Home About us Contact
|
Home About us Contact | ||
|
|
||
Pentoxifylline
Selected AbstractsNew and innovative therapies for Behcet's diseaseINTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 2 2004Fereydoun DAVATCHI Abstract Background:, Behcet's disease (BD) is a vasculitis progressing by attacks and remissions. Not all patients will respond even to the classical treatments. New treatments are emerging with the hope to overcome this failure. Biologic agents:, Interferon-, (IFN-,), anti-tumour necrosis factor-, (TNF-,), and tolerization have been used in BD. IFN-, is mainly used for ocular manifestations of BD. The result seems impressive, 92% of cases had good or excellent results. It was less impressive for mucocutaneous and joint manifestations. The dosage is 6,9 million IU/day for 4 weeks, then 4.5 million daily for 4 weeks, and then 3 million/day. The maintenance dose is 3 millions, three times/week, to continue for 8 weeks after complete remission. Etanercept (anti-TNF-,) was effective in mucocutaneous lesions of BD at the dosage of 25 mg twice weekly for 3 months (double-blind control study). Attacks relapsed after discontinuation. Etanercept was ineffective in ocular lesions (open study). Infliximab (anti-TNF-,) was very effective in many studies of ocular lesions. It dramatically suppressed the inflammatory attack. The dosage is one injection of 5 mg/kg (intravenous infusion) at weeks 0, 2, 6, and then every 8 weeks. Tolerization with oral administration of HSP peptide 336,351 seems to protect from uveitis relapse. Pentoxifylline is not particularly effective unless for oral aphthae (50% response rate). Pimecrolimus ointment may be of help in resistant genital aphthosis, reducing the healing time. [source] The Effects of Pentoxifylline on the Myocardial Inflammation and Ischemia-Reperfusion Injury During Cardiopulmonary BypassJOURNAL OF CARDIAC SURGERY, Issue 1 2006Hasim Ustunsoy M.D. The aim of this study is to investigate whether the addition of Ptx into the cardioplegic solutions avoids myocardial inflammatory reactions and ischemia/reperfusion (I/R) injury during extracorpereal circulation. Methods: Between December 1999 and February 2002, we operated 75 patients with the diagnoses of atrial septal defect (ASD), ventricular septal defect (VSD), valve disease, and coronary disease. The average age of patients was 42.4 and male,female ratio was 1: 1.5. The patients were divided into two groups, which were the study group (n = 40) and the control group (n = 35). We used cold blood cardioplegia mixed with St. Thomas' Hospital II cardioplegic solution for both of the groups. Ptx was added into the cardioplegic solution (500 mg/L) in the study group. Interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrotisis factor-, (TNF-,) levels in coronary sinus blood samples during cross-clamp time (X-clamp) and after releasing of it and tissue TNF-, in the right atrial appendix biopsy material that was taken after X-clamp were studied to compare the both groups. Results: After releasing X-clamp, results of blood TNF-,, IL-6, and IL-8 of both groups were statistically significant (p < 0.005). At the pathological examination, we also observed that the amount of tissue TNF-, in the control group (66 ± 17.1) was much higher than the study group (16.6 ± 5.9, p <0.005). Conclusions: These results show that Ptx may be added into cardioplegic solution to avoid the myocardial inflammation and I/R injury during open heart surgery. [source] Effects of pentoxifylline on coagulation profile and disseminated intravascular coagulation incidence in Egyptian septic neonatesJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2010M. Adel Msc Summary Background and objectives:, Neonatal sepsis is frequently associated with pathological activation of the coagulation system, leading to microcirculatory derangement and multiple organ dysfunction syndrome (MODS). The key role in the pathogenesis of sepsis has been attributed to proinflammatory cytokines. These trigger the development of disseminated intravascular coagulation (DIC) via the tissue factor-dependent pathway of coagulation. Pentoxifylline (PTX), a methylxanthine derivative that is used in peripheral vascular disease, has the potential to modify inflammatory response. The current work was designed to evaluate the potential protective effects of PTX against sepsis-induced microcirculatory derangement in Egyptian neonates. Methods:, A double-blind placebo-controlled quasi-randomized design was used. Thirty-seven neonates with sepsis were randomly allocated into two groups. Seventeen patients were given PTX (5 mg/kg/h for 6 h; for 6 successive days). Twenty patients received equivalent volume of normal saline and represented the placebo group. Prothrombin time (PT), Activated partial thromboplastin time (APTT), fibrinogen, d -dimer, C-reactive protein (CRP), complete blood count (CBC), also hemodynamic parameters comprising arterial blood pressure, heart rate, capillary refill and urinary output were assessed in both groups before and after treatment. Results:, Coagulation parameters in the two groups showed no significant differences. However, a higher incidence of DIC was observed in the placebo group neonates. PTX significantly lowered the percentage of bleeding (P = 0·0128) and less frequent use of FFP was observed in the PTX group (35·53% in PTX group vs. 80% in placebo group, P = 0·003). Incidence of MODS was significantly lower (P = 0·037) and hospital stay duration of survivors was significantly shorter (P = 0·044) in the PTX treated-infants. Conclusion:, Pentoxifylline protects against sepsis-induced microcirculatory derangement in neonates. It significantly lowered the incidence of bleeding and MODS and shortened the length of hospital stay. [source] Pilot study of pentoxifylline in hepatopulmonary syndrome,LIVER TRANSPLANTATION, Issue 8 2008Rajasekhar Tanikella Hepatopulmonary syndrome (HPS) results when chronic liver disease or portal hypertension causes intrapulmonary microvascular dilatation with hypoxemia. In experimental HPS, tumor necrosis factor alpha (TNF-,) overproduction contributes to vasodilatation, which is improved by pentoxifylline, a TNF-, inhibitor. The effectiveness of pentoxifylline in humans is unknown. The aim of this open-label, single-arm clinical trial was to assess the efficacy and tolerability of pentoxifylline in patients with cirrhosis and advanced HPS undergoing liver transplantation evaluation. Nine adults with cirrhosis and moderate to severe HPS were enrolled. All patients had an initial 2-week titration to a target dose of pentoxifylline of 400 mg by mouth every 8 hours, which was continued for 6 weeks. Baseline and follow-up arterial blood gases and TNF-, levels were evaluated. Adverse effects and tolerability were assessed. The 9 patients had a mean age of 55 ± 10 years, and 67% were female. The most common causes of cirrhosis were hepatitis C virus and alcohol (55%). The mean Model for End-Stage Liver Disease score was 11 (range, 6-19), and patients had advanced hypoxemia [mean partial pressure of arterial oxygen (PaO2) = 54 ± 12 mm Hg, mean alveolar-arterial oxygen gradient (A-a PaO2) = 57 ± 15 mm Hg]. Of the 9 patients enrolled, follow-up blood gases were done in 7. There was no significant change in PaO2 (P = 0.3) or A-a PaO2 (P = 0.3) with treatment. Pentoxifylline was poorly tolerated. Nausea (100%) and vomiting (56%) were the predominant side effects, and only a single patient was able to complete full-dose therapy. Treatment with pentoxifylline did not improve arterial oxygenation in advanced HPS, and tolerance was limited by gastrointestinal toxicity. Liver Transpl 14:1199,1203, 2008. © 2008 AASLD. [source] Pentoxifylline improves haemoglobin and interleukin-6 levels in chronic kidney diseaseNEPHROLOGY, Issue 3 2010PAOLO FERRARI ABSTRACT Aim: 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 m2) 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 ± 6 mL/min) completed the study. At the end of the run-in period average haemoglobin was 111 ± 5 g/L, ferritin 92 ± 26 µg/L, transferrin saturation 15 ± 3% and circulating IL-6 10.6 ± 3.8 pg/mL. Tumour necrosis factor alpha values were below threshold for detection. Treatment with pentoxifylline reduced circulating IL-6 (6.6 ± 1.6 pg/mL, P < 0.01), increased transferrin saturation (20 ± 5%, P < 0.003) and decreased serum ferritin (81 ± 25 µg/L, P = NS). Haemoglobin increased after the second week of pentoxifylline, reaching 123 ± 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. [source] Pharmacodynamics of pentoxifylline and/or praziquantel in murine schistosomiasis mansoni,APMIS, Issue 3 2007NAGLAA EL-LAKKANY Pentoxifylline (PTX) was proved to exert both anti-inflammatory and anti-fibrotic effects, and was used therapeutically in this experimental model to investigate its role alone or with praziquantel (PZQ) in Schistosoma mansoni -infected mice, and to explore its impact on the tissue expression of transforming growth factor-,1 (TGF-,1). S. mansoni -infected mice were divided into seven groups: Control untreated (I), treated with curative dose of PZQ, 500 mg/kg/day for 2 consecutive days (II), or subcurative dose, 100 mg/kg/day for 2 consecutive days (III), treated with PTX (10 mg/kg/day for 5 days/wk) alone for 4 weeks (IV) or in addition to subcurative dose of PZQ (V), and treated with PTX alone for 8 weeks (VI) or in addition to subcurative dose of PZQ (VII). All animals were killed 10 weeks post infection. Parasitological assessment of worm burden, tissue egg load and oogram pattern was carried out. The degree of granulomatous fibrosis and eosinophilic cell population was quantified in Sirius-red-stained sections and tissue transforming growth factor beta-1 expression was estimated immunohistochemically. Serum ALAT and GGT, as well as hepatic content of reduced GSH, were measured. The results revealed the highest percent of worm reduction and dead ova in groups (II) and (VII) accompanied by significant diminution in granulomatous parameters, collagen content and TGF-,1 tissue expression. Moreover, treatments with PTX and/or PZQ ameliorated the liver functions. In conclusion, prolonged treatment with PTX has a potent anti-fibrogenic role especially when used in the early stages of infection, with limited toxic effects on schistosome worms and eggs. Thus, PTX can be used as an adjuvant therapeutic tool with anti-helminthic drugs in the treatment of human schistosomiasis. [source] Seasonality effects on pharmaceuticals and s -triazine herbicides in wastewater effluent and surface water from the Canadian side of the upper Detroit RiverENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 9 2006Wen Yi Hua Abstract The influence of seasonal changes in water conditions and parameters on several major pharmacologically active compounds (PhACs) and s -triazine herbicides was assessed in the wastewater and sewage treatment plant (WSTP) effluent as well as the downstream surface water from sites on the Canadian side of the upper Detroit River, between the Little River WSTP and near the water intake of a major drinking water treatment facility for the City of Windsor (ON, Canada). The assessed PhACs were of neutral (carbamazepine, cotinine, caffeine, cyclophosphamide, fluoxetine, norfluoxetine, pentoxifylline, and trimethoprim) and acidic (ibuprofen, bezafibrate, clofibric acid, diclofenac, fenoprofen, gemfibrozil, indomethacin, naproxen, and ketoprofen) varieties. The major assessed s -triazine herbicides were atrazine, simazine, propazine, prometon, ametryn, prometryn, and terbutryn. At sampling times from September 2002 to June 2003, 15 PhACs were detected in the WSTP effluent at concentrations ranging from 1.7 to 1,244 ng/L. The PhAC concentrations decreased by as much 92 to 100% at the Little River/Detroit River confluence because of the river dilution effect, with further continual decreases at sites downstream from the WSTP. The only quantifiable s -triazine in WSTP effluent, atrazine, ranged from 6.7 to 200 ng/L and was higher in Detroit River surface waters than in WSTP effluent. Only carbamazepine, cotinine, and atrazine were detectable at the low-nanogram and subnanogram levels in surface waters near a drinking water intake site. Unlike the PhACs, atrazine in the Detroit River is not attributable to point sources, and it is heavily influenced by seasonal agricultural usage and runoff. Detroit River surface water concentrations of carbamazepine, cotinine, and atrazine may present a health concern to aquatic wildlife and to humans via the consumption of drinking water. [source] Efficacy screening trials of paroxetine, pentoxifylline, riluzole, pramipexole and venlafaxine in cocaine dependenceADDICTION, Issue 2005Domenic A. Ciraulo ABSTRACT Aims The two studies presented here were conducted to assess the efficacy of paroxetine, pentoxifylline, riluzole, venlafaxine and pramipexole as medications for the treatment of cocaine dependence. Design A multi-arm, modified blinded, placebo-controlled design was used. Setting The studies were conducted at the Boston VA Healthcare System and the Boston University School of Medicine Medication Development Research Unit (MDRU). Participants Participants met criteria for cocaine dependence during a 2-week screening period. Intervention Following random assignment to one of the treatment groups, subjects received active medication or placebo for 8 weeks in combination with cognitive behavioral counseling. In the first study the efficacy of the antidepressant paroxetine (20 mg daily), the phosphodiesterase inhibitor pentoxifylline (1200 mg daily) and the glutamate release inhibitor riluzole (100 mg daily) was assessed. The antidepressant venlafaxine (150 mg daily) and the dopamine agonist pramipexole (1.5 mg daily) were evaluated in the second study. Measurements Urine benzoylecgonine (BE) concentrations, self-report of cocaine use and global impression scores served as primary outcome measures. Secondary measures included assessments of cocaine craving and psychiatric functioning. Adverse events were monitored during the treatment period. Findings None of the active medications produced greater reductions in urine BE concentrations over the treatment period than did placebo. There were trends for BE levels to become reduced in the pentoxifylline group during the first 4 weeks of treatment and for Addiction Severity Index (ASI) drug composite scores to be lower in the pentoxyfylline group at end-point compared to the placebo group. Significant within-group reductions in reported cocaine use and craving were found for all treatment groups, but none of the active medications were superior to placebo on these measures. The accuracy of self-reported cocaine use declined over the study period. Overall, the active medications were well tolerated. Conclusions This study does not support the use of paroxetine, pentoxifylline, riluzole, venlafaxine or pramipexole for the treatment of cocaine dependence. However, these results need to be interpreted with caution because of the small size and lack of homogeneity of the experimental groups. [source] Induction of apoptosis in monocytes by Mycobacterium leprae in vitro: a possible role for tumour necrosis factor-,IMMUNOLOGY, Issue 1 2003M. O. Hernandez Summary A diverse range of infectious organisms, including mycobacteria, have been reported to induce cell death in vivo and in vitro. Although morphological features of apoptosis have been identified in leprosy lesions, it has not yet been determined whether Mycobacterium leprae modulates programmed cell death. For that purpose, peripheral blood mononuclear cells obtained from leprosy patients were stimulated with different concentrations of this pathogen. Following analysis by flow cytometry on 7AAD/CD14+ cells, it was observed that M. leprae induced apoptosis of monocyte-derived macrophages in a dose-dependent manner in both leprosy patients and healthy individuals, but still with lower efficiency as compared to M. tuberculosis. Expression of tumour necrosis factor-, (TNF-,), Bax-,, Bak mRNA and TNF-, protein was also detected in these cultures; in addition, an enhancement in the rate of apoptotic cells (and of TNF-, release) was noted when interferon-, was added to the wells. On the other hand, incubation of the cells with pentoxifylline impaired mycobacterium-induced cell death, the secretion of TNF-,, and gene expression in vitro. In addition, diminished bacterial entry decreased both TNF-, levels and the death of CD14+ cells, albeit to a different extent. When investigating leprosy reactions, an enhanced rate of spontaneous apoptosis was detected as compared to the unreactive lepromatous patients. The results demonstrated that M. leprae can lead to apoptosis of macrophages through a mechanism that could be at least partially related to the expression of pro-apoptotic members of the Bcl-2 protein family and of TNF-,. Moreover, while phagocytosis may be necessary, it seems not to be crucial to the induction of cell death by the mycobacteria. [source] Effect of pentoxifylline on motility and membrane integrity of cryopreserved human spermatozoaINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 3 2002P. Stanic The purpose of this study was to examine the effects of pentoxifylline used before and after semen cryopreservation,thawing on sperm motility and membrane integrity. Twenty-four semen samples were split into four equal aliquots. Aliquots were incubated at 37 °C for 30 min, followed by cryopreservation with TEST-yolk freezing medium using slow programmable freezing protocol. After 2 weeks the sperm samples were thawed, washed twice in Quinn's Sperm Washing Medium (modified HTF with 5.0 mg/mL Human Albumin) and incubated at 37 °C for 30 min. Aliquots were treated by adding 3 mmol/L pentoxifylline to: (1) fresh sperm samples during incubation period prior to cryopreservation, (2) sperm samples as a supplement to the cryoprotectant prior to cryopreservation, and (3) thawed sperm samples during incubation period. One aliquot received no treatment (control group). The addition of 3 mmol/L pentoxifylline to fresh semen during incubation period prior to cryopreservation significantly decreased progressive and total motility compared with controls. However, the addition of 3 mmol/L pentoxifylline to cryopreserved semen after thawing significantly increased progressive and total motility compared with controls. After post-thaw, no differences in motion characteristics between sperm samples treated by adding 3 mmol/L pentoxifylline as a supplement to the cryoprotectant and control groups were observed. Post-thaw hypoosmotic swelling (HOS) test scores did not improve with the addition of pentoxifylline compared with the control group. It is concluded that pentoxifylline enhanced post-thaw motility of cryopreserved human spermatozoa when added after thawing. No improvement was found by freezing sperm with pentoxifylline. [source] Effects of pentoxifylline on coagulation profile and disseminated intravascular coagulation incidence in Egyptian septic neonatesJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2010M. Adel Msc Summary Background and objectives:, Neonatal sepsis is frequently associated with pathological activation of the coagulation system, leading to microcirculatory derangement and multiple organ dysfunction syndrome (MODS). The key role in the pathogenesis of sepsis has been attributed to proinflammatory cytokines. These trigger the development of disseminated intravascular coagulation (DIC) via the tissue factor-dependent pathway of coagulation. Pentoxifylline (PTX), a methylxanthine derivative that is used in peripheral vascular disease, has the potential to modify inflammatory response. The current work was designed to evaluate the potential protective effects of PTX against sepsis-induced microcirculatory derangement in Egyptian neonates. Methods:, A double-blind placebo-controlled quasi-randomized design was used. Thirty-seven neonates with sepsis were randomly allocated into two groups. Seventeen patients were given PTX (5 mg/kg/h for 6 h; for 6 successive days). Twenty patients received equivalent volume of normal saline and represented the placebo group. Prothrombin time (PT), Activated partial thromboplastin time (APTT), fibrinogen, d -dimer, C-reactive protein (CRP), complete blood count (CBC), also hemodynamic parameters comprising arterial blood pressure, heart rate, capillary refill and urinary output were assessed in both groups before and after treatment. Results:, Coagulation parameters in the two groups showed no significant differences. However, a higher incidence of DIC was observed in the placebo group neonates. PTX significantly lowered the percentage of bleeding (P = 0·0128) and less frequent use of FFP was observed in the PTX group (35·53% in PTX group vs. 80% in placebo group, P = 0·003). Incidence of MODS was significantly lower (P = 0·037) and hospital stay duration of survivors was significantly shorter (P = 0·044) in the PTX treated-infants. Conclusion:, Pentoxifylline protects against sepsis-induced microcirculatory derangement in neonates. It significantly lowered the incidence of bleeding and MODS and shortened the length of hospital stay. [source] Is pentoxifylline therapy effective for the treatment of acute rheumatic carditis?JOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 3 2003A pilot study Objective: The aim of the present study was to determine whether pentoxifylline has a beneficial effect on the treatment of rheumatic carditis. Methods: A total of 33 children between the ages 6 and 16 were studied in two groups. The first group (5 boys, 10 girls, mean age: 12.2 ± 2.9 years) was treated with steroid plus pentoxifylline and the second group (6 boys, 12 girls, mean age; 11.6 ± 2.8 years) was treated with steroid only for 3,6 weeks until the acute-phase reactants became normal. At admission and on the 7th, 30th, and 90th days of the treatment, laboratory studies including white blood cell count, erythrocyte sedimentation rate, C-reactive protein, throat culture and cytokines (interleukin-1,, tumour necrosis factor-,) were performed. Cardiac evaluation with chest X-ray, electrocardiography and echocardiography was performed in all patients. In the control group (12 boys, 3 girls, mean age; 10.7 ± 3.2 years) all parameters were evaluated once only. Results: In both groups, the similar white blood cell count was significantly decreased on the 90th day, and there was no significant difference between the two groups. C-reactive protein, erythrocyte sedimentation rate and interleukin-1, were significantly decreased on the 30th and 90th days. In the first group (treated with steroid plus pentoxifylline), the cardiothoracic index was significantly greater at the beginning of the therapy. In the first group, tumour necrosis factor-, became normal on the 30th day and in the second group, tumour necrosis factor-, became normal on the 7th day of therapy. For all parameters, there was no significant difference between the two groups with respect to the type of therapy used. Conclusion: The present study showed that pentoxifylline plus steroid treatment has no beneficial effects on the treatment of acute rheumatic carditis when compared with steroid alone. [source] Understanding and Treating Patients With Alcoholic Cirrhosis: An UpdateALCOHOLISM, Issue 7 2009Giovanni Addolorato Alcoholic cirrhosis represents the terminal stage of alcoholic liver disease (ALD) and one of the main causes of death among alcohol abusers. The aim of this review was to provide an update on alcoholic cirrhosis, with an emphasis on recent findings. Increased alcohol consumption in developing countries is expected to increase cirrhosis mortality. There is a need, therefore, to develop new approaches to the prevention of ALD, including more attention to co-factors that may increase risk of ALD (i.e., obesity and diabetes, chronic HCV infection, and smoking). Furthermore, a better understanding of the pathological mechanisms on the basis of alcohol cirrhosis represents a cornerstone in order to develop new pharmacological treatments. Inflammatory and immune responses along with oxidative stress and alterations in adipokine secretion might contribute in different ways to the evolution of alcohol-induced fibrosis/cirrhosis. As of this date, patients with severe alcoholic hepatitis with a Maddrey Discriminant Factor (MDF) 32 should be offered pentoxifylline and/or corticosteroids unless contraindications exist. For ambulatory patients, S-adenosylmethionine (SAMe) may be considered in a motivated patient with nutritional support. Current studies do not support use of anti-tumor necrosis factor (TNF)-alpha antibody. Finally, achieving total alcohol abstinence should represent the main aim in the management of patients affected by any stage of cirrhosis. In the last decades, several drugs able to increase abstinence and prevent alcohol relapse have been evaluated and some of them have obtained approval for alcohol dependence. Patients with alcoholic cirrhosis; however, are usually excluded from such treatments. A recent study demonstrated the efficacy and safety of baclofen in inducing and maintaining alcohol abstinence in cirrhotic alcohol-dependent patients with cirrhosis. All together the information available suggests the need of a multimodal approach in the clinical management of these patients. [source] Practical aspects of management of recurrent aphthous stomatitisJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 8 2007A Altenburg Treatment of recurrent aphthous stomatitis (RAS) remains, to date, empirical and non-specific. The main goals of therapy are to minimize pain and functional disabilities as well as decrease inflammatory reactions and frequency of recurrences. Locally, symptomatically acting modalities are the standard treatment in simple cases of RAS. Examples include topical anaesthetics and analgesics, antiseptic and anti-phlogistic preparations, topical steroids as cream, paste or lotions, antacids like sucralfate, chemically stable tetracycline suspension, medicated toothpaste containing the enzymes amyloglucosidase and glucoseoxidase in addition to the well-known silver nitrate application. Dietary management supports the treatment. In more severe cases, topical therapies are again very useful in decreasing the healing time but fail to decrease the interval between attacks. Systemic immunomodulatory agents, like colchicine, pentoxifylline, prednisolone, dapsone, levamisol, thalidomide, azathioprine, methotrexate, cyclosporin A, interferon alpha and tumour necrosis factor (TNF) antagonists, are helpful in resistant cases of major RAS or aphthosis with systemic involvement. [source] Review article: the diagnosis and management of alcoholic hepatitisALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2009S. M. COHEN Summary Background, Alcoholic hepatitis is a severe, cholestatic liver disease occurring in patients with alcohol abuse. Mortality is substantial; however, therapies may improve clinical outcomes. Aim, To provide an updated review of the epidemiology, diagnosis, staging and treatment of alcoholic hepatitis. Methods, A MEDLINE literature search was performed to identify pertinent articles. Relevant clinical abstracts were also reviewed. Results, Severe alcoholic hepatitis occurs in a small fraction of patients who abuse alcohol. The 28-day mortality ranges from 30% to 50% in most series. Diagnosis is generally based on clinical features, with a limited role for liver biopsy. Beneficial treatment options include alcohol abstinence and nutritional therapy. Despite variable results in clinical trials, corticosteroids and pentoxifylline appear to provide moderate survival benefit. Anti-tumour necrosis factor agents and antioxidants have not proven beneficial, and should be limited to clinical trials. Liver transplant is not a frequent option given the active or recent alcohol use. Conclusions, Severe alcoholic hepatitis is a clinically-diagnosed condition associated with significant mortality. Alcohol abstinence and nutritional therapy have been associated with improved clinical parameters and should be considered in all patients. Corticosteroid therapy and pentoxifylline therapy appear to show moderate survival benefit and should be considered as first-line therapeutic agents. [source] The effects of pentoxifylline on liver regeneration after portal vein ligation in ratsLIVER INTERNATIONAL, Issue 2 2007Uzer Kucuktulu Abstract Aim: To determine the effects of pentoxifylline, a methyl xanthine derivative on hepatic cell production of uninterferred lobe after portal vein branch ligation. Methods: Sixty-six rats were randomly allocated into 9 groups with 8 rats in PVL groups and 6 rats in sham operation groups. The portal branches of the median and the lateral liver lobes, corresponding to approximately 70% of the liver voluma were ligated in the PVL groups. The control group received 0.9% NaCl solution. The rats in the treatment groups received pentoxypilline at the dose of 50 mg/kg/dy. After 1,2,4 days of portal vein ligation in both PVL and PVNL lobes the levels of adenine nucleotides were determined and flowcytometric analysis of cell cycles were performed. Results: On the first day of portal branch ligation energy charge was significantly lower, in pentoxifylline treated group comparing to pentoxfylline untreated group, both in PVL and PVNL lobes (P<0.05). Proliferative indexes were 0.38 and 0.29 in pentoxifylline treated and pentoxifylline untreated PVNL lobes respectively (P<0.05). Conclusion: Pentoxifylline treatment resulted in an increase of percentage of calls entering mitosis phase on the first day after PVL, somehow accelerating the regenaration process. [source] Pilot study of pentoxifylline in hepatopulmonary syndrome,LIVER TRANSPLANTATION, Issue 8 2008Rajasekhar Tanikella Hepatopulmonary syndrome (HPS) results when chronic liver disease or portal hypertension causes intrapulmonary microvascular dilatation with hypoxemia. In experimental HPS, tumor necrosis factor alpha (TNF-,) overproduction contributes to vasodilatation, which is improved by pentoxifylline, a TNF-, inhibitor. The effectiveness of pentoxifylline in humans is unknown. The aim of this open-label, single-arm clinical trial was to assess the efficacy and tolerability of pentoxifylline in patients with cirrhosis and advanced HPS undergoing liver transplantation evaluation. Nine adults with cirrhosis and moderate to severe HPS were enrolled. All patients had an initial 2-week titration to a target dose of pentoxifylline of 400 mg by mouth every 8 hours, which was continued for 6 weeks. Baseline and follow-up arterial blood gases and TNF-, levels were evaluated. Adverse effects and tolerability were assessed. The 9 patients had a mean age of 55 ± 10 years, and 67% were female. The most common causes of cirrhosis were hepatitis C virus and alcohol (55%). The mean Model for End-Stage Liver Disease score was 11 (range, 6-19), and patients had advanced hypoxemia [mean partial pressure of arterial oxygen (PaO2) = 54 ± 12 mm Hg, mean alveolar-arterial oxygen gradient (A-a PaO2) = 57 ± 15 mm Hg]. Of the 9 patients enrolled, follow-up blood gases were done in 7. There was no significant change in PaO2 (P = 0.3) or A-a PaO2 (P = 0.3) with treatment. Pentoxifylline was poorly tolerated. Nausea (100%) and vomiting (56%) were the predominant side effects, and only a single patient was able to complete full-dose therapy. Treatment with pentoxifylline did not improve arterial oxygenation in advanced HPS, and tolerance was limited by gastrointestinal toxicity. Liver Transpl 14:1199,1203, 2008. © 2008 AASLD. [source] Tyrphostin-A47 inhibitable tyrosine phosphorylation of flagellar proteins is associated with distinct alteration of motility pattern in hamster spermatozoaMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 2 2006Daniel Mariappa Abstract To acquire fertilizing potential, mammalian spermatozoa must undergo capacitation and acrosome reaction. Our earlier work showed that pentoxifylline (0.45 mM), a sperm motility stimulant, induced an early onset of hamster sperm capacitation associated with tyrosine phosphorylation of 45,80 kDa proteins, localized to the mid-piece of the sperm tail. To assess the role of protein tyrosine phosphorylation in sperm capacitation, we used tyrphostin-A47 (TP-47), a specific protein tyrosine kinase inhibitor. The dose-dependent (0.1,0.5 mM) inhibition of tyrosine phosphorylation by TP-47 was associated with inhibition of hyperactivated motility and 0.5 mM TP-47-treated spermatozoa exhibited a distinct circular motility pattern. This was accompanied by hypo-tyrosine phosphorylation of 45,60 kDa proteins, localized to the principal piece of the intact-sperm and the outer dense fiber-like structures in detergent treated-sperm. Sperm kinematic analysis (by CASA) of spermatozoa, exhibiting circular motility (at 1st hr), showed lower values of straight line velocity, curvilinear velocity and average path velocity, compared to untreated controls. Other TP-47 analogues, tyrphostin-AG1478 and -AG1296, had no effect either on kinematic parameters or sperm protein tyrosine phosphorylation. These studies indicate that TP-47-induced circular motility of spermatozoa is compound-specific and that the tyrosine phosphorylation status of 45,60 kDa flagellum-localized proteins could be key regulators of sperm flagellar bending pattern, associated with the hyperactivation of hamster spermatozoa. Mol. Reprod. Dev. © 2005 Wiley-Liss, Inc. [source] Pentoxifylline improves haemoglobin and interleukin-6 levels in chronic kidney diseaseNEPHROLOGY, Issue 3 2010PAOLO FERRARI ABSTRACT Aim: 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 m2) 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 ± 6 mL/min) completed the study. At the end of the run-in period average haemoglobin was 111 ± 5 g/L, ferritin 92 ± 26 µg/L, transferrin saturation 15 ± 3% and circulating IL-6 10.6 ± 3.8 pg/mL. Tumour necrosis factor alpha values were below threshold for detection. Treatment with pentoxifylline reduced circulating IL-6 (6.6 ± 1.6 pg/mL, P < 0.01), increased transferrin saturation (20 ± 5%, P < 0.003) and decreased serum ferritin (81 ± 25 µg/L, P = NS). Haemoglobin increased after the second week of pentoxifylline, reaching 123 ± 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. [source] Acute pulmonary toxicity following intralesional administration of bleomycin for a lymphovenous malformationPEDIATRIC PULMONOLOGY, Issue 2 2010Khalid Atwa MD Abstract Objective To describe the clinical course and treatment of an infant with acute pulmonary toxicity following intralesional administration of bleomycin for a lymphovenous malformation. Design Case report. Setting A tertiary care University-affiliated hospital. Patient, Intervention, and Results An 8-month-old girl developed acute respiratory distress with profound hypoxemia complicated by pneumothorax and pneumomediastinum 1 day following intralesional administration of bleomycin. She was treated with bilateral chest tube insertion, systemic corticosteroids, pentoxifylline, and supportive care. At the most recent follow-up 5 months after the onset of the respiratory event, the patient is active, walks, and talks without any evidence of pulmonary diseases clinically. This is the youngest infant reported, to date, with acute bleomycin pulmonary toxicity following intralesional administration of bleomycin resulting in acute respiratory insufficiency followed by complete recovery. Conclusions This case illustrates the importance of early recognition and aggressive treatment of acute bleomycin toxicity resulting from intralesional administration of this medication for lymphovenous malformations. Pediatr Pulmonol. 2010; 45:192,196. © 2009 Wiley-Liss, Inc. [source] Open comedones overlying granuloma annulare in a photoexposed areaPHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 5 2006Emilio Sudy A 57-year-old, fair-skinned female patient with lesions of granuloma annulare located on her forearms , with signs of actinic damage , is described. No response was observed after successive treatments with topical corticosteroids and oral pentoxifylline. Four years later, the patient developed open comedones on the rim of granuloma annulare lesions. The loss of elastic fibers seen in both granuloma annulare and solar elastosis is presumed to have induced the appearance of open comedones, because of a loss of supporting properties of the dermis inducing a distension of the infundibular canal of the sebaceous follicle, as seen in the Favre,Racouchot disease and actinic comedonal plaque. Concomitantly, the patient developed insulin-dependent diabetes mellitus. Treatment with insulin resulted in the disappearance of open comedones and notably regression of lesions of granuloma annulare. Response to insulin therapy in our case supports the hypothesis that insulinopenia could participate in the development of granuloma annulare in some cases. [source] Sudden bilateral sensorineural hearing loss after intravenous cocaine injection: A case report and review of the literatureTHE LARYNGOSCOPE, Issue 12 2009Markus Stenner MD Abstract Little is known about the effects of intravenous abuse of cocaine, especially on the inner ear. We report on a 26-year-old man who presented to our outpatient department with a sudden severe hearing loss after intravenous injection of cocaine. The audiogram on admission showed symmetric air conduction levels up to 80 dB at 4 kHz. After treatment with intravenous sodium chloride, prednisolone, and pentoxifylline, the audiogram 2 days later showed a bilateral normacusis. A review of the literature on the topic is given and possible reasons for inner ear damages caused by cocaine are discussed. Laryngoscope, 2009 [source] Intracytoplasmic sperm injection with motile and immotile frozen-thawed testicular spermatozoa (the Hungarian experience)ANDROLOGIA, Issue 1 2005Sz. Mátyás Summary The authors summarize their experience in 75 in vitro fertilization cycles, where frozen-thawed testicular spermatozoa were used for intracytoplasmic sperm injection. In 32 cases, motile spermatozoa could be observed in the frozen-thawed sample. In 34 cases, motility could be induced by pentoxifylline and in nine cases immotile spermatozoa, selected with hypoosmotic swelling test, were used for fertilization. The fertilization rates obtained with motile and immotile spermatozoa (66.1% versus 52.3%) were not significantly different. Our data demonstrate that freezing of testicular spermatozoa opened new possibilities for the treatment of azoospermic men. The clinical pregnancy rate per embryo transfer (ET) (21.87%) was comparable with previous results use of fresh testicular spermatozoa (27.7%). The quality and number of transferred embryos had the most significant impact on the pregnancy rate. The fertilization rate and frequency distribution of good-quality embryos were lower in the case of immotile spermatozoa, and pregnancies were only achieved when motile spermatozoa had been used. [source] Pharmacodynamics of pentoxifylline and/or praziquantel in murine schistosomiasis mansoni,APMIS, Issue 3 2007NAGLAA EL-LAKKANY Pentoxifylline (PTX) was proved to exert both anti-inflammatory and anti-fibrotic effects, and was used therapeutically in this experimental model to investigate its role alone or with praziquantel (PZQ) in Schistosoma mansoni -infected mice, and to explore its impact on the tissue expression of transforming growth factor-,1 (TGF-,1). S. mansoni -infected mice were divided into seven groups: Control untreated (I), treated with curative dose of PZQ, 500 mg/kg/day for 2 consecutive days (II), or subcurative dose, 100 mg/kg/day for 2 consecutive days (III), treated with PTX (10 mg/kg/day for 5 days/wk) alone for 4 weeks (IV) or in addition to subcurative dose of PZQ (V), and treated with PTX alone for 8 weeks (VI) or in addition to subcurative dose of PZQ (VII). All animals were killed 10 weeks post infection. Parasitological assessment of worm burden, tissue egg load and oogram pattern was carried out. The degree of granulomatous fibrosis and eosinophilic cell population was quantified in Sirius-red-stained sections and tissue transforming growth factor beta-1 expression was estimated immunohistochemically. Serum ALAT and GGT, as well as hepatic content of reduced GSH, were measured. The results revealed the highest percent of worm reduction and dead ova in groups (II) and (VII) accompanied by significant diminution in granulomatous parameters, collagen content and TGF-,1 tissue expression. Moreover, treatments with PTX and/or PZQ ameliorated the liver functions. In conclusion, prolonged treatment with PTX has a potent anti-fibrogenic role especially when used in the early stages of infection, with limited toxic effects on schistosome worms and eggs. Thus, PTX can be used as an adjuvant therapeutic tool with anti-helminthic drugs in the treatment of human schistosomiasis. [source] Bioanalysis of pentoxifylline and related metabolites in plasma samples through LC-MS/MSBIOMEDICAL CHROMATOGRAPHY, Issue 6 2010Daniela Iuliana Sora Abstract Analytical aspects related to the assay of pentoxifylline (PTX), lisofylline (M1) and carboxypropyl dimethylxanthine (M5) metabolites are discussed through comparison of two alternative analytical methods based on liquid chromatography separation and atmospheric pressure electrospray ionization tandem mass spectrometry detection. One method is based on a ,pure' reversed-phase liquid chromatography mechanism, while the second one uses the additional polar interactions with embedded amide spacers linking octadecyl moieties to the silicagel surface (C-18 Aqua stationary phase). In both cases, elution is isocratic. Both methods are equally selective and allows separation of unknowns (four species associated to PTX, two species associated to M1) detected through specific mass transitions of the parent compounds and owning respective structural confirmation. Plasma concentration,time patterns of these compounds follow typical metabolic profiles. It has been advanced that in-vivo formation of conjugates of PTX and M1 is possible, such compounds being cleaved back to the parent ones within the ion source. The first method was associated with a sample preparation procedure based on plasma protein precipitation by strong organic acid addition. The second method used protein precipitation by addition of a water miscible organic solvent. Both analytical methods were fully validated and used to assess bioequivalence between a prolonged release generic formulation and the reference product, under multidose and single dose approaches. Copyright © 2009 John Wiley & Sons, Ltd. [source] Enantioselective reduction of pentoxifylline to lisofylline using whole-cell Lactobacillus kefiri biotransformationBIOTECHNOLOGY JOURNAL, Issue 4 2007bieta P, kala; Dr. Abstract Lisofylline (LSF) is a drug candidate that has been under investigation for acute respiratory distress syndrome, acute lung injury, septic shock and mucositis. As LSF is not commercially available in our country, we produced it for pharmacokinetic studies. In the present work whole-cell reduction of pentoxifylline [1-(5-oxohexyl)-3,5-dimethylxanthine] to LSF [1-(5R-hydroxyhexyl)-3,5-dimethylxanthine] using Lactobacillus kefiri DSM 20587 was investigated. Glucose or 2-propanol was used as a co-substrate to regenerate the NADPH cofactor. The reaction conditions were optimized. The influence of different concentrations of co-substrates on the yield and enantioselectivity of the biotransformation of pentoxifylline into LSF were tested. Maximum yield (100%) of biotransformation was reached in the presence of glucose as a co-substrate. At glucose concentrations of 675 and 900 mM the bioreduction of pentoxifylline proceeded highly enantioselectively (enantiomeric excess for the R enantiomer of 98%). [source] A double-blind placebo-controlled study of the efficacy and safety of pentoxifylline in early chronic Peyronie's diseaseBJU INTERNATIONAL, Issue 2 2010Mohammad Reza Safarinejad Study Type , Therapy (RCT) Level of Evidence 1b OBJECTIVE To analyse the safety and efficacy of pentoxifylline sustained-release (PTX-SR) treatment in patients with early chronic Peyronie's disease (PD). PATIENTS AND METHODS In all, 228 patients with a mean (sd) age of 51 (9) years who had early chronic PD were randomized to receive 400 mg PTX-SR (Apo-Pentoxifylline, Apotex Inc., Toronto, Canada) twice daily (group 1, 114) or similar regimen of placebo (group 2, 114) for 6 months. A medical history was taken and the men had a complete physical examination. The following variables were assessed before and after therapy: penile curvature and penile artery spectral traces (end-diastolic velocity, EDV, peak systolic velocity, PSV, and resistivity index, RI, of the right and left cavernous arteries assessed with dynamic penile duplex ultrasonography), plaque characteristics (assessed by penile X-ray and penile ultrasonography), pain (assessed by visual analogue scale), erectile function (assessed by the International Index of Erectile Function, IIEF questionnaire), treatment satisfaction (assessed by Erectile Dysfunction Inventory of Treatment Satisfaction questionnaire), and side-effects. Patient perception of penile curvature and plaque size, and mean weekly intercourse attempts were also assessed. RESULTS Overall, 36.9% of patients who received PTX-SR reported a positive response, vs only 4.5% in the placebo group. Of patients in PTX-SR group, 12 (11%) had disease progression, vs 46 (42%) in placebo group (P = 0.01). Improvement in penile curvature (P = 0.01), and plaque volume (P = 0.001) was significantly greater in patients treated with PTX-SR than placebo. The increase in IIEF total score was significantly higher in the PTX-SR group (P = 0.02). Mean PSV changes after therapy compared to baseline were statistically significant between PTX-SR (right, +11.4%, left, +11.7%) and placebo-treated (+0.2% and ,4.2%, respectively) patients (both P = 0.04). CONCLUSIONS PTX-R was moderately effective in reducing penile curvature and plaque volume in patients with early chronic PD. Further studies with different treatment regimens are needed to better elucidate the beneficial effects of PTX-SR in PD. [source] Hypereosinophilic syndrome presenting as cutaneous necrotizing eosinophilic vasculitis and Raynaud's phenomenon complicated by digital gangreneBRITISH JOURNAL OF DERMATOLOGY, Issue 3 2000K-A. Jang Cutaneous necrotizing eosinophilic vasculitis is a recently identified type of vasculitis that is characterized by an eosinophil-predominant necrotizing vasculitis affecting small dermal vessels. Clinically, it presents with pruritic erythematous and purpuric papules and plaques, peripheral eosinophilia and a good response to systemic steroid therapy. This vasculitis can be idiopathic or associated with connective tissue diseases. Although the pathogenic roles of eosinophil-derived granule proteins and interleukins have been documented in diseases associated with eosinophilia, a role of CD40 (a glycoprotein of the tumour necrosis factor receptor superfamily) has rarely been described. We describe two patients with idiopathic hypereosinophilic syndrome (HES) presenting with multiple erythematous patches and plaques on the lower extremities and Raynaud's phenomenon. They satisfied the criteria for the diagnosis of HES by clinical and laboratory investigations. Histopathology of the cutaneous lesions revealed prominent eosinophilic infiltration with local fibrinoid change in vessel walls in the dermis and subcutis. Immunohistochemical detection of CD3, CD4, CD8 and CD40 was performed. Infiltrating eosinophils were strongly stained by anti-CD40 monoclonal antibody. One patient improved with prednisolone, pentoxifylline and nifedipine, without recurrence. The other patient initially improved with steroids, but after self-withdrawal of steroid developed digital ischaemia that evolved to severe necrosis and required amputation. Cutaneous necrotizing eosinophilic vasculitis, Raynaud's phenomenon and digital gangrene may develop as cutaneous manifestations of HES. CD40 may play a part in the pathogenesis of eosinophilic vasculitis in HES. [source] Spinal glial TLR4-mediated nociception and production of prostaglandin E2 and TNFBRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2010O Saito Background and purpose:, Toll-like receptor 4 (TLR4) expressed on spinal microglia and astrocytes has been suggested to play an important role in the regulation of pain signalling. The purpose of the present work was to examine the links between TLR4, glial activation and spinal release of prostaglandin E2 (PGE2) and tumour necrosis factor (TNF), and the role these factors play in TLR4-induced tactile allodynia. Experimental approach:, Toll-like receptor 4 was activated by intrathecal (i.t.) injection of lipopolysaccharide (LPS) and KDO2 -Lipid A (KDO2) to rats. Tactile allodynia was assessed using von Frey filaments and cerebrospinal fluid collected through spinal dialysis and lumbar puncture. PGE2 and TNF levels were measured by mass spectometry and elisa. Minocycline and pentoxifylline (glia inhibitors), etanercept (TNF-blocker) and ketorolac (COX-inhibitor) were given i.t. prior to injection of the TLR4-agonists, in order to determine if these agents alter TLR4-mediated nociception and the spinal release of PGE2 and TNF. Key results:, Spinal administration of LPS and KDO2 produced a dose-dependent tactile allodynia, which was attenuated by pentoxifylline, minocycline and etanercept but not ketorolac. Both TLR4 agonists induced the spinal release of PGE2 and TNF. Intrathecal pentoxifylline blunted PGE2 and TNF release, while i.t. minocycline only prevented the spinal release of TNF. The release of PGE2 induced by LPS and KDO2 was attenuated by i.t. administration of ketorolac. Conclusions and implications:, Activation of TLR4 induces tactile allodynia, which is probably mediated by TNF released by activated spinal glia. [source] Effects of pentoxifylline on the different steps during adhesion and transendothelial migration of flowing neutrophilsCELL BIOCHEMISTRY AND FUNCTION, Issue 4 2001P.S. Bahra Abstract We used a flow system to observe the stepwise adhesion and migration of neutrophils on cultured human umbilical vein endothelial cells (HUVEC) stimulated with tumour necrosis factor-, (TNF) for 4,h, and to evaluate the effects of pentoxifylline (PTX) at each step. When HUVEC had been stimulated with 100,U,ml,1 TNF, treatment of neutrophils with PTX did not reduce the number captured from flow but did cause nearly all adherent cells (,>,90%) to roll, whereas most untreated cells became immobilized and ,30% transmigrated within minutes. On washout of the PTX, many rolling cells halted and started to migrate. Treatment of the HUVEC with PTX at the same time as 100,U,ml,1 TNF did not affect the number of neutrophils adhering, but there was a significant increase in the percentage of cells rolling even though PTX was no longer present. Thus PTX reduced presentation of activating agents by HUVEC, as well as inhibiting the response by neutrophils to surface-presented activating agent(s). If HUVEC were stimulated with 10,U,ml,1 TNF with PTX, the adhesion of flowing neutrophils was greatly inhibited compared to TNF alone. Surface ELISA indicated that PTX reduced TNF-induced upregulation of E-selectin. This reduction was only sufficient to reduce capture of neutrophils at the low dose of TNF. Thus, by using a flow-based model, we have been able to separate the effects of a multipotent agent such as pentoxifylline, which acts on leucocytes and endothelial cells, at each stage of migration. Copyright © 2001 John Wiley & Sons, Ltd. [source] | ||||||||||||||||||||||||||||