hemoglobin levels decreased (ES:-0.33) during treatment (Table 1). > Summary and conclusions. > Taken together, these findings suggest that eculizumab-treated PNH > patients experience a larger improvement infatiguethan EPO-treated > cancer patients due to the improvement inhemolysiswith eculizumab. > Also, there is improvement infatiguewith eculizumab that is > independent of any improvement in anemia. In contrast to the > observations with EPO in which patients did not experience meaningful > improvement infatigueunless they also showed an improvement in > anemia, meaningful improvements infatiguewere experienced with > eculizumab by both those patients who had an improvement in anemia as > well as by patients that had no improvement in anemia. Since > improvement infatiguewith eculizumab is associated with relatively > rapid reduction inhemolysisand occurs independent of change in > anemia, eculizumab can benefit a broader PNH patient population than > those who realize improvement in anemia. > > Who loves ya. > Tom > > Jesus Was A Vegetarian!http://tinyurl.com/2r2nkh > > Man Is A Herbivore!http://tinyurl.com/a3cc3 > > DEAD PEOPLE WALKINGhttp://tinyurl.com/zk9fk > > > > >http://www.medicalnewstoday.com/articles/111618.php > > > Soliris,HemolysisandFatiguein PNH > > >Fatiguelevels in patients with PNH are often severe and similar to > > those experienced by anemic cancer patients. Soliris previously has > > been shown to reduce substantially the frequently disablingfatigue > > associated with PNH. The data presented today provide additional > > insight into the mechanism through which Soliris positively impacts > > PNH-relatedfatigue. While treatments designed to improve anemia can > > improvefatiguein both PNH and cancer, these data demonstrate that > >fatiguein PNH is also related directly to chronichemolysisand can > > be improved independent of correction of anemia. Soliris has also been > > associated with other significant benefits in patients with PNH, > > including reduction inhemolysisand reduction in thrombotic events > > during treatment phase compared to the same period of time prior to > > treatment (see SmPC on EMEA website). (5-7) > > > In the presentation by Dr. Hill, data on 164 patients with PNH were > > derived from two Phase 3 studies of Soliris as a treatment for PNH: > > TRIUMPH, a six-month, double-blind, placebo-controlled study, and > > SHEPHERD, a 12-month, open-label study. Data on anemic cancer patients > > were obtained from a published report. (8) Patient-reportedfatiguein > > both groups of patients was determined utilizing the Functional > > Assessment of Chronic Illness Therapy (FACIT) -Fatiguescale. Anemia > > was measured by levels of hemoglobin, andhemolysiswas measured by > > levels of lactate dehydrogenase (LDH). Key findings included the > > following: > > While intravascularhemolysisreduction (decreased LDH) and anemia > > improvement (increased hemoglobin) were both significantly associated > > withfatigueimprovement (odds ratio 1.11, P<0.001 and 1.29, P=0.005, > > respectively),hemolysisreduction was predictive of an improvement in > >fatigueindependent of an improvement in anemia in patients with PNH > > (1.07, P=0.028). > > > The improvement infatiguewas greater (P=0.002) in Soliris-treated > > PNH patients compared to EPO-treated anemic cancer patients. > > > When the magnitude of clinical impact was analyzed by using standard > > descriptors for the Effect Size (ES) measurement offatiguein both > > groups, (9) > > > PNH patients treated with Soliris experienced a large improvement in > >fatigue, (ES: +1.0) when the hemoglobin level increased as compared to > > anemic cancer patients treated with EPO who experienced only a small > > improvement infatigue(ES: +0.48) > > Similarly, PNH patients treated with Soliris experienced a moderate > > improvement infatigue(ES:+0.72) when hemoglobin levels did not > > improve compared to EPO-treated anemic cancer patients for whom > >fatiguescores did not change meaningfully (ES:+0.15) when hemoglobin > > levels did not improve. > > Importantly Soliris-treated PNH patients still experienced a moderate > > improvement infatigue(ES: +0.61) even when hemoglobin levels > > decreased, while EPO-treated anemic cancer patients experienced a > > small worsening offatigue(ES:-0.33) when hemoglobin levels > > decreased. > > The improvement infatigueassociated with Soliris therapy in clinical > > trials was observed within the first week of treatment and has been > > sustained for the duration of the clinical trials. (10) > > > "As in cancer patients,fatiguein PNH patients is often severe enough > > to make the ordinary activities of daily life impossible," said > > Leonard Bell, M.D., Chief Executive Officer of Alexion. "This study > > indicates that patients can experience life-changing improvements in > >fatiguewith long-term Soliris therapy regardless of changes in their > > anemia. This, and the other compelling clinical benefits that Soliris > > offers patients with PNH, are the basis for our commitment that every > > patient who can benefit from Soliris should have access to it." > > > About PNH > > > PNH is a rare blood disease that affects an estimated 8,000 to 10,000 > > people in North America and Europe and, using similar prevalence > > estimates, potentially 1,000 - 2,000 patients in Japan.(11) Although > > affecting all age groups, PNH often strikes people in the prime of > > their lives, with an average age of onset in the early 30's. (12) > > Approximately 10 percent of all patients first develop symptoms at 21 > > years of age or younger. (4) PNH develops without warning and can > > occur in men and women of all backgrounds and ages. PNH often goes > > unrecognized, with delays in diagnosis often ranging from one to more > > than 10 years. (3) The estimated median survival for PNH patients is > > between 10 and 15 years from the time of diagnosis. (3,12) > > > PNH has been identified more commonly among patients with disorders of > > the bone marrow, including aplastic anemia (AA) and myelodysplastic > > syndrome (MDS). (13,14,15,16) In patients with thrombosis of unknown > > origin, PNH may be an underlying cause. (3,12) > > > Prior to approval of Soliris, there were no therapies specifically > > available for the treatment of PNH. PNH treatment was limited to > > symptom management through periodic blood transfusions, non-specific > > immunosuppressive therapy and, infrequently, bone marrow > > transplantations - a procedure that carries considerable mortality > > risk. > > ... > > read more »- Hide quoted text - > > - Show quoted text -
From: ironjustice on 15 Aug 2008 23:17 On Aug 15, 8:06 pm, ironjustice <ironjust...(a)aol.com> wrote:hemolysis and fatigue << "Decreased erythrocyte glutathione and glutamine" These are the primary antioxidants in the cell which can be targeted and REpleted with tocopherol. BUT if there is an increased LIP / labile iron pool .. in the cell .. tocopherol is unable to accomplish this. One must target the same 'vicinity' OF the glutathione **because OF** the increased iron. Soooo .. again .. after the cows have gone. The iron must be removed in order to accomplish a healthy red blood cell. This has been shown to be accomplished with a very low iron state in those that suffer from the above diseases. Blood, 1 January 2008, Vol. 111, No. 1, pp. 402-410. Prepublished online as a Blood First Edition Paper on September 11, 2007; DOI 10.1182/blood-2007-04-081703. Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease Claudia R. Morris1, Jung H. Suh2, Ward Hagar3, Sandra Larkin2, D. Anton Bland4, Martin H. Steinberg5, Elliott P. Vichinsky3, Mark Shigenaga2, Bruce Ames2, Frans A. Kuypers2, and Elizabeth S. Klings4,5 1 Department of Emergency Medicine, Children's Hospital and Research Center Oakland, CA; 2 Children's Hospital Oakland Research Institute, CA; 3 Department of Hematology/Oncology, Children's Hospital and Research Center Oakland, CA; 4 The Pulmonary Center, Boston University School of Medicine, MA; and 5 Boston Comprehensive Sickle Cell Center, Department of Medicine, Boston University School of Medicine, MA Erythrocyte glutathione depletion has been linked to hemolysis and oxidative stress. Glutamine plays an additional antioxidant role through preservation of intracellular nicotinamide adenine dinucleotide phosphate (NADPH) levels, required for glutathione recycling. Decreased nitric oxide (NO) bioavailability, which occurs in the setting of increased hemolysis and oxidative stress, contributes to the pathogenesis of pulmonary hypertension (PH) in sickle cell disease (SCD). We hypothesized that altered glutathione and glutamine metabolism play a role in this process. Total glutathione (and its precursors) and glutamine were assayed in plasma and erythrocytes of 40 SCD patients and 9 healthy volunteers. Erythrocyte total glutathione and glutamine levels were significantly lower in SCD patients than in healthy volunteers. Glutamine depletion was independently associated with PH, defined as a tricuspid regurgitant jet velocity (TRV) of at least 2.5 m/s. The ratio of erythrocyte glutamine:glutamate correlated inversely to TRV (r = – 0.62, P < .001), plasma arginase concentration (r = –0.45, P = ..002), and plasma-free hemoglobin level (r = –0.41, P = .01), linking erythrocyte glutamine depletion to dysregulation of the arginine-NO pathway and increased hemolytic rate. Decreased erythrocyte glutathione and glutamine levels contribute to alterations in the erythrocyte redox environment, which may compromise erythrocyte integrity, contribute to hemolysis, and play a role in the pathogenesis of PH of SCD. Who loves ya. Tom Jesus Was A Vegetarian! http://tinyurl.com/2r2nkh Man Is A Herbivore! http://tinyurl.com/a3cc3 DEAD PEOPLE WALKING http://tinyurl.com/zk9fk > On Aug 3, 7:29 pm, ironjustice <ironjust...(a)aol.com> wrote: hemolysis > and fatigue << > > "May be explained by the very feature they all share, intravascular > hemolysis" > > http://tinyurl.com/6gr5ww > > "We, therefore, propose that paroxysmal nocturnal hemoglobinuria, > sickle cell, thalassemia, red cell membrane disorders, red cell > enzymopathies, thrombotic thrombocytopenic purpura, malaria, > cardiopulmonary bypass, transfusion of aged blood, and alloimmune > hemolysis, may be explained by the very feature they all share, > intravascular hemolysis. " > > Therefore .. iron excess .. because hemolytic anemia is iron loading. > > Who loves ya. > Tom > > Jesus Was A Vegetarian!http://tinyurl.com/2r2nkh > > Man Is A Herbivore!http://tinyurl.com/a3cc3 > > DEAD PEOPLE WALKINGhttp://tinyurl.com/zk9fk > > > > > On Jun 18, 9:47 am, "ironjust...(a)aol.com" <ironjust...(a)aol.com> wrote:fatigueandhemolysis<< > > > IMPROVEMENT INFATIGUEWITH ECULIZUMAB TREATMENT OF PATIENTS WITH > > PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) OCCURS INDEPENDENT OF > > CHANGES IN ANEMIA > > Authors  A. Hill,1 P. Muus,2 U. Dührsen,3 G. Socié,4 A. Risitano,5 R. > > De Paz,6 E. Van den Neste,7 A. Zanella,8 J.S. Lai,9 P. Hillmen,10 R. > > Rother,11 D. Cella9 > > Address  1Teaching Hospitals NHS Foundation Trust, BRADFORD, UK; > > 2Radboud University, NIJMEGEN, Netherlands; 3University Essen, ESSEN, > > Germany; 4Hospital Saint Louis and INSERM, PARIS, France; 5Midiche > > Federico II University of Naple, NAPLES, Italy; 6Hospital De La Paz, > > MADRID, Spain; 7Ucl St. Luc, BRUSSELS, Belgium; 8Ospedale Maggiore di > > Milano, MILAN, Italy; 9Northwestern University and Evanston > > Northwestern Healthcare, EVANSTON, IL, USA; 10Leeds Teaching Hospitals > > NHS Trust, LEEDS, UK; 11Alexion Pharmaceuticals, Inc., CHESHIRE, CT, > > USA > > > Abstract   > > Background. > > In patients with paroxysmal nocturnal hemoglobinuria (PNH), RBCs > > undergo chronic complement-mediatedhemolysisresulting in serious > > sequelae including anemia, thrombosis, pain, dyspnea, poor quality of > > life and disablingfatigue.Fatiguelevels in patients with PNH are > > similar to that experienced by anemic cancer patients, and treatment > > measures to improve anemia can improvefatiguein both disease > > settings. > > In PNH, however,fatigueis also related directly to chronichemolysis. > > Aims. > > To elucidate the contribution ofhemolysisversus anemia to the > > improvement infatiguein eculizumab-treated PNH patients. > > Methods. > > Patient-reportedfatiguewas determined utilizing the Functional > > Assessment of Chronic Illness Therapy (FACIT)-Fatiguescale and anemia > > andhemolysiswere objectively recorded in the double-blind placebo > > controlled phase 3 TRIUMPH and the open label phase 3 SHEPHERD PNH > > studies. The effect of eculizumab treatment onfatiguein PNH patients > > was compared to changes infatiguein anemic cancer patients who > > received EPO using the samefatiguequestionnaire; patients were > > analyzed as 3 strata: >1 g/dL increase; no change; or a >1 g/dL > > decrease in hemoglobin during treatment. Effect sizes (ES) indicating > > large, moderate or small clinical improvements were assessed. > > Results. > > Treatment independent univariate analysis of PNH patients showed that > > intravascularhemolysisreduction (decreased lactate dehydrogenase > > levels) and anemia improvement (increased hemoglobin) were both > > significantly associated withfatigueimprovement (odds ratio 1.11, > > p<0.001 and 1.29, p=0.005, respectively). Further, multivariate > > analysis indicated thathemolysisreduction was predictive of an > > improvement infatigueindependent of an improvement in anemia (1.07, > > p=0.028). Eculizumab treatment was associated with a significant > > improvement infatigueby one week and the improvement has been > > sustained for over two years. The improvement infatiguewas larger > > (p=0.002) in eculizumab-treated anemic PNH patients compared to EPO- > > treated anemic cancer patients. Patients treated with eculizumab > > experienced a large improvement (ES:1.0) when the hemoglobin level > > increased, and a moderatefatigueimprovement when hemoglobin showed > > no change (ES:0.72) or even decreased (ES:0.61). By contrast, patients > > treated with EPO experienced a small improvement in FACIT-Fatigue > > score only when hemoglobin level increased (ES:0.48);fatiguescores > > in EPO treated patients did not change meaningfully when hemoglobin > > levels did not change (ES:0.15) and actually showed worsening when > > hemoglobin levels decreased (ES:-0.33) during treatment (Table 1). > > Summary and conclusions. > > Taken together, these findings suggest that eculizumab-treated PNH > > patients experience a larger improvement infatiguethan EPO-treated > > cancer patients due to the improvement inhemolysiswith eculizumab. > > Also, there is improvement infatiguewith eculizumab that is > > independent of any improvement in anemia. In contrast to the > > observations with EPO in which patients did not experience meaningful > > improvement infatigueunless they also showed an improvement in > > anemia, meaningful improvements infatiguewere experienced with > > eculizumab by both those patients who had an improvement in anemia as > > well as by patients that had no improvement in anemia. Since > > improvement infatiguewith eculizumab is associated with relatively > > rapid reduction inhemolysisand occurs independent of change in > > anemia, eculizumab can benefit a broader PNH patient population than > > those who realize improvement in anemia. > > > Who loves ya. > > Tom > > > Jesus Was A Vegetarian!http://tinyurl.com/2r2nkh > > > Man Is A Herbivore!http://tinyurl.com/a3cc3 > > > DEAD PEOPLE WALKINGhttp://tinyurl.com/zk9fk > > > >http://www.medicalnewstoday.com/articles/111618.php > > > > Soliris,HemolysisandFatiguein PNH > > > >Fatiguelevels in patients with PNH are often severe and similar to > > > those experienced by anemic cancer patients. Soliris previously has > > > been shown to reduce substantially the frequently disablingfatigue > > > associated with PNH. The data presented today provide additional > > > insight into the mechanism through which Soliris positively impacts > > > PNH-relatedfatigue. While treatments designed to improve anemia can > > > improvefatiguein both PNH and cancer, these data demonstrate that > > >fatiguein PNH is also related directly to chronichemolysisand can > > > be improved independent of correction of anemia. Soliris has also been > > > associated with other significant benefits in patients with PNH, > > > including reduction inhemolysisand reduction in thrombotic events > > > during treatment phase compared to the same period of time prior to > > > treatment (see SmPC on EMEA website). (5-7) > > > > In the presentation by Dr. Hill, data on 164 patients with PNH were > > > derived from two Phase 3 studies of Soliris as a treatment for PNH: > > > TRIUMPH, a six-month, double-blind, placebo-controlled study, and > > > SHEPHERD, a 12-month, open-label study. Data on anemic cancer patients > > > were obtained from a published report. (8) Patient-reportedfatiguein > > > both groups of patients was determined utilizing the Functional > > > Assessment of Chronic Illness Therapy (FACIT) -Fatiguescale. Anemia > > > was measured by levels of hemoglobin, andhemolysiswas measured by > > > levels of lactate dehydrogenase (LDH). Key findings included the > > > following: > > > While intravascularhemolysisreduction (decreased LDH) and anemia > > > improvement (increased hemoglobin) were both significantly associated > > > withfatigueimprovement (odds ratio 1.11, P<0.001 and 1.29, P=0.005, > > > respectively),hemolysisreduction was predictive of an improvement in > > >fatigueindependent of an improvement in anemia in patients with PNH > > > (1.07, P=0.028). > > > > The improvement infatiguewas greater (P=0.002) in Soliris-treated > > > PNH patients compared to EPO-treated anemic cancer patients. > > > > When the magnitude of clinical impact was analyzed by using standard > > > descriptors for the Effect Size (ES) measurement offatiguein both > > > groups, (9) > > > > PNH patients treated with Soliris experienced a large improvement in > > >fatigue, (ES: +1.0) when the hemoglobin level increased as compared to > > > anemic cancer patients treated with EPO who experienced only a small > > > improvement infatigue(ES: +0.48) > > > Similarly, PNH patients treated with Soliris experienced a moderate > > > improvement infatigue(ES:+0.72) when hemoglobin levels did not > > > improve compared to EPO-treated anemic cancer patients for whom > > >fatiguescores did not change meaningfully (ES:+0.15) when hemoglobin > > > levels did not improve. > > > Importantly Soliris-treated PNH patients still experienced a moderate > > > improvement infatigue(ES: +0.61) even when hemoglobin levels > > > decreased, while EPO-treated anemic cancer patients experienced a > > > small worsening offatigue(ES:-0.33) when hemoglobin levels > > > decreased. > > > The improvement infatigueassociated with Soliris therapy in clinical > > > trials was observed within the first week of treatment and has been > > > sustained for the duration of the clinical trials. (10) > > > > "As in cancer patients,fatiguein PNH patients is often severe enough > > > to make the ordinary activities of daily life impossible," said > > > Leonard Bell, M.D., Chief Executive Officer of Alexion. "This study > > > indicates that patients can experience life-changing improvements in > > >fatiguewith long-term Soliris therapy regardless of changes in their > > > anemia. This, and the other compelling clinical benefits that Soliris > > > offers patients with PNH, are the basis for our commitment that every > > > patient who can benefit from Soliris should have access to it." > > > > About PNH > > > > PNH is a rare blood disease that affects an estimated 8,000 to 10,000 > > > people in North America and Europe and, using similar prevalence > > > estimates, potentially 1,000 - 2,000 patients in Japan.(11) Although > > > affecting all age groups, PNH often strikes people in the prime of > > > their lives, with an average age of onset in the early 30's. (12) > > > Approximately 10 percent of all patients > > ... > > read more »- Hide quoted text - > > - Show quoted text -
From: ironjustice on 15 Aug 2008 23:40 On Aug 15, 8:17 pm, "ironjust...(a)aol.com" <ironjust...(a)aol.com> "Decreased erythrocyte glutathione and glutamine" These are the primary antioxidants in the cell which can be targeted and REpleted with tocopherol. << "Increased hemolysis could be reversed by administration of tocopherol" PEDIATRICS Vol. 17 No. 4 April 1956, pp. 502 Studies of Tocopherol Deficiency in Infants and Children: I. Hemolysis of Erythrocytes in Hydrogen Peroxide The question of the essentiality of vitamin E in the diet has been the object of study for many years. Recently a method has become available for estimation of tocopherol (vitamin E) in the blood through its prevention of hemolysis of erythrocytes by hydrogen peroxide. The method is applicable to 0.2 ml. of blood. The hemolysis test was applied to the blood of 282 normal full-term newborn infants and 67 premature infants. Additional determinations were performed in young well babies who had been born at term and others born prematurely ranging in age from a few days to approximately 3 months. The test was also applied to blood obtained from a variety of diseases including examples of steatorrhea. A large proportion of the normal newborn and premature infants showed more than 50 per cent hemolysis as compared with normal adults in which hemolysis is uniformly less than 10 per cent. Administration of tocopherol in those tested led to prompt reversal of the test in newborns and prematures to values comparable to those found in adults. Infants fed cows' milk formulae showed significantly less hemolysis at an average age of 7 weeks and infants who were breast fed showed still less hemolysis at the same average age. Infants and children with steatorrhea showed increased hemolysis which could be reversed by administration of tocopherol. Significant hemolysis was not found in the infants and children with a variety of other diseases. The significance of these findings is discussed and a cautious attitude is expressed towards taking these results to indicate the desirability of supplementing the diets of artifically fed infants with tocopherol. Who loves ya. Tom Jesus Was A Vegetarian! http://tinyurl.com/2r2nkh Man Is A Herbivore! http://tinyurl.com/a3cc3 DEAD PEOPLE WALKING http://tinyurl.com/zk9fk > On Aug 15, 8:06 pm, ironjustice <ironjust...(a)aol.com> wrote:hemolysis > and fatigue << > > "Decreased erythrocyte glutathione and glutamine" > > These are the primary antioxidants in the cell which can be targeted > and REpleted with tocopherol. > BUT if there is an increased LIP / labile iron pool .. in the cell .. > tocopherol is unable to accomplish this. > One must target the same 'vicinity' OF the glutathione **because OF** > the increased iron. > Soooo .. again .. after the cows have gone. The iron must be removed > in order to accomplish a healthy red blood cell. > This has been shown to be accomplished with a very low iron state in > those that suffer from the above diseases. > > Blood, 1 January 2008, Vol. 111, No. 1, pp. 402-410. > Prepublished online as a Blood First Edition Paper on September 11, > 2007; DOI 10.1182/blood-2007-04-081703. > > Erythrocyte glutamine depletion, altered redox environment, and > pulmonary hypertension in sickle cell disease > Claudia R. Morris1, Jung H. Suh2, Ward Hagar3, Sandra Larkin2, D. > Anton Bland4, Martin H. Steinberg5, Elliott P. Vichinsky3, Mark > Shigenaga2, Bruce Ames2, Frans A. Kuypers2, and Elizabeth S. > Klings4,5 > 1 Department of Emergency Medicine, Children's Hospital and Research > Center Oakland, CA; 2 Children's Hospital Oakland Research Institute, > CA; 3 Department of Hematology/Oncology, Children's Hospital and > Research Center Oakland, CA; 4 The Pulmonary Center, Boston University > School of Medicine, MA; and 5 Boston Comprehensive Sickle Cell Center, > Department of Medicine, Boston University School of Medicine, MA > > Erythrocyte glutathione depletion has been linked to hemolysis and > oxidative stress. Glutamine plays an additional antioxidant role > through preservation of intracellular nicotinamide adenine > dinucleotide phosphate (NADPH) levels, required for glutathione > recycling. Decreased nitric oxide (NO) bioavailability, which occurs > in the setting of increased hemolysis and oxidative stress, > contributes to the pathogenesis of pulmonary hypertension (PH) in > sickle cell disease (SCD). We hypothesized that altered glutathione > and glutamine metabolism play a role in this process. Total > glutathione (and its precursors) and glutamine were assayed in plasma > and erythrocytes of 40 SCD patients and 9 healthy volunteers. > Erythrocyte total glutathione and glutamine levels were significantly > lower in SCD patients than in healthy volunteers. Glutamine depletion > was independently associated with PH, defined as a tricuspid > regurgitant jet velocity (TRV) of at least 2.5 m/s. The ratio of > erythrocyte glutamine:glutamate correlated inversely to TRV (r = – > 0.62, P < .001), plasma arginase concentration (r = –0.45, P = .002), > and plasma-free hemoglobin level (r = –0.41, P = .01), linking > erythrocyte glutamine depletion to dysregulation of the arginine-NO > pathway and increased hemolytic rate. Decreased erythrocyte > glutathione and glutamine levels contribute to alterations in the > erythrocyte redox environment, which may compromise erythrocyte > integrity, contribute to hemolysis, and play a role in the > pathogenesis of PH of SCD. > > Who loves ya. > Tom > > Jesus Was A Vegetarian!http://tinyurl.com/2r2nkh > > Man Is A Herbivore!http://tinyurl.com/a3cc3 > > DEAD PEOPLE WALKINGhttp://tinyurl.com/zk9fk > > > > > On Aug 3, 7:29 pm, ironjustice <ironjust...(a)aol.com> wrote: hemolysis > > and fatigue << > > > "May be explained by the very feature they all share, intravascular > > hemolysis" > > >http://tinyurl.com/6gr5ww > > > "We, therefore, propose that paroxysmal nocturnal hemoglobinuria, > > sickle cell, thalassemia, red cell membrane disorders, red cell > > enzymopathies, thrombotic thrombocytopenic purpura, malaria, > > cardiopulmonary bypass, transfusion of aged blood, and alloimmune > > hemolysis, may be explained by the very feature they all share, > > intravascular hemolysis. " > > > Therefore .. iron excess .. because hemolytic anemia is iron loading. > > > Who loves ya. > > Tom > > > Jesus Was A Vegetarian!http://tinyurl.com/2r2nkh > > > Man Is A Herbivore!http://tinyurl.com/a3cc3 > > > DEAD PEOPLE WALKINGhttp://tinyurl.com/zk9fk > > > > On Jun 18, 9:47 am, "ironjust...(a)aol.com" <ironjust...(a)aol.com> wrote:fatigueandhemolysis<< > > > > IMPROVEMENT INFATIGUEWITH ECULIZUMAB TREATMENT OF PATIENTS WITH > > > PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) OCCURS INDEPENDENT OF > > > CHANGES IN ANEMIA > > > Authors  A. Hill,1 P. Muus,2 U. Dührsen,3 G. Socié,4 A. Risitano,5 R. > > > De Paz,6 E. Van den Neste,7 A. Zanella,8 J.S. Lai,9 P. Hillmen,10 R. > > > Rother,11 D. Cella9 > > > Address  1Teaching Hospitals NHS Foundation Trust, BRADFORD, UK; > > > 2Radboud University, NIJMEGEN, Netherlands; 3University Essen, ESSEN, > > > Germany; 4Hospital Saint Louis and INSERM, PARIS, France; 5Midiche > > > Federico II University of Naple, NAPLES, Italy; 6Hospital De La Paz, > > > MADRID, Spain; 7Ucl St. Luc, BRUSSELS, Belgium; 8Ospedale Maggiore di > > > Milano, MILAN, Italy; 9Northwestern University and Evanston > > > Northwestern Healthcare, EVANSTON, IL, USA; 10Leeds Teaching Hospitals > > > NHS Trust, LEEDS, UK; 11Alexion Pharmaceuticals, Inc., CHESHIRE, CT, > > > USA > > > > Abstract   > > > Background. > > > In patients with paroxysmal nocturnal hemoglobinuria (PNH), RBCs > > > undergo chronic complement-mediatedhemolysisresulting in serious > > > sequelae including anemia, thrombosis, pain, dyspnea, poor quality of > > > life and disablingfatigue.Fatiguelevels in patients with PNH are > > > similar to that experienced by anemic cancer patients, and treatment > > > measures to improve anemia can improvefatiguein both disease > > > settings. > > > In PNH, however,fatigueis also related directly to chronichemolysis. > > > Aims. > > > To elucidate the contribution ofhemolysisversus anemia to the > > > improvement infatiguein eculizumab-treated PNH patients. > > > Methods. > > > Patient-reportedfatiguewas determined utilizing the Functional > > > Assessment of Chronic Illness Therapy (FACIT)-Fatiguescale and anemia > > > andhemolysiswere objectively recorded in the double-blind placebo > > > controlled phase 3 TRIUMPH and the open label phase 3 SHEPHERD PNH > > > studies. The effect of eculizumab treatment onfatiguein PNH patients > > > was compared to changes infatiguein anemic cancer patients who > > > received EPO using the samefatiguequestionnaire; patients were > > > analyzed as 3 strata: >1 g/dL increase; no change; or a >1 g/dL > > > decrease in hemoglobin during treatment. Effect sizes (ES) indicating > > > large, moderate or small clinical improvements were assessed. > > > Results. > > > Treatment independent univariate analysis of PNH patients showed that > > > intravascularhemolysisreduction (decreased lactate dehydrogenase > > > levels) and anemia improvement (increased hemoglobin) were both > > > significantly associated withfatigueimprovement (odds ratio 1.11, > > > p<0.001 and 1.29, p=0.005, respectively). Further, multivariate > > > analysis indicated thathemolysisreduction was predictive of an > > > improvement infatigueindependent of an improvement in anemia (1.07, > > > p=0.028). Eculizumab treatment was associated with a significant > > > improvement infatigueby one week and the improvement has been > > > sustained for over two years. The improvement infatiguewas larger > > > (p=0.002) in eculizumab-treated anemic PNH patients compared to EPO- > > > treated anemic cancer patients. Patients treated with eculizumab > > > experienced a large improvement (ES:1.0) when the hemoglobin level > > > increased, and a moderatefatigueimprovement when hemoglobin showed > > > no change (ES:0.72) or even decreased (ES:0.61). By contrast, patients > > > treated with EPO experienced a small improvement in FACIT-Fatigue > > > score only when hemoglobin level increased (ES:0.48);fatiguescores > > > in EPO treated patients did not change meaningfully when hemoglobin > > > levels did not change (ES:0.15) and actually showed worsening when > > > hemoglobin levels decreased (ES:-0.33) during treatment (Table 1). > > > Summary and conclusions. > > > Taken together, these findings suggest that eculizumab-treated PNH > > > patients experience a larger improvement infatiguethan EPO-treated > > > cancer patients due to the improvement inhemolysiswith eculizumab. > > > Also, there is improvement infatiguewith eculizumab that is > > > independent of any improvement in anemia. In contrast to the > > > observations with EPO in which patients did not experience meaningful > > > improvement infatigueunless they also showed an improvement in > > > anemia, meaningful improvements infatiguewere experienced with > > > eculizumab by both those patients who had an improvement in anemia as > > > well as by patients that had no improvement in anemia. Since > > > improvement infatiguewith eculizumab is associated with relatively > > > rapid reduction inhemolysisand occurs independent of change in > > > anemia, eculizumab can benefit a broader PNH patient population than > > > those who realize improvement in anemia. > > > > Who loves ya. > > > Tom > > > > Jesus Was A Vegetarian!http://tinyurl.com/2r2nkh > > > > Man Is A Herbivore!http://tinyurl.com/a3cc3 > > > > DEAD PEOPLE WALKINGhttp://tinyurl.com/zk9fk > > > > >http://www.medicalnewstoday.com/articles/111618.php > > > > > Soliris,HemolysisandFatiguein PNH > > > > >Fatiguelevels in patients with PNH are often severe and similar to > > > > those experienced by anemic cancer patients. Soliris previously has > > > > been shown to reduce substantially the frequently disablingfatigue > > > > associated with PNH. The data presented today provide additional > > > > insight into the mechanism through which Soliris positively impacts > > > > PNH-relatedfatigue. While treatments designed to improve anemia can > > > > improvefatiguein both PNH and cancer, these data demonstrate that > > > >fatiguein PNH is also related directly to chronichemolysisand can > > > > be improved independent of correction of anemia. Soliris has also been > > > > associated with other significant benefits in patients with PNH, > > > > including reduction inhemolysisand reduction in thrombotic events > > > > during treatment phase compared > > ... > > read more »- Hide quoted text - > > - Show quoted text -
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