Pentoxifylline Research Articles

Sperm Activation with Pentoxifylline Is Beneficial For Non-Obstructive Azoospermia Patients Using Testicular Sperm before Intracytoplasmic Sperm Injection

Purpose: This study aimed to assess the efficacy and safety of sperm activation with pentoxifylline (PF) for non-obstructive azoospermia (NOA) patients that underwent testicular sperm aspiration (TESA) for intracytoplasmic sperm injection (ICSI) in in vitro fertilization (IVF) program. Methods: A total of 457 patients with 457 TESA- ICSI cycles who identified no motile spermatozoa under through scrutiny were included and divided into two groups. 121 cycles without PF treatment were recorded as control group. The other 336 cycles with PF treatment were recruited as PF group. The two groups were compared for demographics, routine parameters of IVF treatment, pregnancy rates, and neonatal outcomes. Results: The rates of fertilization, 2PN fertilization, D3 oocyte utilization and good-quality embryo in PF group were significantly higher than the control group (P < 0.05). Moreover, PF significantly reduced the total fertilization failure cycle rate, rate of cycles with no transferable embryo and the mean ICSI time per oocyte when compared with the control group (P < 0.05). Although no significant differences were observed between the two groups in the implantation rate, clinical pregnancy rate, miscarriage rates and live birth rate (P > 0.05), significantly increased cumulative live birth rate were found in the PF group (P > 0.05). Neonatal outcomes were comparable between the two groups, and no congenital anomalies were reported in the two groups. Conclusion: Sperm activation with pentoxifylline is beneficial for NOA patients who underwent TESA- ICSI treatment. However, further research with larger groups of couples to assess the long-term effect were still required.

Pentoxifylline Reduces Inflammation And Myocardial Perfusion Derangements In Experimental Chronic Chagas Cardiomyopathy In Hamsters.

Introduction Microvascular perfusion disturbance (MPD) is common in chronic Chagas cardiomyopathy (CCC) and may cause myocardial damage. Hypothesis Pentoxifylline (PT) is a phosphodiesterase inhibitor with anti-inflammatory properties that may lead to reduction of inflammation and MPD and attenuate the progression of the myocardial dysfunction in CCC. Methods We investigated 3 groups of hamsters: controls and treated with saline (CO, n=9), infected with T. cruzi and treated with saline (CH+SL, n=12), infected and treated with PT (CH+PT, n=12). After 6 months of infection and 60 days of PT (20 mg/kg/day, ip) or saline, the animals were submitted to echocardiography and to rest Sestamibi-Tc99m SPECT myocardial perfusion scintigraphy (MPS). The area of myocardial perfusion defects (PD) was assessed through the calculation of polar maps. After euthanasia, we performed a histopathological study of cardiac inflammation and gene expression of TNF-α. Results At baseline all groups showed similar areas of PD (CO: 0.0±0.0%, CH+SL:0.8±1.6%, CH+PT:1.9±3.0%, p>0.05) and LVEF (CO:53.4±5.6%, CH+SL:47.0±10.1%, CH+PT:53.9±6.5%, p>0.05). After treatment, there was a significant increase of the PD only in the CH+SL group (0.8±1.6 to 9.4±9.7%, p>0.05), and CH+PT animals exhibited PD area similar to CO animals 2.7±2.7% and 0.0±0.0%, respectively (p>0.05). Similar decrease of LVEF was seen in both infected groups: (CH+SL:40.0±13.7% and CH+PT:42.7±9.0%). No change of the LVEF was observed in CO (53.4±5.6%). Quantitative histological analysis revealed a larger number of nuclei of mononuclear inflammatory cells in CH+SL, 615.1±133.0 cel/mm² and CH+PT groups, 395.7±88.3 cel/mm² when compared to CO, 193.0 ± 25.7 cel/mm², p<0.001. A higher number of inflammatory cells was found in the CH+SL group when compared to the CH+PT group, p<0.001. TNF-α expression was higher in the CH+SL group (2.5±1.7) when compared to the CO (0.9±0.4), but similar to the CH+PT (2.4±1.7), p>0.9. There was a moderate correlation between PD and inflammatory cells (R=0.6) and LVEF (R=-0.7), p<0.0001 for both; and between LVEF and inflammatory cells (R=-0.4, p=0.01). Conclusions The prolonged use of PT in CCC animals was effective in reducing inflammation and progression of MPD evaluated in vivo. However, PT did not prevent the progression of left ventricular systolic dysfunction in this model. These results suggest that PD may represent a surrogate marker for inflammation and its potential use to monitor disease progression. Microvascular perfusion disturbance (MPD) is common in chronic Chagas cardiomyopathy (CCC) and may cause myocardial damage. Pentoxifylline (PT) is a phosphodiesterase inhibitor with anti-inflammatory properties that may lead to reduction of inflammation and MPD and attenuate the progression of the myocardial dysfunction in CCC. We investigated 3 groups of hamsters: controls and treated with saline (CO, n=9), infected with T. cruzi and treated with saline (CH+SL, n=12), infected and treated with PT (CH+PT, n=12). After 6 months of infection and 60 days of PT (20 mg/kg/day, ip) or saline, the animals were submitted to echocardiography and to rest Sestamibi-Tc99m SPECT myocardial perfusion scintigraphy (MPS). The area of myocardial perfusion defects (PD) was assessed through the calculation of polar maps. After euthanasia, we performed a histopathological study of cardiac inflammation and gene expression of TNF-α. At baseline all groups showed similar areas of PD (CO: 0.0±0.0%, CH+SL:0.8±1.6%, CH+PT:1.9±3.0%, p>0.05) and LVEF (CO:53.4±5.6%, CH+SL:47.0±10.1%, CH+PT:53.9±6.5%, p>0.05). After treatment, there was a significant increase of the PD only in the CH+SL group (0.8±1.6 to 9.4±9.7%, p>0.05), and CH+PT animals exhibited PD area similar to CO animals 2.7±2.7% and 0.0±0.0%, respectively (p>0.05). Similar decrease of LVEF was seen in both infected groups: (CH+SL:40.0±13.7% and CH+PT:42.7±9.0%). No change of the LVEF was observed in CO (53.4±5.6%). Quantitative histological analysis revealed a larger number of nuclei of mononuclear inflammatory cells in CH+SL, 615.1±133.0 cel/mm² and CH+PT groups, 395.7±88.3 cel/mm² when compared to CO, 193.0 ± 25.7 cel/mm², p<0.001. A higher number of inflammatory cells was found in the CH+SL group when compared to the CH+PT group, p<0.001. TNF-α expression was higher in the CH+SL group (2.5±1.7) when compared to the CO (0.9±0.4), but similar to the CH+PT (2.4±1.7), p>0.9. There was a moderate correlation between PD and inflammatory cells (R=0.6) and LVEF (R=-0.7), p<0.0001 for both; and between LVEF and inflammatory cells (R=-0.4, p=0.01). The prolonged use of PT in CCC animals was effective in reducing inflammation and progression of MPD evaluated in vivo. However, PT did not prevent the progression of left ventricular systolic dysfunction in this model. These results suggest that PD may represent a surrogate marker for inflammation and its potential use to monitor disease progression.

The protective effect of co-administration of platelet-rich plasma (PRP) and pentoxifylline (PTX) on cyclophosphamide-induced premature ovarian failure in mature and immature rats

Cyclophosphamide (CP), as an antineoplastic agent, causes premature ovarian failure (POF) due to ovarian toxicity and subsequent infertility in women. Platelet-rich plasma (PRP) has accumulated significant attention in regenerative medicine. Pentoxifylline (PTX) as a methylxanthine derivative has been shown to have antioxidant and antiapoptotic properties. The aim of this study was to evaluate the protective effect of PRP and PTX on CP-induced POF. Fifty mature and immature female rats were assigned into five groups: control, CP (75 mg/kg, intraperitoneal [ip] on days 1 and 10 to induce POF), CP + PRP (200 μl, ip, half an hour after CP injection on day 1 and 10), CP + PTX (50 mg/kg, orally, half an hour after CP injection daily for 21 day), and CP + PRP + PTX. At the end of experiments on day 21, measurement of body weight, ovarian parameters (ovarian volume, follicular granulosa cell layers diameter, oocyte diameter, and the number of granulosa cells), measurement of ovarian hormone in sera for estradiol (E2), and anti-Mullerian hormone (AMH), as well as biochemical assessment were performed. The results showed that CP significantly reduced the ovarian parameters, E2, AMH, superoxide dismutase (SOD) activity and increased Malondialdehyde (MDA) levels compared to the control group (p < 0.001). Our results also indicated that all histomorphometric parameters and biochemical markers in CP-induced POF, were preserved close to normal by PRP and PTX treatments in both mature and immature rats (p < 0.001). Therefore, it is concluded that the co-administration of PRP and PTX can protect the ovary from CP-induced POF.

Fat Grafts Augmented With Vitamin E Improve Volume Retention and Radiation-Induced Fibrosis.

Treatments for radiation-induced fibrosis range from vitamin E (VE) and pentoxifylline (PTX) systemically to deferoxamine and fat grafting locally. Regarding fat grafting, volume retention hinders its long-term functionality and is affected by 2 factors: inflammation and necrosis secondary to hypovascularity. The authors aimed to simultaneously improve fat graft retention and radiation-induced fibrosis by integrating VE and PTX into fat grafts locally. Forty adult CD-1 nude male mice, 6 weeks old, underwent scalp irradiation and recovered for 4 weeks to allow for development of fibrosis. Mice received 200 μL of donor human fat graft to the scalp. Mice were separated into 4 conditions: no grafting, fat graft without treatment, graft treated with PTX, and graft treated with VE. Fat graft volume retention was monitored in vivo with micro-computed tomography scans at weeks 0, 1, 2, 4, 6, and 8 after grafting. Histological and cytokine analysis of the scalp skin and fat grafts were performed. VE-treated grafts had significant improvement in dermal thickness and collagen density of overlying skin compared with all other groups. VE decreased 8-isoprostane and increased CD31+ staining compared with the other grafted groups. Cytokine analysis revealed decreased inflammatory and increased angiogenic markers in both the fat graft and overlying skin of the VE group. Fat graft volume retention was significantly improved in the VE group starting at 1 week post grafting. Radiation-induced fibrosis and fat graft volume retention are both simultaneously improved with local administration of VE.

Pentoxifylline-induced protein expression change in RAW 264.7 cells as determined by immunoprecipitation-based high performance liquid chromatography.

Although pentoxifylline (PTX) was identified as a competitive non-selective phosphodiesterase inhibitor, its pharmacological effect has not been clearly elucidated. The present study explored the effect of low dose 10 μg/mL PTX (therapeutic dose) compared to high dose 300 μg/mL PTX (experimental dose) in RAW 264.7 cells through immunoprecipitation-based high performance liquid chromatography (IP-HPLC), immunohistochemistry, and western blot. 10 μg/mL PTX increased the expression of proliferation (Ki-67, PCNA, cyclin D2, cdc25A), epigenetic modification (KDM4D, PCAF, HMGB1), protein translation (DOHH, DHPS, eIF5A1), RAS signaling (KRAS, pAKT1/2/3, PI3K), NFkB signaling (NFkB, GADD45, p38), protection (HSP70, SOD1, GSTO1/2), survival (pAKT1/2/3, SP1, sirtuin 6), neuromuscular differentiation (NSEγ, myosin-1a, desmin), osteoblastic differentiation (BMP2, RUNX2, osterix), acute inflammation (TNFα, IL-1, CXCR4), innate immunity (β-defensin 1, lactoferrin, TLR-3, -4), cell-mediated immunity (CD4, CD8, CD80), while decreased the expression of ER stress (eIF2α, eIF2AK3, ATF6α), fibrosis (FGF2, CTGF, collagen 3A1), and chronic inflammation (CD68, MMP-2, -3, COX2) versus the untreated controls. The activation of proliferation by 10 μg/mL PTX was also supported by the increase of cMyc-MAX heterodimer and β-catenin-TCF1 complex in double IP-HPLC. 10 μg/mL PTX enhanced FAS-mediated apoptosis but diminished p53-mediated apoptosis, and downregulated many angiogenesis proteins (angiogenin, VEGF-A, and FLT4), but upregulated HIF1α, VEGFR2, and CMG2 reactively. Whereas, 300 μg/mL PTX consistently decreased proliferation, epigenetic modification, RAS and NFkB signaling, neuromuscular and osteoblastic differentiation, but increased apoptosis, ER stress, and fibrosis compared to 10 μg/mL PTX. These data suggest PTX has different biological effect on RWA 264.7 cells depending on the concentration of 10 μg/mL and 300 μg/mL PTX. The low dose 10 μg/mL PTX enhanced RAS/NFkB signaling, proliferation, differentiation, and inflammation, particularly, it stimulated neuromuscular and osteoblastic differentiation, innate immunity, and cell-mediated immunity, but attenuated ER stress, fibrosis, angiogenesis, and chronic inflammation, while the high dose 300 μg/mL PTX was found to alleviate the 10 μg/mL PTX-induced biological effects, resulted in the suppression of RAS/NFkB signaling, proliferation, neuromuscular and osteoblastic differentiation, and inflammation.

Pentoxifylline in the Treatment of Cutaneous Leishmaniasis: A Randomized Clinical Trial in Colombia.

Addition of the immunomodulator pentoxifylline (PTX) to antimonial treatment of mucosal leishmaniasis has shown increased efficacy. This randomized, double-blind, placebo-controlled trial evaluated whether addition of pentoxifylline to meglumine antimoniate (MA) treatment improves therapeutic response in cutaneous leishmaniasis (CL) patients. Seventy-three patients aged 18–65 years, having multiple lesions or a single lesion ≥ 3 cm were randomized to receive: intramuscular MA (20 mg/kg/day × 20 days) plus oral PTX 400 mg thrice daily (intervention arm, n = 36) or MA plus placebo (control arm, n = 37), between 2012 and 2015. Inflammatory gene expression was evaluated by RT-qPCR in peripheral blood mononuclear cells from trial patients, before and after treatment. Intention-to-treat failure rate was 35% for intervention vs. 25% for control (OR: 0.61, 95% CI: 0.21–1.71). Per-protocol failure rate was 32% for PTX, and 24% for placebo (OR: 0.50, 95% CI: 0.13–1.97). No differences in frequency or severity of adverse events were found (PTX = 142 vs. placebo = 140). Expression of inflammatory mediators was unaltered by addition of PTX to MA. However, therapeutic failure was associated with significant overexpression of il1β and ptgs2 (p < 0.05), irrespective of study group. No clinical benefit of addition of PTX to standard treatment was detected in early mild to moderate CL caused by Leishmania (V.) panamensis.

Bronco T (Shirisadi kasaya), a polyherbal formulation prevents LPS induced septicemia in rats.

Here, Bronco T (BT), a polyherbal formulation developed in 1984 for treating asthma, has been repurposed against septicemia-induced ALI. Lipopolysaccharides (3 mg/kg BW) were injected intraperitoneally before 24 hours of surgery to assess the cardiorespiratory parameters, blood PaO2/FiO2 and MPO, pulmonary water content and histological changes in the lungs. The pentoxifylline (PTX) (25 mg/kg BW) was used as the positive control and given one hour before LPS. BT was given 3 hours (orally at different doses of 3, 1.5 and 0.75 g/kg BW) before LPS. The LPS treated group showed significant bradypnea, hypotension and bradycardia, through elongated peaks (RR) and (MAP) respectively and finally death after 95 minutes of LPS injection. The PTX and BT (3 g/kg BW) pretreatment significantly prevented these changes (dose-dependent in the BT group). The survival in these groups was maintained up to 190 min after LPS. The Pentoxifylline showed a better response (75%) than Bronco T (72%). In both the treatments, a significant decrease in pulmonary water content and minimal neutrophil infiltration and intact alveoli-capillary membrane was seen in the transverse section (T.S) of the lungs. Significant improvement was noted in survival time with lesser tissue damage and improved pulmonary function was observed by pre-treating with Bronco T in LPS induced septicemia.

Protective effects of recombinant human golimumab and pentoxifylline in nephrotoxicity induced by cisplatin.

In cisplatin-induced nephrotoxicity, the significant role of activation of inflammatory pathways has been reported earlier. Studies indicate elevated expression and activity of tumor necrosis factor-α (TNF-α) in both, serum and kidneys of cisplatin-treated animals. Golimumab, an anti-TNF biologic, has been approved for the management of many inflammatory conditions. This experiment was planned and executed to evaluate the impact of golimumab on renal function, inflammation in cisplatin-induced nephrotoxicity in mice, and oxidative stress. Cisplatin (22 mg/kg) as a single intraperitoneal injection was used to induce nephrotoxicity in mice. Golimumab was administered at 24 mg/kg for 7 days by subcutaneous route. Pentoxifylline (PTX) was administered for 7 days (150 mg/kg) as a reference standard. Renal functions, oxidative stress, and inflammation were evaluated on the seventh day. Cisplatin administration in mice caused a significant rise in serum cystatin C, creatinine, blood urea nitrogen, and neutrophil gelatinase-associated lipocalin. A significant rise of urinary clusterin, kidney injury molecule-1, and β-N-acetylglucosaminidase levels was also seen in cisplatin-treated animals. Furthermore, cisplatin-induced nephrotoxicity was associated with a significant increase in oxidative stress and inflammation in serum and kidneys. Golimumab treatment significantly prevented the cisplatin-induced alteration in markers of renal function and renal damage. There was a significant reduction in oxidative stress and inflammation in golimumab-treated animals. Furthermore, the histopathological evaluation also revealed inverted changes in the proximal tubules after golimumab treatment in kidneys after cisplatin toxicity. The standard drug, PTX, also prevented nephrotoxicity caused by cisplatin as indicated by the recovery in renal function, reduction in oxidative stress and inflammation. These results indicate that golimumab was effective in nephrotoxicity induced by cisplatin through inhibition of oxidative stress, and inflammatory response.

Efficacy and Safety of Pentoxifylline for Venous Leg Ulcers: An Updated Meta-Analysis

In this meta-analysis, pentoxifylline (PTX) use significantly improved venous ulcer healing rates compared with placebo but was associated with a greater incidence of gastrointestinal (GI) disturbances.

A Potential Role of Ethosuximide and Pentoxifylline in Relieving Abdominal Pain in Irritable Bowel Syndrome Patients Treated with Mebeverine: A Randomized, Double-Blind, Placebo-Controlled Trial.

Background and PurposeIrritable bowel syndrome (IBS) is defined as an association of chronic abdominal pain with bowel habit abnormalities, without clear organic dysfunction. T-type calcium channels and low-grade mucosal inflammation are linked to abdominal pain; however, medical treatments for IBS abdominal pain are largely ineffective. In this study, we investigated if pentoxifylline (PTX) and ethosuximide could potentially alleviate abdominal pain in patients with IBS treated with mebeverine.MethodsWe recruited 150 patients from Tanta University Hospital to this randomized, prospective, and double blinded study. Patients were randomly allocated to three groups (n = 50). Group 1 (mebeverine) received 135 mg mebeverine three times/day (t.i.d). Group 2 (ethosuximide group) received 135 mg mebeverine t.i.d plus 250 mg ethosuximide twice daily (b.i.d) and group 3 (PTX group) received 135 mg mebeverine t.i.d plus 400 mg PTX b.i.d. Patients were assessed by a gastroenterologist at baseline and 6 months after therapy. Serum interleukin-8 (IL-8), IL-6, tumor necrosis-α (TNF-α), fecal myeloperoxidase, and fecal neutrophil gelatinase associated lipocalin (NGAL) levels were measured before and after therapy. The numeric pain rating scale (NRS) was also assessed before and after therapy.Primary OutcomesReduced NRS scores and abdominal pain relief.Secondary OutcomesDecreased inflammatory biomarkers.ResultsAfter 6 months, groups 2 and 3 showed a significantly greater reduction in serum IL-8, IL-6, TNF-α, fecal myeloperoxidase, and fecal NGAL levels when compared to group 1 after therapy. Both groups 2 and 3 showed significant reductions in NRS scores when compared to the group 1.ConclusionEthosuximide and PTX may be promising, novel adjunct drugs to antispasmodics for relieving abdominal pain in patients with IBS.Trial RegistrationIdentifier: NCT04217733.

Modulation of miR-145-5p and miR-146b-5p levels is linked to reduced parasite load in H9C2 Trypanosoma cruzi infected cardiomyoblasts

In the heart tissue of acutely Trypanosoma cruzi-infected mice miR-145-5p and miR-146b-5p are, respectively, downregulated and upregulated. Here, we used the H9C2 rat cardiomyoblast cell line infected with the Colombian T. cruzi strain to investigate the parasite-host cell interplay, focusing on the regulation of miR-145-5p and miR-146b-5p expression. Next, we explored the effects of interventions with the trypanosomicidal drug Benznidazole (Bz) alone or combined with Pentoxifylline (PTX), a methylxanthine derivative shown to modulate immunological and cardiac abnormalities in a model of chronic chagasic cardiomyopathy, on parasite load and expression of miR-145-5p and miR-146b-5p. The infection of H9C2 cells with trypomastigote forms allowed parasite cycle with intracellular forms multiplication and trypomastigote release. After 48 and 144 h of infection, upregulation of miR-145-5p (24 h: 2.38 ± 0.26; 48 h: 3.15 ± 0.9-fold change) and miR-146b-5b (24 h: 2.60 ± 0.46; 48 h: 2.97 ± 0.23-fold change) was detected. The peak of both miRNA levels paralleled with release of trypomastigote forms. Addition of 3 µM and 10 µM of Bz 48 h after infection reduced parasite load but did not interfere with miR-145-5p and miR-146b-5p levels. Addition of PTX did not interfere with Bz-induced parasite control efficacy. Conversely, combined Bz + PTX treatment decreased the levels of both microRNAs, resembling the expression levels detected in non-infected H9C2 cells. Moreover, the use of miR-145-5p and miR-146b-5p mimic/inhibitor systems before infection of H9C2 cells decreased parasite load, 72 h postinfection. When H9C2 cells were treated with miR-145-5p and miR-146b-5p mimic/inhibitor 48 h after infection, all the used systems, except the miR-146b-5p inhibitor, reduced parasite load. Altogether, our data indicate that these microRNAs putatively control signaling pathways crucial for parasite–host cell interaction. Thus, miR-145-5p and miR-146b-5p deserve to be further investigated as biomarkers of parasite control and tools to identify therapeutic adjuvants to etiological treatment in Chagas disease.

Treatment of Poor Sperm Quality and Erectile Dysfunction With Oral Pentoxifylline: A Systematic Review.

Background: Pentoxifylline (PTX) is a member of methylxanthine chemicals and a type of non-selective phosphodiesterase-5 inhibitors, which has been used in male infertility treatment to improve sperm quality and erectile dysfunction (ED) treatment. Mutually tight associations existed between ED and male infertility. Using PTX might kill two birds with one stone by improving sperm quality and erectile function in infertile men with ED. Methods: PubMed, Cochrane Library, EMBASE, and Web of Science were searched by October 2021. Based on available evidence from observational studies and randomized-controlled trials (RCTs), we conducted a systematic review to summarize the efficacy and safety of PTX in treating ED and male infertility. The protocol of the article was registered and updated in PROSPERO (CRD42021291396). Results: From 202 records, eight studies (7 RCTs) evaluating the role of PTX in ED and three studies (2 RCTs) assessing the efficacy of PTX in male infertility were included in the systematic review. Three studies (100.00%) and two studies (100.00%) reported the beneficial role of PTX in improving sperm progressive motility and normal sperm morphology rate, respectively. In contrast, only one study (33.33%) indicated the favorable role of PTX in enhancing sperm concentration. As for ED, three (60.00%) studies supported the treatment role of PTX alone in ED, and two studies (66.67%) favored the combination use of PTX and selective PDE5Is compared with selective PDE5Is alone. Safety analysis showed that PTX was a well-tolerated drug in ED and male infertility treatment. Conclusion: Given the association between ED and male infertility and satisfying findings from available evidence, PTX administration for the simultaneous treatment of poor sperm quality and mild ED in infertile men will highly enhance the treatment compliance. However, the finding should be treated carefully until validated by further studies.

Protective Effects of Trehalose and Pentoxifylline on Goat Sperm Exposed to Chilling-Freezing Process.

Freezing of sperm is known as an important part of assisted reproduction. However, many studies have illustrated that cryopreservation negatively affects the quality and fertility rate of sperm. This study aimed to evaluate the effects of trehalose and pentoxifylline (PTX) in diluents on cooled and frozen-thawed Markhoz goat sperm. Preassessed samples were pooled and diluted with a basic diluent using trehalose and PTX. The cooled sperm showed significant improvement. The motion characteristics of cryopreserved sperm were evaluated based on computer-assisted system analysis. In this study, we investigated the viability, membrane integrity, malondialdehyde concentration, total abnormality, acrosome integrity, and seminal hyaluronidase enzyme. Also, the hypo-osmotic swelling test, mitochondrial activity, apoptotic features, caspase activity, chromatin dispersion test, active mitochondria, and reactive oxygen species (ROS) activity were assessed as complementary parameters. The data illustrate that the total motility, progressive motility, average path velocity (VAP), straight-line velocity (VSL), curvilinear velocity (VCL), and the ratio of sperm chromatin dispersion, viable sperm were improved significantly (p < 0.05) using 3 mM PTX alone or 3 mM PTX plus 50 mM trehalose, while other characteristics indicate significant enhancement by 3 and 6 mM PTX and 50 and 70 mM trehalose alone or in combination, except amplitude of lateral head displacement (ALH), beat/cross frequency (BCF), and intracellular ROS-(O-), which demonstrate no significant difference among treatments. In conclusion, this study indicates that addition of 3 and 6 mM PTX alone or with 50 and 70 mM trehalose seems to reduce the damage caused by cooling and cryopreservation processes.

Protective effects of pentoxifylline on T-cell viability under inflammatory conditions

Introduction: Pentoxifylline (PTX) reduces the levels of pro-inflammatory cytokines; however, its effects on immune system is not well understood. The aim of this study was to investigate the effect of PTX on T cells under inflammatory conditions in co-culture with THP-1-derived macrophages.Methods: Toll-like receptor 4 (TLR4) and macrophage migration inhibitory factor (MIF) levels were measured after addition of PTX to lipopolysaccharide (LPS)-stimulated differentiated THP-1 cells. T cell viability and MIF levels were measured after PTX was added to prostaglandin E2(PGE2)-stimulated Jurkat T-cell leukemia line. Co-culture was conducted to determine the effect of LPS-stimulated differentiated THP-1 cells that are affected by PTX on Jurkat cells. To prevent the direct effects of LPS and PTX on Jurkat cells, LPS and PTX were washed from THP-1 cells before co-culture. T cell viability and interleukin-2 (IL-2) levels were determined in Jurkat cells. Results: Increase in the MIF concentration and TLR4expression level in differentiated THP-1 cells stimulated with LPS were reversed after PTX addition. However, PTX did not improve T cell viability in PGE2–stimulated Jurkat cells. Co-culturing Jurkat cell and LPS-stimulated differentiated THP-1 cells resulted in a decreased viability of T cells. The addition of PTX restored T cell viability to normal control levels and IL-2 expression level in Jurkat cells. Conclusion: LPS-stimulated THP-1-derived macrophages reduced the T cell viability under inflammation. However, PTX restored T cells viability and IL-2 back to normal levels. Therefore, the immunomodulatory action of PTX may be mediated by macrophage-T cell interactions.

Possible ameliorative effects of pentoxifylline on cisplatin-induced ototoxicity in rats: a study with hearing test, light, and scanning electron microscopy

Cisplatin is an antineoplastic drug widely used to treat various types of cancer. Ototoxicity is still cisplatin’s most critical side-effect. Some patients may experience dose limitations due to hearing loss. Pentoxifylline (PX) exhibits powerful antioxidant, anti-inflammatory, and immune-regulatory effects. Our study was designed to investigate the protective effects of pentoxifylline on cisplatin-induced ototoxicity. Forty adult male healthy Sprague-Dawley rats were used through the entire experiment. Four groups of animals were categorized: Group I (control group); Group II (PX group) received 25 mg/kg/day of oral PX by gavage for 8 consecutive days; Group III (Cisplatin group) received cisplatin single intraperitoneal dose of 10 mg/kg; Group IV (PX + Cisplatin group) received 25 mg/kg/day of oral PX by gavage for 8 successive days and a single intraperitoneal dose of 10 mg/kg cisplatin at the 4th day. First and 9th-day Distortiondistortion-product otoacoustic emissions (DPOAE) tests were conducted. An intracardiac blood sample was collected for total antioxidant capacity (TAC) measurement, and the cochleae of rats were examined histopathologically. A significant reduction in serum TAC value was detected in the cisplatin group, while PX treatment significantly reduced TAC. Cisplatin decreased the DPOAE amplitudes in rats; conversely, the PX+cisplatin group showed a significant increase at all frequencies. Upon histopathological examination, the Ciplastin group revealed perturbation of the normal architecture of the organ of Corti, increased collagen deposition and marked expression of caspase-3, while the PX+cisplatin group revealed preserved architecture of the organ of Corti, minimal collagen deposition and downregulation of Caspase-3 expression. As evidenced by our findings and results from DPOAE results, biochemical findings, histological and ultrastructural analyses, PX significantly protects rats against ototoxicity caused by cisplatin.

The impacts of oxygen and pentoxifylline in hypoxic condition

Introduction:Among major trauma patients in the emergency department, the leading cause of morbidity and mortality is a hemorrhagic shock. The low oxygen flow with hypovolemia in trauma patients is believed to play a significant role. Hence, oxygen supply is essential in severe trauma patients with massive hemorrhage. This study aimed to investigate the effect of oxygen supply in hypoxic condition and variable treatments such as pentoxifylline (PTX), glycerol, hypertonic saline (HTS), protease inhibitor, and dexamethasone (DEXA) in macrophage and T cells. Method:Nitric oxide synthase (iNOS) and macrophage migration inhibitory factor (MIF) were measured for macrophage. MIF, interleukin (IL)-2, and IL-8 were measured for T cells. T cell viability was measued by MTT assay. Results: Pentoxifylline decreased iNOS expression mostly followed by glycerol under hypoxia. Under the hyperoxia, PTX and other treatments decreased iNOS expressions in macrophage. MIF expression was lowered with PTX under hypoxia. PTX, glycerol, HTS, and protease inhibitor were effective under hyperoxia in macrophage. PTX increased T cell survival under hypoxia. Under the hyperoxia, IL-2 expressions were upregulated with PTX, glycerol, and HTS. PTX and other treatments were effective for IL-8. Our results indicate that the PTX and the other agents tested reversed the effects of stimulation of lipopolysaccharide, PGE2in hypoxia or hypoxia. Conclusion:Our study demonstrated potential usefulness in improving immune systems during severe inflammatory conditions similar to septic shock possibly caused by massive hemorrhage.

Pentoxifylline induces caspase-dependent apoptosis in colorectal cancer cells

BackgroundColorectal cancer is a leading cause of mortality worldwide. Resistance of this cancer to the available chemotherapeutic agents creates a need to develop new therapeutic agents. Pentoxifylline (PTX) has been shown to have anticancer effects on multiple cancer types. ObjectiveIn this study, we evaluated the anticancer effect of PTX in CRC cells. MethodsWe measured PTX's effect on cell proliferation using the MTT assay and on cell death induction by PI staining/flowcytometry. We also assessed the effect of treatment on mitochondrial membrane potential (MMP). ResultsWe found that PTX arrested the growth SW480 CRC cells with a peak effect plateauing at 10 mM of PTX after 72 h of treatment. Surprisingly, similar effect wasn't noticed in HCT-116 cells. Similar pattern of effect was noticed on apoptosis of both cell lines, as PTX induced more apoptosis on SW480 cells with no similar effect on HCT-116 cells. Studies using variable caspase inhibitors showed involvement of primarily capsase-9, as well as caspases-2 and -3 but not capsase-8. PTX also induced MMP changes leading to caspase-dependent apoptotic cell death. In addition to that, results indicated that apoptosis was caspase-dependent and was mediated through the mitochondria. ConclusionThese findings indicate that PTX has a promising antitumor activity against CRC cells and warrants further clinical evaluation.

Pentoxifylline Prevents Restenosis by Inhibiting Cell Proliferation via p38MAPK Pathway in Rat Vein Graft Model

Coronary artery bypass grafting remains the gold standard in the therapy of advanced-stage patients. But the vein grafts are prone to restenosis or failure. Pentoxifylline (PTX) is a methylxanthine derivative with a function of inhibiting cell proliferation. We thus applied PTX locally to the vein grafts to study its effect on the inhibition of graft restenosis using a rat vein graft model. Morphometric results showed a significant decrease in the thickness of vein grafts intimal and medial at day 28 after the bypass operation. Results from Western blot and immunohistochemistry showed that PTX also significantly reduced the proliferating cell nuclear antigen (PCNA), alpha-smooth muscle actin (α-SMA) expression, and phosphorylation of p38 in vein grafts. These results firstly discovered the positive role of PTX in preventing the vein grafts restenosis and the mechanism may be inhibition of vascular smooth muscle cells (VSMCs) proliferation via the p38MAPK pathway.

Effect of pentoxifylline on colon cancer patients treated with chemotherapy (Part I).

Cancer progression is associated with significant systemic clinical manifestations including cachexia induced weight loss and anorexia. Pentoxifylline (PTX) is a drug that has been shown to have multiple beneficial effects in cancer patients through its anti-inflammatory properties. To evaluate PTX effects on colon cancer patients treated with chemotherapy. Forty metastatic colon cancer patients receiving chemotherapy were enrolled in this randomized study. 17 patients were treated with a full dose of PTX (400 mg TID), 9 patients with a reduced dose PTX (200 mg TID) and 23 served as controls (no PTX). Follow-up evaluations of patients included the following: physical examination; leukopenia determination; weight determination; stomatitis determination; and survival rate. Patients treated with PTX (both full and reduced doses), experienced a significant increase in weight and a reduction in stomatitis relative to the control group. Treatment with PTX also significantly increased patient survival rate. All patients treated with PTX, had a median overall survival (OS) rate of 20.4 months as compared to 13.2 months in the control group. PTX treatment of colon cancer patients, in addition to chemotherapy, significantly improved survival rates, induced weight gain and reduced stomatitis occurrence -all important parameters of cachexia.

In vitro effects of pentoxifylline and coenzyme Q10 on the sperm of oligoasthenoteratozoospermia patients

The effect of in-vitro sperm incubation with Pentoxifylline (PTX) and Coenzyme Q10 (CoQ10) in Oligoasthenoteratozoospermia (OAT) patients was evaluated. Semen samples were obtained from men with Normozoospermia and men with OAT. Motile sperm from the two groups were subdivided into four subgroups: (i) without incubation with PTX + CoQ10; (ii) incubation with PTX; (iii) Incubation with CoQ10; and (iv) incubation with a combination of PTX + CoQ10. Then, sperm parameters, chromatin, DNA and membrane integrity, protamine deficiency, apoptosis, mitochondrial activity, sperm chromatin dispersion test (SCD), hypo-osmotic swelling test (HOS), chromomycin A3 (CMA3), Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL), and diaminobenzidine (DAB) assays were evaluated, respectively. Sperm incubated with CoQ10 and a combination of CoQ10 and PTX resulted in a significant increase in the sperm parameters. Also, a significant decrease was noted with a combination of PTX and CoQ10 in normal men. There was a significant difference between CoQ10 treated and CoQ10 + PTX treated groups in comparison with the OAT group in the percentage of the DNA fragmentation, sperm apoptosis, AB+, HOS test + and sperm mitochondrial activity. Incubated sperm with CoQ10, PTX, and in combination with each other can improve sperm parameters in OAT patients.