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PubMed2000

Oral pentoxifylline for treatment of venous leg ulcers.

BACKGROUND: Healing of venous leg ulcers is improved by the use of compression bandaging but some venous ulcers do not respond to compression therapy. Pentoxifylline, a drug which helps blood flow, has been used to treat venous leg ulcers but to date there has been no systematic review. OBJECTIVES: To assess the effects of pentoxifylline ('Trental 400') for treating venous leg ulcers, when compared with placebo, or in comparison with other therapies, in the presence or absence of compression therapy. SEARCH STRATEGY: We searched the Cochrane Peripheral Vascular Diseases and Wounds Groups specialised registers (date of search August 1999), and reference lists of relevant articles. We hand searched relevant journals and conference proceedings, and contacted Hoechst (the manufacturer of the drug) and experts in the field. SELECTION CRITERIA: Randomised trials comparing pentoxifylline with placebo or other therapy in the presence or absence of compression, in patients with venous leg ulcers. DATA COLLECTION AND ANALYSIS: Details from eligible trials were extracted and summarised by one reviewer using a coding sheet. Data extraction was independently verified by one other reviewer. MAIN RESULTS: Nine trials involving 572 adults were included. The quality of trials was variable. Eight trials compared pentoxifylline with placebo; in five of these trials patients received compression therapy. In one trial pentoxifylline was compared with defibrotide in patients who also received compression. By pooling eight trials that compared pentoxifylline with placebo (with or without compression) it was found pentoxifylline was more effective than placebo in terms of complete healing or significant improvement (relative risk for healing with pentoxifylline compared with placebo 1.41, 95% confidence interval 1.19 -1.66). Pentoxifylline and compression was more effective than placebo and compression (relative risk for healing with pentoxifylline 1.30, 95% confidence interval 1.10-1.54). Combination of similar trials using compression obtained a number needed to treat (NNT) of 7 (95%confidence interval 4-17). A comparison between pentoxifylline and defibrotide found no difference in healing rates. More adverse effects were reported in the pentoxifylline group, although this was not statistically significant (relative risk for adverse effects with pentoxifylline 1. 25, 95% confidence interval 0.87-1.80). Nearly half of the adverse effects were reported to be gastro-intestinal. REVIEWER'S CONCLUSIONS: Pentoxifylline appears to be an effective adjunct to compression bandaging for treating venous ulcers. There was no cost effectiveness data available and healthcare commissioners may therefore conclude that it not be considered a routine adjunct. Pentoxifylline in the absence of compression may be effective for treating venous ulcers in the absence of compression, although the evidence should be cautiously interpreted. The majority of adverse effects are likely to be tolerated by patients, and gastrointestinal disturbances (indigestion, diarrhoea and nausea) are the most frequent adverse effect.

Administration, Oral↗

PubMed2002

Selective down-regulation of c-jun gene expression by pentoxifylline and c-jun antisense interrupts platelet-derived growth factor signaling: pentoxifylline inhibits phosphorylation of c-Jun on serine 73.

Platelet-derived growth factor (PDGF) signals through several pathways, including mitogen-activated protein (MAP) kinase, Jun kinase, and C kinase, and stimulates proliferation of fibroblasts. Pentoxifylline inhibits PDGF-driven proliferation of fibroblasts. We have reported that pentoxifylline did not inhibit binding of PDGF to its specific cell-surface receptors or PDGF receptor phosphorylation. In this study, we investigated the effect of PDGF on the expression of c-fos and c-jun, because c-fos and c-jun form activator protein-1 complexes that stimulate genes involved in proliferation. We determined whether pentoxifylline would alter the expression of c-fos and c-jun. Our results indicate that PDGF induced the expression of both c-fos and c-jun. Pentoxifylline effectively reduced c-jun gene expression, which had been up-regulated by PDGF, but did not alter c-fos gene expression. The lack of effect on c-fos supports other studies from this laboratory, which indicate that pentoxifylline did not inhibit PDGF activation of MAP kinase. Treatment of fibroblasts with a phosphothioate c-jun antisense oligodeoxynucleotide reduced the levels of c-Jun protein and blocked PDGF-stimulated proliferation, suggesting a critical role for c-jun in PDGF-mediated proliferation. Combination of pentoxifylline and c-jun antisense suggested that they were likely inhibiting PDGF-stimulated proliferation at a single site in the PDGF signaling pathway. These results suggest that pentoxifylline inhibits PDGF-stimulated proliferation by selectively decreasing c-jun expression. To further define the mechanism of action of pentoxifylline, we assessed the effect of pentoxifylline on c-Jun and phosphorylated c-Jun immunoreactivity in cells treated with PDGF and cells that were transfected with wild-type c-jun plasmid using immunocytochemistry and Western blot analyses, and our results indicate that pentoxifylline inhibited phosphorylation of c-Jun on serine 73.

Animals↗

PubMed1991

Interaction of pentoxifylline with human erythrocytes. III. Comparison of fluidity change of erythrocyte membrane caused by S-adenosyl-L-methionine with that by pentoxifylline.

The change in fluidity by adding pentoxifylline to erythrocyte membranes was compared with that caused by S-adenosyl-L-methionine (SAM) by the method of electron spin resonance (ESR) spectroscopy. When SAM or pentoxifylline was added externally to the erythrocyte suspension (outside), the fluidity of the membrane bilayer was increased after incubation at 37 degrees C. However, the fluidity change in the inner part of the bilayer was relatively small compared to that in its outer part. These fluidity changes were dependent on the incubation time and the temperature. When the erythrocyte suspension was preincubated overnight at 4 degrees C in the presence of drugs (inside), the fluidity of the inner part of the membrane changed significantly. Nevertheless, that of the outer part of the lipid bilayer was not affected. Such an asymmetric fluidity change in the lipid bilayer was not observed by the addition of other xanthine derivatives such as caffeine, theophylline and theobromine. S-Adenosyl-L-homocysteine suppressed and MgCl2 enhanced the increase of the membrane fluidity by SAM or pentoxifylline. Furthermore, the effects of SAM and pentoxifylline on erythrocyte deformability were determined by a filtering technique method. In increasing order the additive effects of SAM and pentoxifylline on the erythrocyte filterability were SAM (outside) less than pentoxifylline (inside) less than pentoxifylline (outside) less than SAM (inside). These results suggest that pentoxifylline also affects the membrane fluidity through the enzymatic methylation of phospholipids.

Erythrocyte Membrane↗

PubMed2006

Pharmacokinetics of pentoxifylline and its 5-hydroxyhexyl metabolite after oral and intravenous administration of pentoxifylline to healthy adult horses.

OBJECTIVE: To determine serum pharmacokinetics of pentoxifylline and its 5-hydroxyhexyl metabolite in horses after administration of a single IV dose and after single and multiple oral doses. ANIMALS: 8 healthy adult horses. PROCEDURES: A crossover study design was used with a washout period of 6 days between treatments. Treatments were IV administration of a single dose of pentoxifylline (8.5 mg/kg) and oral administration of generic sustained-release pentoxifylline (10 mg/kg, q 12 h, for 8 days). Blood samples were collected 0, 1, 3, 6, 12, 20, 30, and 45 minutes and 1, 2, 4, 6, 8, and 12 hours after IV administration. For oral administration, blood samples were collected 0, 0.25, 0.5, 0.75, 1, 2, 4, 8, and 12 hours after the first dose and 0, 0.25, 0.5, 0.75, 1, 2, 4, 8, 12, and 24 hours after the last dose. RESULTS: Elimination of pentoxifylline was rapid after IV administration. After oral administration, pentoxifylline was rapidly absorbed and variably eliminated. Higher serum concentrations of pentoxifylline and apparent bioavailability were observed after oral administration of the first dose, compared with values after administration of the last dose on day 8 of treatment. CONCLUSIONS AND CLINICAL RELEVANCE: In horses, oral administration of 10 mg of pentoxifylline/kg results in serum concentrations equivalent to those observed for therapeutic doses of pentoxifylline in humans. Twice daily administration appears to be appropriate. However, serum concentrations of pentoxifylline appear to decrease with repeated dosing; thus, practitioners may consider increasing the dosage if clinical response diminishes with repeated administration.

Administration, Oral↗

PubMed1993

Serum levels of pentoxifylline and its metabolites in non-tumor-bearing mice after chronic oral pentoxifylline administration.

Pentoxifylline lowers blood viscosity and increases erythrocyte flexibility in patients with atherosclerosis, thus increasing tissue oxygen delivery. Since tumor neo-vessels are associated with tissue hypoxia, which contributes to failure of radiation therapy, pentoxifylline might also be useful as a radiation sensitizer. Such drugs are often evaluated in the murine model, but serum levels of pentoxifylline and its metabolites have not been determined in the mouse after chronic oral dosing. We investigated this by administering pentoxifylline via liquid diet or solid diet to young adult male CF1 mice for one to six weeks and assaying plasma for the parent drug and its metabolites. At one, three, and six weeks, plasma levels of pentoxifylline and major derivatives were consistently detectable. Mice remained healthy during this period, indicating that ingestion of large amounts of this drug is well tolerated.

Administration, Oral↗

PubMed1996

Efficacy and clinical tolerance of parenteral pentoxifylline in the treatment of critical lower limb ischemia. A placebo controlled multicenter study. Norwegian Pentoxifylline Multicenter Trial Group.

A total of 114 patients with critical lower limb ischemia from 11 hospitals were randomized to either Pentoxifylline 600 mg or placebo given intravenously twice a day. Rest pain was evaluated both by the investigator and the patient. Pain was evaluated with the patient in the supine as well as in the sitting position using a pain score scale, a pain relief scale and a visual analogue scale. All patients underwent a clinical examination, measurement of ankle systolic blood pressure and arteriography. These arteriograms were evaluated by a radiologist who did not know which treatment had been given. If no beneficial effect of the treatment was observed after one week, further medication was discontinued. Otherwise the treatment continued for two additional weeks. There was no statistically significant difference in pain-free or absolute walking distance between the two groups. Evaluating the patients with the most pronounced amelioration of rest pain in the supine position (divided by 4 to divided by 2 points), there was a beneficial effect of Pentoxifylline compared to placebo. Evaluation of the total material did not, however, show any statistical significances between the groups. From further subgroup analysis excluding patients who had only slight pain at the entrance of the study, there was a significant improvement in rest pain in favour of Pentoxifylline following seven days of treatment. In this group the pain evaluated according to this visual analogue scale had decreased 37 points (54%) compared to 14 points (25%) in the placebo group. More side effects, mainly gastrointestinal, were observed in the Pentoxifylline group. Most of these could be eliminated by increasing the infusion time. Further investigations are necessary to evaluated the place of Pentoxifylline in the treatment of patients with critical limb ischemia.

Aged↗

PubMed1993

Effects of dipyridamole, pentoxifylline or dipyridamole plus pentoxifylline on platelet reactivity in patients with ischemic cerebrovascular insufficiency.

Platelet activation and the subsequent platelet recruitment induced by activated platelets released products constitute the initial events of platelet thrombus formation. We have evaluated the recruiting activity of collagen-stimulated whole blood in patients with ischemic cerebrovascular insufficiency. This was done using an experimental approach that allows independent evaluation of platelet activation and recruitment. The effects of of treating the patients with dipyridamole (DIP) (300 mg/day), pentoxifylline (POX) (1200 mg/day) or a combination of the two drugs at the same doses was also evaluated before and after 7, 15, and 45 days of treatment. DIP decreased the recruiting activity in a time-dependent manner, while POX did not show any effect. However, the combined treatment with DIP+POX was more effective than DIP alone in reducing platelet recruitment, which was abolished after 45 days of treatment. Studies using the drugs in vitro indicated a greater inhibitory activity of the drug association than either drug individually. The effects of the drug association in vitro, even at high concentrations, was lower than those observed ex vivo after 45 days of treatment. This suggests that DIP+POX in vivo may have effects that condition a reduced platelet response.

Aged↗

PubMed1993

Pentoxifylline alone versus pentoxifylline combined with superoxide dismutase prolongs survival in a rat hemorrhagic shock model.

Pentoxifylline (PTX) and superoxide dismutase (SOD) have each proven effective in improving survival when administered during resuscitation in animal models of hemorrhagic shock. This study was conducted to determine if PTX and SOD combined would have synergistic effectiveness in the treatment of hemorrhagic shock. Sprague-Dawley rats (n = 40) were phlebotomized at 25 ml/kg for 2 min, then subjected to a 45-min ischemic period, and resuscitated with lactated Ringer's solution (LR) (50 ml/kg) over 1 h. This model resulted in 70% mortality over 72 h when resuscitation was with LR alone. Animals were randomized into groups to receive one of the following agents during resuscitation: PTX in LR, SOD in LR, a combination of PTX and SOD in LR, or LR alone. PTX or SOD alone were effective in prolonging survival. However, the combination of PTX and SOD did not prolong survival above LR control.

Animals↗

PubMed1990

Interaction of pentoxifylline with human erythrocytes. II. Effects of pentoxifylline on the erythrocyte membrane.

The effects of pentoxifylline and other hemorheologically active drugs on the human erythrocyte membrane were examined by means of electron spin resonance spectroscopy. It was observed that the fluidity in the region of the phospholipid head groups in the erythrocyte bilayer was increased by an externally added drug. In this region, membrane fluidity was dependent on the incubation time, suggesting an interaction with membrane proteins. On the other hand, the acyl chain motion in the lower portion of the chain, the hydrophobic end, was reduced in the presence of the drugs. In this case, the acyl chain motion was not time-dependent. These changes of the membrane fluidity at different depths of the membrane induced by the drugs may correlate to the erythrocyte deformability.

Erythrocyte Membrane↗

PubMed2002

Carbonyl group of aliphatic side chain of pentoxifylline does not play role for P-glycoprotein antagonizing effect of pentoxifylline.

Previously we have found that pentoxifylline (PTX), but not caffeine, theophylline, or 1-methyl-3-isobutylxanthine, affects sensitivity of L1210/VCR cells, a line with multidrug resistance mediated by P-glycoprotein (P-gp) to vincristine (VCR) and doxorubicine. Comparison of chemical structure of PTX with other above xanthines has revealed only one marked difference. PTX contains extended aliphatic chain containing reactive electrophilic carbonyl group in the position N1. The investigation of possibility that this group is crucial for PTX-induced MDR reversal represents the aim of the current paper. To prove this hypothesis, we used the new synthesized PTX derivative in which the carbonyl group is modified by a substance containing amino-group and the product of reaction is the respective Schiff base (SB). Successful reaction was observed when PTX reacted with 3,5-diaminobenzenesulfonyl acid (DABS). The product of reaction of DABS with carbonyl group of aliphatic part of PTX was proved using NMR and IR spectroscopy. We found that the resulting PTX derivative PTX-SB revealed higher cytotoxicity on both sensitive L1210 and multidrug resistant L1210/VCR cells than PTX. Moreover, PTX-SB exerts more pronounced MDR reversal effect on L1210/VCR cells than PTX. These results indicate that electrophilic carbonyl group on aliphatic chain located in position N1 of PTX is not essential for MDR reversal effects of PTX.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

A placebo-controlled study of retinal blood flow changes by pentoxifylline and metabolites in humans.

AIM: To investigate the possible effects of pentoxifylline metabolites on retinal blood flow in humans. METHODS: A randomized, placebo-controlled, four-period cross-over study that was observer blinded and partly blinded for the eight participants. On one occasion a placebo was given as an intravenous (i.v.) infusion over 100 min. On the other three occasions pentoxifylline was administered as i.v. infusions over 100 min at a rate of 3 mg min(-1). Before two of the pentoxifylline infusions the subjects were pretreated with either ciprofloxacin or rifampicin. Retinal blood flow was measured by scanning laser doppler flowmetry (SLDF) in a selected area of the central temporal retina before, during and until 5 h after the end of infusion. Blood samples for concentration analyses of pentoxifyllin, R-M1, S-M1, M4 and M5 were taken serially and areas under the curves (AUCs) were calculated. Linear mixed models were used for the statistical analyses. RESULTS: Mean AUCs (ng h ml(-1)) were significantly increased for pentoxifylline (1964 vs. 1453) and S-M1 (5804 vs. 4227), but not R-M1 when pentoxifylline was co-administered with ciprofloxacin. The mean AUC for M5 was significantly reduced when subjects were pretreated with rifampicin (2041 vs. 3080). Pentoxifylline with and without pretreatment with rifampicin significantly increased retinal blood flow assessed as mean flow, pulsation (i.e. 1-systole/diastole), and diastolic flow (but not during systole), compared with placebo. The increases over placebo were more pronounced on diastolic flow, 9.7% (95% confidence interval 4.2, 15.5) than on mean flow, 4.6% (1.1, 8.3) after pentoxifylline administration. With pentoxifylline after rifampicin pretreatment the corresponding differences were 11.7% (5.8, 17.9) and 5.1% (1.4, 7.8) over placebo, respectively. After co-administration of pentoxifylline and ciprofloxacin we saw only a nonsignificant trend towards increased flow during diastole, but a significant decrease in pulsation. When AUCs for pentoxifylline and its metabolites were used as regressor variables to retinal mean flow we found that pentoxifylline, R-M1 and M5 had coefficients with a positive sign indicating that they enhanced the retinal blood flow. In contrast, S-M1 and M4 had coefficients with negative sign and thus appeared to decrease the blood flow in subjects treated with pentoxifylline. CONCLUSION: The R-M1 and M5 metabolites of pentoxifylline contributed significantly to the effects of pentoxifylline on retinal blood flow.

Adult↗

PubMed1996

Inhibition of fibroproliferation by pentoxifylline. Activity of metabolite-1 and lack of role of adenosine receptors.

We have reported previously that pentoxifylline and adenosine decrease platelet-derived growth factor- (PDGF) stimulated fibroproliferation. To determine the role of adenosine receptors in the inhibition of fibroproliferation observed with pentoxifylline, we used a non-selective adenosine receptor antagonist, 8-phenyltheophylline, and specific A1 and A2 adenosine receptor antagonists. If the A2 receptor, which is present on fibroblasts, mediates the inhibition of fibroproliferation which occurs with pentoxifylline, then pretreatment of fibroblasts with receptor antagonists prior to the addition of pentoxifylline should prevent the action of pentoxifylline. The results indicated that pretreatment of fibroblasts with 8-phenyltheophylline (100 microM) did not alter the inhibitory effect of pentoxifylline on PDGF-stimulated fibroproliferation. These results argue against a mechanism involving inhibition of adenosine reuptake as the mechanism for pentoxifylline's effect in this system. 8-Phenyltheophylline also did not alter the effect of pentoxifylline on baseline proliferation, suggesting that these effects of pentoxifylline are not mediated by adenosine receptors. Pentoxifylline is metabolized to several metabolites including 1-(5-hydroxyhexyl)-3,7-dimethylxanthine (metabolite-1). Metabolite-1 significantly reduced PDGF-stimulated fibroproliferation and was as effective as pentoxifylline. The combination of pentoxifylline and metabolite-1 had an additive effect. Metabolite-1 and pentoxifylline also reduced baseline proliferation. Preincubation of fibroblasts with 8-phenyltheophylline did not prevent the inhibitory action of metabolite-1 on PDGF-stimulated proliferation or on basal proliferation of fibroblasts, suggesting that the action of metabolite-1 on fibroproliferation was not mediated by adenosine receptors. Results using A1 and A2 adenosine receptor antagonists further suggest that the effect of pentoxifylline was not mediated by adenosine receptors.

Dose-Response Relationship, Drug↗

PubMed1994

Beneficial cardiopulmonary effects of pentoxifylline in experimental sepsis are lost once septic shock is established.

OBJECTIVE: To determine the effects of pretreatment and posttreatment with pentoxifylline in a porcine model of gram-negative sepsis. DESIGN: Nonrandomized controlled trial. STUDY SUBJECTS: Young Yorkshire swine. INTERVENTIONS: Six groups of ventilated swine were studied for 5 hours. Group 1 swine (control, n = 8) received saline solution only. Group 2 swine (sepsis, n = 8) received a 1-hour infusion of Pseudomonas aeruginosa. Groups 3, 4, and 5 swine received the P aeruginosa infusion and a 20 mg/kg bolus followed by a 6 mg/kg per hour infusion of pentoxifylline. Group 3 swine (n = 6) received pentoxifylline prior to the onset of sepsis; group 4 swine (n = 6) received pentoxifylline at 1 hour and group 5 swine (n = 4) at 2 hours after the onset of the P aeruginosa infusion. Group 6 swine (control pentoxifylline, n = 3) received pentoxifylline only. OUTCOME MEASURES: Hemodynamic variables, neutrophil counts and CD18 expression, tumor necrosis factor activity, and arterial blood gases were measured hourly. Bronchoalveolar lavage was performed at 0 and 5 hours to measure neutrophil and protein content. RESULTS: All variables remained unchanged in the control and control pentoxifylline groups. Both pretreatment and posttreatment with pentoxifylline significantly attenuated lung injury and improved arterial PaO2. The cardiac index was significantly improved by administration of pentoxifylline in groups 3 and 4. Administration of pentoxifylline to group 5 animals in established septic shock caused uncontrolled, fatal systemic hypotension in two of the four animals. Plasma tumor necrosis factor activity, blood polymorphonuclear leukocyte counts, and CD18 expression were unaffected by the administration of pentoxifylline. CONCLUSIONS: Pentoxifylline protects against pulmonary and systemic hemodynamic derangements in fulminant sepsis and protects against pulmonary dysfunction. Pentoxifylline has a "therapeutic window" when given in established sepsis; if administration is delayed until overt septic shock occurs, it may then have deleterious effects.

Animals↗

PubMedDate not supplied

Systemic treatment of venous leg ulcers with high doses of pentoxifylline: efficacy in a randomized, placebo-controlled trial.

Several small studies have indicated that the systemic administration of pentoxifylline may accelerate healing of venous leg ulcers. The goal of this study was to further evaluate these findings in a larger scale placebo controlled trial and to explore the effect of the dose of pentoxifylline on healing. The study used a prospective, randomized, double-blind, parallel group placebo controlled design in a multicenter outpatient setting. Patients with one or more venous ulcer were enrolled, with all patients receiving standardized compression bandaging for treatment for their ulcers. Patients were also randomized to receive either pentoxifylline 400 mg, pentoxifylline 800 mg (two 400 mg tablets), or placebo tablets three times a day for up to 24 weeks. The main outcome measure was time to complete healing of all leg ulcers, using life table analysis. The study was completed as planned in 131 patients. Patients receiving 800 mg three times a day of pentoxifylline healed faster than placebo (p = 0.043, Wilcoxon test). The median time to complete healing was 100, 83, and 71 days for placebo, pentoxifylline 400 mg, and pentoxifylline 800 mg three times a day, respectively. Over half of all patients were ulcer free at week 16 (placebo) and at week 12 in both pentoxifylline groups. Whereas the placebo group had only achieved complete healing in half of the cases by week 16, all of the subjects remaining in the group receiving the high dose of pentoxifylline had healed completely. Treatment with pentoxifylline was well tolerated with similar drop-out rates in all three treatment groups. Complete wound closure occurred at least 4 weeks earlier in the majority of patients treated with pentoxifylline by comparison to placebo. A higher dose of pentoxifylline (800 mg three times a day) was more effective than the lower dose. We conclude that pentoxifylline is effective in accelerating healing of leg ulcers.

Adult↗

PubMedDate not supplied

Pentoxifylline promotes development of murine colon adenocarcinoma-derived metastatic tumors in liver.

Pentoxifylline is commonly used in the treatment of peripheral vascular diseases. It improves microcirculatory flow and tissue perfusion. Moreover, pentoxifylline displays some immunomodulatory properties that presumably might affect the anticancer response. Therefore, the aim of the present study was to evaluate the influence of pentoxifylline on tumor development. Balb/c mice were injected with murine colon adenocarcinoma C-26 cells intravenously, into the vena portae, and divided into two groups. Mice from the experimental groups received daily intraperitoneal injections of pentoxifylline (30 mg/kg) while the controls were injected with 0.9% NaCl. Two weeks after C-26 cell inoculation mice were sacrificed and autopsy was performed. It was found that the livers of control animals revealed only several small tumor foci, whereas the livers of pentoxifylline-treated mice displayed numerous cancerous outgrowths. The mean liver weight in pentoxifylline group was 2.21+/-0.62 g as compared to 1.36+/-0.15 g in controls (P=0.004). Moreover, the influence of pentoxifylline on murine and human cell line proliferation in vitro was evaluated. It has been observed that pentoxifylline, at pharmacologically achievable concentrations, stimulated the proliferation of murine (C-26) and human (CaSki, U-937) cell lines. However, it did not stimulate human melanoma (WM-35) cell proliferation. Since there has been no evidence so far that pentoxifylline may promote tumor progression, it is still considered to be a safe drug. Moreover, some beneficial properties of pentoxifylline, which could be useful in cancer treatment, have been reported and a few clinical trials with oncological patients have been performed. Surprisingly, our study revealed that pentoxifylline significantly promoted C-26-derived metastatic tumor growth in liver. Although this model might be unique in its sensitivity to tumor-promoting effects of pentoxifylline, it cannot be excluded that similar effects might occur in some cases of tumors developing in humans. Such effects could be relevant, since the stimulatory influence of pentoxifylline on proliferation does not appear to be species- or tissue-specific.

Adenocarcinoma↗

PubMed1993

Effects of pentoxifylline on sperm motility and hyperactivation in normozoospermic and normokinetic semen.

OBJECTIVE: To determine the effects of in vitro incubation with pentoxifylline on sperm motion characteristics of spermatozoa from normozoospermic, normokinetic specimens. DESIGN: Prospective, controlled experiment. SETTING: Andrology laboratory, university-based fertility center. PARTICIPANTS: Healthy, untreated male partners of couples attending the fertility center. INTERVENTION: Each specimen was washed, pelleted by centrifugation, then resuspended in human tubal fluid medium (HTF). Two portions were incubated at 37 degrees C, one with pentoxifylline (final concentration = 1 mg/mL = 3.6 mM) and the other without pentoxifylline (control). After 1 hour, the pentoxifylline-treated portion was divided: one half was washed to remove pentoxifylline, then further incubated in HTF; the other half remained incubated in HTF with pentoxifylline. MAIN OUTCOME MEASURES: Motility, hyperactivation, amplitude of lateral head displacement (ALH), curvilinear velocity (VCL), straight line velocity (VSL), linearity (LIN), beat-cross frequency. RESULTS: Incubation with pentoxifylline did not increase motility, VSL, LIN, or beat-cross frequency but did significantly increase HA, VCL, and ALH at 1, 2, and 4 hours, compared with control. Incubation in control medium without pentoxifylline did not significantly increase any of the parameters measured. After 24 hours of incubation with or without pentoxifylline, all parameters measured were significantly decreased, with the exception of LIN. CONCLUSIONS: Pentoxifylline does not increase percentage motility of washed spermatozoa in capacitation medium. Enhancement of sperm HA by pentoxifylline in capacitation medium occurs with normozoospermic, normokinetic semen specimens. This effect persists for up to 4 hours when pentoxifylline is removed from the medium after 1 hour of incubation.

Analysis of Variance↗

PubMed1996

Acute haemodynamic responses and inhibition of tumour necrosis factor-alpha by pentoxifylline in rats with cirrhosis.

1. Although pentoxifylline has been shown to reduce portal hypertension, the mechanism for this is unclear. Since pentoxifylline decreases tumour necrosis factor-alpha production and since this cytokine may induce vasodilatation per se, a pentoxifylline-induced decrease in tumour necrosis factor-alpha production may limit arterial vasodilatation and decrease portal pressure. The aim of the present study was to examine the effects of pentoxifylline administration on plasma tumour necrosis factor-alpha concentration and haemodynamics in normal and cirrhotic rats. 2. In both groups, systemic and splanchnic haemodynamics and plasma tumour necrosis factor-alpha concentrations were measured before and 120 min after the administration of saline or pentoxifylline (20 mg/kg intravenous bolus). 3. In cirrhotic rats, pentoxifylline significantly decreased portal pressure (24 +/- 13%) and tributary blood flow (33 +/- 30%). On the other hand, pentoxifylline significantly increased vascular resistance in portal and hepatic arterial territories. Systemic haemodynamics were not altered. In normal rats, pentoxifylline significantly decreased portal pressure but induced no other significant changes in splanchnic or systemic haemodynamics. In cirrhotic rats, plasma tumour necrosis factor-alpha concentrations were significantly reduced after pentoxifylline administration but not after saline administration. No significant correlations were found between pentoxifylline-induced changes in tumour necrosis factor-alpha levels and changes in splanchnic haemodynamics. In normal rats, plasma tumour necrosis factor-alpha concentrations significantly decreased after pentoxifylline or saline administration. 4. This study shows that in rats with cirrhosis, pentoxifylline induces a decrease in both portal pressure and plasma tumour necrosis factor-alpha concentrations. These reductions were not correlated however.

Animals↗

PubMed1997

The acrosome reaction response assay: a new way to identify patients in whom pentoxifylline would improve the human follicular fluid-induced acrosome reaction.

The effect of pentoxifylline on the spontaneous and follicular fluid (hFF)-induced acrosome reaction (AR) was studied in an attempt to identify those patients who would benefit from the use of pentoxifylline as an AR-stimulating agent. Pentoxifylline (1 mg/ml) produced no significant increase over spontaneous AR at any of the time points studied (60 min: 6.2% +/- 2.0 spontaneous AR vs 7.4% +/- 2.0 pentoxifylline AR; 120 min: 7.1% +/- 1.6 spontaneous vs 9.0% +/- 2.5 pentoxifylline; 180 min: 7.0% +/- 1.8 spontaneous vs 10.9% +/- 4.0 pentoxifylline, n = 6). On the other hand, hFF produced a significant increase in AR (6.9% spontaneous AR vs 11.2% hFF AR, p < 0.001, n = 39) and this effect was enhanced by pre-incubation with pentoxifylline (15.0% pentoxifylline + hFF AR vs 11.2% hFF AR, p < 0.001). There were no differences in percentage AR induced by hFF or pentoxifylline + hFF between patients with normal (n = 16) and abnormal (n = 25) semen samples. Individual analysis of the effects of hFF and pentoxifylline + hFF on AR showed great variability between patients and enabled us to classify them into four categories: inducible-responder (15%), non-inducible-responder (23%), inducible-non-responder (41%) and non-inducible-non-responder (21%). An induction index (II) (induction produced by hFF divided by spontaneous AR) and a response index (RI) (induction produced by pentoxifylline + hFF divided by hFF) were calculated for each sample. Patients previously classified as inducible exhibited an II > 0.30 and patients previously classified as responders showed an RI > 0.26. There was no correlation between II and RI values (Spearman, r = -0.185, p = 1). Our results show that pentoxifylline is an enhancer of the induced AR only in some patients. We propose an 'AR response assay' to identify responder patients and thus enable rational use of this drug.

Acrosome↗