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3,7-Dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione Primary use in medicine is in treating the symptoms of intermittent claudication resulting from peripheral artery disease.
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</br> Recent investigations have revealed that erythrocytes from patients with chronic arterial occlusive disease are significantly less deformable than red blood cells from healthy subjects. The influence of pentoxifylline on red blood cell fluidity was measured by a standard filtration technique using 8 micron membrane filters. Impaired deformability of erythrocytes was significantly improved in patients suffering from peripheral vascular disorders following intravenous injection of 200 mg pentoxifylline. Studies on reduced red cell deformability induced by hyperosmolarity in vitro showed that pentoxifylline (4 and 20 microgram/ml) produced a dose-dependent improvement both in blood from healthy subjects and from patients with peripheral arterial occlusive disease. The results suggest that the positive therapeutic effect of pentoxifylline in peripheral arterial occlusive disease is mediated by improving red cell fluidity in the microcirculation.
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</br> At least two investigators have demonstrated a reduction in O2 extraction during induced hypothermia (Cain and Bradley, J. Appl. Physiol. 55: 1713-1717, 1983; Schumacker et al., J. Appl. Physiol. 63: 1246-1252, 1987). We hypothesized that administration of pentoxiphylline (PTX), a theobromine that lowers blood viscosity and has vasodilator effects, would increase O2 extraction during hypothermia. To test this hypothesis, we studied O2 transport in anesthetized, paralyzed, mechanically ventilated beagles exposed to hypoxic hypoxia during either 1) normothermia (38 degrees C), 2) hypothermia (30 degrees C), or 3) hypothermia + PTX (30 degrees C and PTX, 20 mg.kg-1.h-1). Measurements included arterial and mixed venous PO2, hemoglobin concentration and saturation, cardiac output, systemic vascular resistance (SVR), blood viscosity, and O2 consumption (VO2). Critical levels of O2 delivery (DO2, the product of arterial O2 content and cardiac output) were determined by a system of linear regression. Hypothermia significantly decreased base line cardiac output (-35%), DO2 (-37%), and VO2 (-45%), while increasing SVR and blood viscosity. Addition of PTX increased cardiac output (35%) and VO2 (14%), and returned SVR and blood viscosity to normothermic levels. Hypothermia alone failed to significantly reduce the critical level of DO2, but addition of PTX did [normothermia, 11.4 +/- 4.2 (SD) ml.kg-1.min-1; hypothermia, 9.3 +/- 3.6; hypothermia + PTX, 6.6 +/- 1.3; P less than 0.05, analysis of variance]. The O2 extraction ratio (VO2/DO2) at the critical level of DO2 was decreased during hypothermia alone (normothermia, 0.60 +/- 0.13; hypothermia, 0.42 +/- 0.16; hypothermia + PTX, 0.62 +/- 0.19; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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</br> Pentoxifylline improves haemoglobin and interleukin-6 levels in chronic kidney disease. To assess whether pentoxifylline improves anaemia of chronic kidney disease (CKD) via suppression of interleukin-6 (IL-6) and improved iron mobilization. BACKGROUND: CKD patients may have elevated IL-6 and tumour necrosis factor alpha levels. These cytokines can increase hepcidin production, which in turn reduces iron release from macrophages resulting in reduced availability of iron for erythropoiesis. In experimental models, pentoxifylline was shown to reduce IL-6 expression. METHODS: We studied 14 patients with stages 4-5 CKD (glomerular filtration rate <30mL/min per 1.73 m(2)) due to non-inflammatory renal diseases. None of the patients had received immunosuppressive or erythropoietin-stimulating agents or parenteral iron. Patients had weekly blood tests for iron studies and cytokines during a control run-in period of 3 weeks and during 4 weeks of pentoxifylline treatment. RESULTS: Ten patients (eGFR 23 + or – 6 mL/min) completed the study. At the end of the run-in period average haemoglobin was 111 + or – 5 g/L, ferritin 92 + or – 26 microg/L, transferrin saturation 15 + or – 3% and circulating IL-6 10.6 + or – 3.8 pg/mL. Tumour necrosis factor alpha values were below threshold for detection. Treatment with pentoxifylline reduced circulating IL-6 (6.6 + or – 1.6 pg/mL, P < 0.01), increased transferrin saturation (20 + or – 5%, P < 0.003) and decreased serum ferritin (81 + or – 25 microg/L, P = NS). Haemoglobin increased after the second week of pentoxifylline, reaching 123 + or – 6 g/L by week 4 (P < 0.001). CONCLUSIONS: Pentoxifylline reduces circulating IL-6 and improves haemoglobin in non-inflammatory moderate to severe CKD. These changes are associated with changes in circulating transferrin saturation and ferritin, suggesting improved iron release. It is hypothesized that pentoxifylline improves iron disposition possibly through modulation of hepcidin.
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</br> Effects of pentoxifylline on oxidative stress and levels of EGF and NO in blood of diabetic type-2 patients; a randomized, double-blind placebo-controlled clinical trial.
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</br> BACKGROUND: As oxidative stress contributes to both progression and pathologic complications of diabetes and effective therapeutic strategies to prevent or delay the damage remain limited, the aim of the present study was to assess the efficacy of pentoxifylline in reducing of oxidative stress. Since there is a relationship between nitric oxide (NO), epidermal growth factor (EGF) and oxidative stress, we measured the effect of this drug on these parameters in comparison to placebo. METHODS: Thirty-nine patients with type-2 diabetes mellitus were randomized in a double blind, placebo-controlled clinical trial to receive either pentoxifylline 400 mg four times a day or placebo for 14 days. Blood samples were obtained at baseline and at the end of the study. Samples were analyzed for thiobarbituric reactive substances (TBARS) as a marker of lipid peroxidation, ferric reducing ability (total antioxidant power, TAP), EGF and NO levels. RESULTS: Pentoxifylline in comparison to placebo was effective (P < 0.05) in reduction of lipid peroxidation in plasma of the patients without significant effects on TAP, levels of EGF and NO in plasma. CONCLUSION: Adding of pentoxifylline to drug regimen of diabetic type-2 patients can be helpful. Exact mechanism of action of pentoxifylline in reduction of blood lipid peroxidation remains to be elucidated.
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</br> ABSTRACT. It was hypothesized that pentoxifylline might improve the response to recombinant human erythropoietin (rh-Epo) in anemic renal failure patients. Sixteen patients with ESRD and rh-Epo-resistant anemia, defined by a hemoglobin of <10.7 g/dl for 6 mo before treatment and a rh-Epo dose of ≥12,000 IU/wk, were recruited. They were treated with oral pentoxifylline 400 mg o.d. for 4 mo. Ex vivo T cell generation of tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) from the patients was assessed before treatment and 6 to 8 wk after therapy. A total of 12 of 16 patients completed the study. Before therapy, the 12 patients’ mean hemoglobin concentration was 9.5 ± 0.9 g/dl. After 4 mo of pentoxifylline treatment, the mean hemoglobin concentration increased to 11.7 ± 1.0 g/dl (P = 0.0001). Baseline ex vivo T cell expression of TNF-α decreased from 58% ± 11% to 31% ± 23% (P = 0.0007) after therapy. Likewise, IFN-γ expression decreased from 31% ± 10% to 13% ± 10% (P = 0.0002). Pentoxifylline therapy may significantly improve the hemoglobin response in patients with previously rh-Epo-resistant anemia in renal failure. This may occur due to inhibition of proinflammatory cytokine production, which could interfere with the effectiveness of rh-Epo.
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</br> The widespread use of recombinant erythropoietin (rh-Epo) has transformed the management of anemia in ESRD. Hemoglobin concentration improves in 90% to 95% of patients treated. Nevertheless, there is a small but important minority of patients who show an inadequate response to rh-Epo, and in a subset of these, no obvious cause (such as iron deficiency) can be found (1). Failure to respond to rh-Epo may be due to enhanced immune activation, which is known to occur in renal failure patients (2,3). Some proinflammatory cytokines (IFN-γ, TNF-α, and IL-1) suppress erythropoiesis in vitro (4,5). We have recently shown that T cells from renal failure patients responding poorly to rh-Epo generate more IFN-γ and TNF-α compared with both good responders to rh-Epo and healthy controls (6).
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</br> Pentoxifylline has been used for more than 20 yr in the treatment of peripheral vascular disease because of its potent hemorrheological properties (7). Subsequently, pentoxifylline was found to have antiinflammatory properties, mediated via inhibition of phosphodiesterase (8). In vitro, pentoxifylline inhibits monocyte production of TNF-α (9) and T cell production of IFN-γ (10,11). TNF-α is thought to play a central role in the pathogenesis of many diseases, prompting the experimental use of pentoxifylline in a number of clinical trials. Beneficial effects have been reported in idiopathic dilated cardiomyopathy (12), childhood type 1 diabetes (13), and systemic vasculitis (14–16). Modest clinical effects have also been observed in rheumatoid arthritis (17). To date, however, this drug has not been tested in patients with rh-Epo-resistant anemia, and the aim of the study presented here was to test the hypothesis that pentoxifylline inhibits proinflammatory cytokine production in vivo
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</br> Maximum heart rate declines at high altitude, presumably due to hypoxic depression of the heart. Pentoxifylline, a Theologically active drug, increases maximum heart rate at high altitude. We tested the hypothesis that pentoxifylline increases oxygen saturation of arterial blood, which for coronary arterial blood could explain the chronotropic effect. The study was conducted in Sikkim. Twelve subjects were tested at 2100 m, 2730 m, and 4600 m altitude. In a double blind protocol, 6 subjects took pentoxifylline (1200 mg per day) each day for five weeks before and during the study. Control subjects (n=6) took a placebo. The most important finding was a significantly higher resting arterial saturation at 4600 m in the subjects taking pentoxifylline (80.7% versus 75.4% in the control group). Possible mechanisms of this action of pentoxifylline include improved pulmonary gas exchange.
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</br> Recent investigations have revealed that erythrocytes from patients with chronic arterial occlusive disease are significantly less deformable than red blood cells from healthy subjects. The influence of pentoxifylline on red blood cell fluidity was measured by a standard filtration technique using 8 micron membrane filters. Impaired deformability of erythrocytes was significantly improved in patients suffering from peripheral vascular disorders following intravenous injection of 200 mg pentoxifylline. Studies on reduced red cell deformability induced by hyperosmolarity in vitro showed that pentoxifylline (4 and 20 microgram/ml) produced a dose-dependent improvement both in blood from healthy subjects and from patients with peripheral arterial occlusive disease. The results suggest that the positive therapeutic effect of pentoxifylline in peripheral arterial occlusive disease is mediated by improving red cell fluidity in the microcirculation.
</br>
</br> At least two investigators have demonstrated a reduction in O2 extraction during induced hypothermia (Cain and Bradley, J. Appl. Physiol. 55: 1713-1717, 1983; Schumacker et al., J. Appl. Physiol. 63: 1246-1252, 1987). We hypothesized that administration of pentoxiphylline (PTX), a theobromine that lowers blood viscosity and has vasodilator effects, would increase O2 extraction during hypothermia. To test this hypothesis, we studied O2 transport in anesthetized, paralyzed, mechanically ventilated beagles exposed to hypoxic hypoxia during either 1) normothermia (38 degrees C), 2) hypothermia (30 degrees C), or 3) hypothermia + PTX (30 degrees C and PTX, 20 mg.kg-1.h-1). Measurements included arterial and mixed venous PO2, hemoglobin concentration and saturation, cardiac output, systemic vascular resistance (SVR), blood viscosity, and O2 consumption (VO2). Critical levels of O2 delivery (DO2, the product of arterial O2 content and cardiac output) were determined by a system of linear regression. Hypothermia significantly decreased base line cardiac output (-35%), DO2 (-37%), and VO2 (-45%), while increasing SVR and blood viscosity. Addition of PTX increased cardiac output (35%) and VO2 (14%), and returned SVR and blood viscosity to normothermic levels. Hypothermia alone failed to significantly reduce the critical level of DO2, but addition of PTX did [normothermia, 11.4 +/- 4.2 (SD) ml.kg-1.min-1; hypothermia, 9.3 +/- 3.6; hypothermia + PTX, 6.6 +/- 1.3; P less than 0.05, analysis of variance]. The O2 extraction ratio (VO2/DO2) at the critical level of DO2 was decreased during hypothermia alone (normothermia, 0.60 +/- 0.13; hypothermia, 0.42 +/- 0.16; hypothermia + PTX, 0.62 +/- 0.19; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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</br> Pentoxifylline improves haemoglobin and interleukin-6 levels in chronic kidney disease. To assess whether pentoxifylline improves anaemia of chronic kidney disease (CKD) via suppression of interleukin-6 (IL-6) and improved iron mobilization. BACKGROUND: CKD patients may have elevated IL-6 and tumour necrosis factor alpha levels. These cytokines can increase hepcidin production, which in turn reduces iron release from macrophages resulting in reduced availability of iron for erythropoiesis. In experimental models, pentoxifylline was shown to reduce IL-6 expression. METHODS: We studied 14 patients with stages 4-5 CKD (glomerular filtration rate <30mL/min per 1.73 m(2)) due to non-inflammatory renal diseases. None of the patients had received immunosuppressive or erythropoietin-stimulating agents or parenteral iron. Patients had weekly blood tests for iron studies and cytokines during a control run-in period of 3 weeks and during 4 weeks of pentoxifylline treatment. RESULTS: Ten patients (eGFR 23 + or – 6 mL/min) completed the study. At the end of the run-in period average haemoglobin was 111 + or – 5 g/L, ferritin 92 + or – 26 microg/L, transferrin saturation 15 + or – 3% and circulating IL-6 10.6 + or – 3.8 pg/mL. Tumour necrosis factor alpha values were below threshold for detection. Treatment with pentoxifylline reduced circulating IL-6 (6.6 + or – 1.6 pg/mL, P < 0.01), increased transferrin saturation (20 + or – 5%, P < 0.003) and decreased serum ferritin (81 + or – 25 microg/L, P = NS). Haemoglobin increased after the second week of pentoxifylline, reaching 123 + or – 6 g/L by week 4 (P < 0.001). CONCLUSIONS: Pentoxifylline reduces circulating IL-6 and improves haemoglobin in non-inflammatory moderate to severe CKD. These changes are associated with changes in circulating transferrin saturation and ferritin, suggesting improved iron release. It is hypothesized that pentoxifylline improves iron disposition possibly through modulation of hepcidin.
</br>
</br> Effects of pentoxifylline on oxidative stress and levels of EGF and NO in blood of diabetic type-2 patients; a randomized, double-blind placebo-controlled clinical trial.
</br>
</br> BACKGROUND: As oxidative stress contributes to both progression and pathologic complications of diabetes and effective therapeutic strategies to prevent or delay the damage remain limited, the aim of the present study was to assess the efficacy of pentoxifylline in reducing of oxidative stress. Since there is a relationship between nitric oxide (NO), epidermal growth factor (EGF) and oxidative stress, we measured the effect of this drug on these parameters in comparison to placebo. METHODS: Thirty-nine patients with type-2 diabetes mellitus were randomized in a double blind, placebo-controlled clinical trial to receive either pentoxifylline 400 mg four times a day or placebo for 14 days. Blood samples were obtained at baseline and at the end of the study. Samples were analyzed for thiobarbituric reactive substances (TBARS) as a marker of lipid peroxidation, ferric reducing ability (total antioxidant power, TAP), EGF and NO levels. RESULTS: Pentoxifylline in comparison to placebo was effective (P < 0.05) in reduction of lipid peroxidation in plasma of the patients without significant effects on TAP, levels of EGF and NO in plasma. CONCLUSION: Adding of pentoxifylline to drug regimen of diabetic type-2 patients can be helpful. Exact mechanism of action of pentoxifylline in reduction of blood lipid peroxidation remains to be elucidated.
</br>
</br> ABSTRACT. It was hypothesized that pentoxifylline might improve the response to recombinant human erythropoietin (rh-Epo) in anemic renal failure patients. Sixteen patients with ESRD and rh-Epo-resistant anemia, defined by a hemoglobin of <10.7 g/dl for 6 mo before treatment and a rh-Epo dose of ≥12,000 IU/wk, were recruited. They were treated with oral pentoxifylline 400 mg o.d. for 4 mo. Ex vivo T cell generation of tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) from the patients was assessed before treatment and 6 to 8 wk after therapy. A total of 12 of 16 patients completed the study. Before therapy, the 12 patients’ mean hemoglobin concentration was 9.5 ± 0.9 g/dl. After 4 mo of pentoxifylline treatment, the mean hemoglobin concentration increased to 11.7 ± 1.0 g/dl (P = 0.0001). Baseline ex vivo T cell expression of TNF-α decreased from 58% ± 11% to 31% ± 23% (P = 0.0007) after therapy. Likewise, IFN-γ expression decreased from 31% ± 10% to 13% ± 10% (P = 0.0002). Pentoxifylline therapy may significantly improve the hemoglobin response in patients with previously rh-Epo-resistant anemia in renal failure. This may occur due to inhibition of proinflammatory cytokine production, which could interfere with the effectiveness of rh-Epo.
</br>
</br> The widespread use of recombinant erythropoietin (rh-Epo) has transformed the management of anemia in ESRD. Hemoglobin concentration improves in 90% to 95% of patients treated. Nevertheless, there is a small but important minority of patients who show an inadequate response to rh-Epo, and in a subset of these, no obvious cause (such as iron deficiency) can be found (1). Failure to respond to rh-Epo may be due to enhanced immune activation, which is known to occur in renal failure patients (2,3). Some proinflammatory cytokines (IFN-γ, TNF-α, and IL-1) suppress erythropoiesis in vitro (4,5). We have recently shown that T cells from renal failure patients responding poorly to rh-Epo generate more IFN-γ and TNF-α compared with both good responders to rh-Epo and healthy controls (6).
</br>
</br> Pentoxifylline has been used for more than 20 yr in the treatment of peripheral vascular disease because of its potent hemorrheological properties (7). Subsequently, pentoxifylline was found to have antiinflammatory properties, mediated via inhibition of phosphodiesterase (8). In vitro, pentoxifylline inhibits monocyte production of TNF-α (9) and T cell production of IFN-γ (10,11). TNF-α is thought to play a central role in the pathogenesis of many diseases, prompting the experimental use of pentoxifylline in a number of clinical trials. Beneficial effects have been reported in idiopathic dilated cardiomyopathy (12), childhood type 1 diabetes (13), and systemic vasculitis (14–16). Modest clinical effects have also been observed in rheumatoid arthritis (17). To date, however, this drug has not been tested in patients with rh-Epo-resistant anemia, and the aim of the study presented here was to test the hypothesis that pentoxifylline inhibits proinflammatory cytokine production in vivo
</br>
</br> Maximum heart rate declines at high altitude, presumably due to hypoxic depression of the heart. Pentoxifylline, a Theologically active drug, increases maximum heart rate at high altitude. We tested the hypothesis that pentoxifylline increases oxygen saturation of arterial blood, which for coronary arterial blood could explain the chronotropic effect. The study was conducted in Sikkim. Twelve subjects were tested at 2100 m, 2730 m, and 4600 m altitude. In a double blind protocol, 6 subjects took pentoxifylline (1200 mg per day) each day for five weeks before and during the study. Control subjects (n=6) took a placebo. The most important finding was a significantly higher resting arterial saturation at 4600 m in the subjects taking pentoxifylline (80.7% versus 75.4% in the control group). Possible mechanisms of this action of pentoxifylline include improved pulmonary gas exchange.
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