Concentrations Of Pentoxifylline Research Articles

Pentoxifylline/Chitosan Films on Wound Healing: In Vitro/In Vivo Evaluation.

This study aimed to develop films of chitosan (CSF) associated with pentoxifylline (PTX) for healing cutaneous wounds. These films were prepared at two concentrations, F1 (2.0 mg/mL) and F2 (4.0 mg/mL), and the interactions between the materials, structural characteristics, in vitro release, and morphometric aspects of skin wounds in vivo were evaluated. The formation of the CSF film with acetic acid modifies the polymeric structure, and the PTX demonstrates interaction with the CSF, in a semi-crystalline structure, for all concentrations. The release for all films was proportional to the concentration, with two phases: a fast one of ≤2 h and a slow one of >2 h, releasing 82.72 and 88.46% of the drug after 72 h, being governed by the Fickian diffusion mechanism. The wounds of the mice demonstrate a reduction of up to 60% in the area on day 2 for F2 when compared to CSF, F1, and positive control, and this characteristic of faster healing speed for F2 continues until the ninth day with wound reduction of 85%, 82%, and 90% for CSF, F1, and F2, respectively. Therefore, the combination of CSF and PTX is effective in their formation and incorporation, demonstrating that a higher concentration of PTX accelerates skin-wound reduction.

Accurate prediction of drug-induced heterogeneous response of red cell in vivo using a gravity-driven flow cytometry based on a microfluidic chip

The drug-induced diverse response among patients is a severe problem for improving hemorheological character. However, there is no validated method for personalized therapy to the best of our knowledge. Here, we apply a gravity-driven deformability cytometry platform (GD-DCP) to profile the drug response of the red cell deformability (RCD) at the single-cell level using pentoxifylline (PTX) as a model drug, the effect of different concentrations of PTX (0, 2, 20, 200 μg mL−1, the clinical dosage of PTX is 20 μg mL−1) on RCD in patients with cardiovascular disease was explored. Based on the GD-DCP, about 38 and 56% of the acute phase of acute myocardial infarction (AMI) patients in the acute phase and coronary heart disease (CHD) patients respond positively to PTX, respectively, indicating that PTX has a strong patient dependency on RCD. Moreover, RCD is observed to be significantly inversely correlated with the activation of membrane protein kinase C (PKC) as well as the concentration of Ca2+ (both P < 0.001). The results of animal experiments show that the protective effects of PTX on myocardial ischemia rats have substantial individual variation, too. It is noted that the effect of PTX is highly consistent between RCD in vitro and in vivo outcomes (blood viscosity, myocardial injury, and electrocardiogram (ECG)) in the same rat. All these new findings suggest that the GD-DCP is a promising method that uses deformability in vitro as one of the important criteria in personalized medicine, and our study provides unique insight into the individual-dependent mechanisms of PTX for improving RCD.

Antioxidant potential of pentoxifylline on spermatozoa of small ruminants

Objective: To investigate antioxidant potential of pentoxifylline on spermatozoa of small ruminants including rams and bucks. Methods: The levels of hydrogen peroxide (H2O2) production in ram and buck spermatozoa incubated with 0 (control), 4 and 8 mM of pentoxifylline were measured after 45-min incubation. Then, the motility parameters of ram and buck spermatozoa incubated with 0 (control), 1 mM of H2O2, 1 mM of H2O2 plus 4 mM of pentoxifylline, and 1 mM of H2O2 plus 8 mM of pentoxifylline were analysed. H2O2 was estimated using a fluorometric assay and spermatozoa motility characteristics were analyzed using computer aided sperm analyzer. Results: Pentoxifylline significantly decreased the levels of H2O2 produced from both ram and buck spermatozoa (P&lt;0.05), and significant lower rates of H2O2 formation were noted when 8 mM of pentoxifylline was added (P&lt;0.05). The values of all sperm motility parameters for the two species significantly decreased after incubation with H2O2 (P&lt;0.05). In contrast, when the spermatozoa were incubated with both H2O2 and two concentrations of pentoxifylline, the motility values rose significantly compared to those incubated with H2O2 alone (P&lt;0.05). For both ram and buck sperm samples, the rapid and static subpopulation motility parameters were the most affected categories by pentoxifylline addition compared to the medium and slow categories. Conclusions: Pentoxifylline possesses an antioxidant capacity proved by its ability of reducing H2O2 levels as well as by increasing motility values of stressed spermatozoa. Therefore, pentoxifylline could be recommended as antioxidant additive for spermatozoa of small ruminants under stress conditions.

HPLC Method Validation for Determination of Pentoxifylline in Pharmaceutical Dosage Forms

Selective and simple reversed phase High Performance Liquid Chromatography (RP-HPLC) method was developed and validated for quantification of pentoxifylline in dosage forms available in local market. Firstly, different chromatographic conditions were tested. Then, the optimized method was validated. The method proven to be linear over 50% to 150% of the nominal concentration of standard pentoxifylline (R2 0.994). The method was accurate (recovery 100.1%) and precise (RSD% &lt;3%). The method could separate pentoxifylline of caffeine and degradation products. The method was suitable for routine analysis of pentoxifylline in tablet dosage forms.

Decrease of Tumor-infiltrating Regulatory T Cells Using Pentoxifylline: An Ex Vivo Analysis in Triple-negative Breast Cancer Mouse Model.

Triple-negative breast cancer (TNBC) is the most aggressive type of BC with the highest percentage of tumor-infiltrating lymphocytes (TILs). Hence, TIL therapy is considered a promising approach to target TNBC. Depletion of regulatory T cells (Tregs) in TILs can improve the antitumor function of TIL therapy. Pentoxifylline (PTXF) is a xanthine derivative that can modulate the nuclear factor kappa B (NF-κB) signaling and probably affect the Treg proportion in TILs. We aimed to evaluate the ex vivo effect of PTXF on the proportion of Treg cells in the TILs derived from a mouse model of TNBC. The 4T1 cells were inoculated subcutaneously to BALB/c mice to induce TNBC. TILs were isolated from tumor tissue by enzymatic digestion and cultured alone or with 4T1 cells for 24, 48, and 72 h in the presence of interleukin (IL)-2 and different concentrations of PTXF. The toxicity of PTXF and its effects on Tregs proportion as well as cytokine production was evaluated using MTT assay, flow cytometry, and ELISA, respectively. PTXF had no significant impact on the viability of TILs. Both 500 and 1000 mg/mL of PTXF decreased the proportion of Tregs in a dose-dependent manner. The level of interferon-g and tumor growth factor-b in TILs supernatant was increased and decreased, respectively. Our data suggest that ex vivo treatment of TILs with pentoxifylline could decrease the proportion of Tregs in the conventional IL-2-mediated TIL expansion and change the cytokine balance of TILs in favor of antitumor immune response.

Immunohistochemistry study of pentoxifylline in the treatment of alopecia induced by cyclophosphamide in male rats

Objective: Hair is the human body's major esthetic display component, especially in cultural and social interactions. Alopecia starts to be diagnosed medically at a level that about 25 to 40 percent of the person's hair is dropped. Throughout this research, the potency of topical pentoxifylline in stimulating regrowth in hair loss caused by cyclophosphamide was established. Methods: The study was performed by treatment with pentoxifylline topically in male Swiss albino rats. The animals divided into seven groups with six animals in each group. To induce alopecia Cyclophosphamide used at a dose of (125 mg/kg) intraperitoneal. The animals in this study have hair clippered at day one and at day six of experiment to induce entrance of hair follicles into anagen phase. All groups injected cyclophosphamide at day 15 of experiment except control group injected only distilled water. The treatment period was fourteen days for rats used in this study. All animals in groups of study sacrificed at day 29 of experiment. Results: Hair weight assessment showed improvement in hair growth with increasing pentoxifylline concentration in groups. Strong follicular proliferation was demonstrated by histopathology and gross morphological observations of hair growth in shaved areas.

Effects of pentoxifylline on canine platelet aggregation.

BackgroundPentoxifylline can decrease platelet function in humans, but the anti‐platelet effects of pentoxifylline in dogs is unknown. The addition of a luciferin–luciferase reagent during platelet aggregometry can induce a dose‐dependent potentiation of platelet aggregation.ObjectiveTo determine if exposure to pentoxifylline, without the addition of a luciferin–luciferase reagent during aggregometry, causes canine platelet dysfunction. Our hypotheses were that pentoxifylline would inhibit platelet function, and that the addition of a luciferin–luciferase reagent would obscure detection of pentoxifylline‐induced platelet dysfunction as measured via aggregometry.MethodsSeven healthy Walker hound dogs. Platelet‐rich plasma (PRP) and whole blood were treated for 30 minutes with pentoxifylline: 0 (control), 1 and 2 μg/mL. The platelet aggregation was determined using optical (maximum amplitude) and impedance (ohms) aggregometry using collagen as the agonists, with and without a luciferin–luciferase reagent. Four samples were analysed per concentration and the results were averaged.ResultsBased on optical aggregometry, there was no difference (p = 0.964) in the mean maximum amplitude at any pentoxifylline concentration, with and without the luciferin–luciferase reagent. During impedance aggregometry, the addition of a luciferin–luciferase reagent was associated with significantly (p < 0.001) greater platelet aggregation in response to a collagen agonist, regardless of the presence or absence of pentoxifylline.ConclusionsPentoxifylline does not exert an in vitro anti‐platelet effect on canine platelet aggregation when collagen is used as an agonist, but it is unknown if long‐term oral drug administration will inhibit platelet aggregation. The addition of a luciferin–luciferase reagent during platelet aggregometry can artificially enhance canine platelet aggregation.

Abstract 4107: The impact of NF-κB inhibition on the sensitivity of breast cancer cells to chemotherapy-induced apoptosis

Abstract Aim: The emergence of breast cancer resistance to chemotherapy represents a major obstacle in cancer therapy. Multiple cellular signalling pathways augment such resistance including the nuclear factor (NF)-κB. In the presented work, we investigated the impact of NF-κB inhibition on the sensitivity of breast cancer cells to chemotherapy-induced apoptotic cell death via Annexin V/PI flow cytometry and other molecular biology-based assays. Methods: Doxorubicin (DOX)-resistant MCF-7 and MDA-MB-231 breast cancer cell lines were developed and utilized for the current study. Cytotoxicity assays were performed to evaluate the median inhibitory concentration (IC50) of different NF-κB pharmacological inhibitors. Chemotherapy-induced apoptosis in parental and resistant breast cancer cells was assessed in the presence or absence of different NF-κB pharmacologic inhibitors such as pentoxifylline (PTX) and bortezomib (BTZ). Results: Treatment of MDA-MB-231 cell line with a sub-cytotoxic concentration of PTX significantly enhanced DOX-induced apoptosis by 6-fold (p&amp;lt;0.001) in wild type cells, and by 8-fold (p&amp;lt;0.01) in the resistant subclones. Similarly, BTZ significantly boosted the percentage of apoptotic cells by 6-fold (p&amp;lt;0.001) in parental cells co-treated with DOX. However, the same treatment boosted the percentage of apoptotic cells by 11-fold (p&amp;lt;0.01) in DOX-resistant MDA-MB-231 cells. It is noteworthy that the increased sensitivity to DOX-induced apoptosis that was mediated via NF-κB inhibition was more prominent in the resistant clones. Conclusion: The data generated from this study support the potential merit of NF-κB inhibitors as adjuvants to improve breast cancer sensitivity to chemotherapy. Further mechanistic investigations are currently in progress in our laboratories to characterize the relationship between NF-κB inhibition and key signaling pathways for breast cancer chemoresistance. Funding: This work was supported by grant # 1801110326-P from the Research Funding Department, University of Sharjah, UAE, and grant #AJF2018050 from Al Jalila Foundation, UAE. Citation Format: Shifaa M. Abdin, Mai F. Tolba, Dana M. Zaher, Hany A. Omar. The impact of NF-κB inhibition on the sensitivity of breast cancer cells to chemotherapy-induced apoptosis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4107.

121 Effect of pentoxifylline on motility of good- and poor-quality frozen-thawed equine sperm

Equine semen used for intracytoplasmic sperm injection (ICSI) is typically frozen-thawed and may be of poor quality. To prepare sperm for ICSI, semen is typically centrifuged to remove freezing extender. However, centrifugation can cause damage to sperm, which is especially meaningful if sperm quality is already poor. We evaluated a method for selection of sperm without centrifugation, using a “swim-over” technique, and assessed the effect of pentoxifylline, a phosphodiesterase inhibitor that increases sperm motility in other species. To mimic poor-quality semen, we thawed frozen semen (1×) and re-froze it three additional times (4×). Aliquots (0.25 µL; 50,000 sperm) of 1× or 4× semen were placed at the bottom of the right leg of an “H,” made using 15µL of medium by tracing a template placed below a Petri dish. The medium used (Hanks’ balanced salt solution with 40mg mL BSA and added lactate and pyruvate) contained different concentrations of pentoxifylline (0, 0.5, 1, 2 or 4mgmL−1). One µL of medium was removed from the tip of the left arm of the H after 15 and 30min incubation, and the number of sperm were counted. In a second study, we evaluated the effect of pentoxifylline on sperm motility parameters using computer-assisted sperm motility analysis. After thawing, 1× and 4× semen was washed to remove freezing extender and resuspended in the same medium but with 7mgmL−1 bovine serum albumin (BSA), containing the different pentoxifylline concentrations. In Study 1, the number of collected sperm did not differ significantly for 1× sperm exposed to 0 to 4mgmL−1 pentoxifylline (means of 15 to 23 sperm at 15min, and 18 to 25 sperm at 30min). Similarly, in 4× frozen semen, there was no significant difference in number of collected sperm between 0mgmL−1 and 2 or 4mgmL−1 pentoxifylline concentrations (&amp;lt;1 to 6 at 15 min; 5 to 6 at 30min). In Study 2, at 0min,% total motility was significantly higher in 1 and 2mgmL−1 pentoxifylline than in 0mgmL−1 for 1× sperm (47.8±1.7 and 49.3±1.9, vs. 32.1±3.9, respectively; P=0.018) and significantly higher for 1, 2, and 4mgmL−1 pentoxifylline than for 0mgmL−1 for 4× sperm (3.9±0.9, 5.7±0.4, and 8.2±0.5, vs. 1.2±0.4; P=0.0001). Similar results were found at 15 and 30min for 1×, and at 15min for 4×. Pentoxifylline at 1 to 4mgmL−1 significantly increased the percentage of progressive motility in 1× sperm at 30min (17.8±1.3, 21.8±2.7, and 20.3±1.2, vs. 10.0±0.4; P=0.002) and, at 4mgmL−1, increased the percentage of progressive motility in 4× sperm at 0min (1.43±0.1 vs. 0.2±0.1; P=0.005) and 15min (1.4±0.2 vs. 0.1±0.0; P=0.0001). Exposure of poor-quality semen to pentoxifylline at 4mgmL−1 improved total and progressive motility but did not increase the recovery of motile sperm in a swim-over collection preparation.

Pharmacokinetics of pentoxifylline and its 5-hydroxyhexyl metabolite after intravenous administration of increasing doses to sheep.

To determine the pharmacokinetics of pentoxifylline (PTX) and its 5-hydroxyhexyl metabolite (M-I) after IV administration of increasing doses of PTX to sheep. 6 healthy adult Merino sheep. Each sheep received 10-, 20-, and 40-mg/kg doses of PTX, IV, with a 15-day washout period between doses. Blood samples were collected before and at predetermined times after administration of each dose to determine plasma PTX and M-I concentrations by high-performance liquid chromatography. Pharmacokinetic parameters for PTX and M-I were estimated by noncompartmental analysis. No adverse effects were observed after administration of the 10- and 20-mg/kg doses. Following administration of the 40-mg/kg dose, all sheep developed tachycardia and hypersalivation and appeared agitated for approximately 4 hours. Plasma PTX concentrations considered therapeutic in other species were achieved in all sheep after administration of all 3 doses. Pharmacokinetic parameters for PTX and M-I varied in a dose-dependent linear manner. For PTX, the mean area under the concentration-time curve (AUC), elimination half-life, and volume of distribution increased with dose and ranged from 15.67 to 94.66 h·μg/mL, 0.68 to 0.91 hours, and 0.55 to 0.66 L/kg, respectively, whereas clearance decreased with dose and ranged from 0.42 to 0.64 L/h/kg. The mean ratio of the AUC for M-I to AUC for PTX ranged from 0.38 to 0.46. Results indicated that pharmacokinetic parameters for PTX and M-I varied in a dose-dependent linear manner in healthy sheep. Further studies are warranted to determine the therapeutic threshold and optimal dosage for PTX in sheep.

Reversal of Osteopenia in Ovariectomized Rats by Pentoxifylline: Evidence of Osteogenic and Osteo-Angiogenic Roles of the Drug

Pentoxifylline (PTX) is a non-selective phosphodiesterase inhibitor and is used for the management of intermittent claudication. We tested whether PTX has oral efficacy in stimulating new bone formation. Rat calvarial osteoblasts (RCO) were used to study the effect of PTX on osteoblast differentiation and angiogenesis. Pharmacokinetic and pharmacodynamic studies were carried out in rats to determine an oral dose of PTX. In ovariectomized (OVX) rats with osteopenia, the effect of PTX on various skeletal parameters was studied, and compared with teriparatide. Effect of PTX on angiogenic signaling was studied by immunoblotting and relevant pharmacologic inhibitors. Bone vascularity was measured by intravenous injection of polystyrene fluorospheres followed by in vivo imaging, and angiogenesis was studied in vitro by tubulogenesis of endothelial cells and in vivo by Matrigel plug assay. Effective concentration (EC50) of PTX in RCO was 8.2nM and plasma PTX level was 7nM/mL after single oral dosing of 25mg/kg, which was 1/6th the clinically used dose. At this dose, PTX enhanced bone regeneration at femur osteotomy site and completely restored bone mass, microarchitecture, and strength in OVX rats. Furthermore, PTX increased surface referent bone formation parameters and serum bone formation marker (PINP) without affecting the resorption marker (CTX-1). PTX increased the expression of vascular endothelial growth factor and its receptor in bones and osteoblasts. PTX also increased skeletal vascularity, tubulogenesis of endothelial cells and in vivo angiogenesis. Taken together, our study suggested that PTX at 16% of adult human oral dose completely reversed osteopenia in OVX rats by osteogenic and osteo-angiogenic mechanisms.

Oral dosing of pentoxifylline, a pan-phosphodiesterase inhibitor restores bone mass and quality in osteopenic rabbits by an osteogenic mechanism: A comparative study with human parathyroid hormone.

The non-selective phosphodiesterase inhibitor pentoxifylline (PTX) is used for the treatment of intermittent claudication due to artery occlusion. Previous studies in rodents have reported salutary effects of the intraperitoneal administration of PTX in segmental bone defect and fracture healing, as well as stimulation of bone formation. We determined the effect of orally dosed PTX in skeletally mature ovariectomized (OVX) rabbits with osteopenia. The half-maximal effective concentration (EC50) of PTX in rabbit bone marrow stromal cells was 3.07 ± 1.37 nM. The plasma PTX level was 2.05 ± 0.522 nM after a single oral dose of 12.5mg/kg, which was one-sixth of the adult human dose of PTX. Four months of daily oral dosing of PTX at 12.5 mg/kg to osteopenic rabbits completely restored bone mineral density, bone mineral content (BMC), microarchitecture and bone strength to the level of the sham-operated (ovary intact) group. The bone strength to BMC relationship between PTX and sham was similar. The bone restorative effect of PTX was observed in both axial and appendicular bones. In osteopenic rabbits, PTX increased serum amino-terminal propeptide, mineralized nodule formation by stromal cells and osteogenic gene expression in bone. PTX reversed decreased calcium weight percentage and poor crystal packing found in osteopenic rabbits. Furthermore, similar to parathyroid hormone (PTH), PTX had no effect on bone resorption. Taken together, our data show that PTX completely restored bone mass, bone strength and bone mineral properties by an anabolic mechanism. PTX has the potential to become an oral osteogenic drug for the treatment of post-menopausal osteoporosis.

Pentoxifylline Alone or in Combination with Gentamicin or Vancomycin Inhibits Live Microbe-Induced Proinflammatory Cytokine Production in Human Cord Blood and Cord Blood Monocytes In Vitro.

Neonatal sepsis and its accompanying inflammatory response contribute to substantial morbidity and mortality. Pentoxifylline (PTX), a phosphodiesterase inhibitor which suppresses transcription and production of proinflammatory cytokines, is a candidate adjunctive therapy for newborn sepsis. We hypothesized that PTX decreases live microbe-induced inflammatory cytokine production in newborn blood. Cord blood was stimulated with live microorganisms commonly encountered in newborn sepsis (Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis, or Candida albicans) and simultaneously treated with antimicrobial agents (gentamicin, vancomycin, or amphotericin B) and/or clinically relevant concentrations of PTX. Microbial colony counts were enumerated by plating, supernatant cytokines were measured by multiplex assay, intracellular cytokines and signaling molecules were measured by flow cytometry, and mRNA levels were measured by quantitative reverse transcription-PCR. PTX inhibited concentration-dependent E. coli-, S. aureus-, S. epidermidis-, and C. albicans-induced tumor necrosis factor (TNF) and E. coli-induced interleukin-1β (IL-1β) production in whole blood, with greater suppression of proinflammatory cytokines in combination with antimicrobial agents. Likewise, PTX suppressed E. coli-induced monocytic TNF and IL-1β, whereby combined PTX and gentamicin led to significantly greater reduction of TNF and IL-1β. The anti-inflammatory effect of PTX on microbe-induced proinflammatory cytokine production was accompanied by inhibition of TNF mRNA expression and was achieved without suppressing the production of the anti-inflammatory IL-10. Of note, microbial colony counts in newborn blood were not increased by PTX. Our findings demonstrated that PTX inhibited microbe-induced proinflammatory cytokine production, especially when combined with antimicrobial agents, without enhancing microbial proliferation in human cord blood in vitro, thus supporting its utility as candidate adjunctive agent for newborn sepsis.

Effects of maturation and size on population pharmacokinetics of pentoxifylline and its metabolites in very preterm infants with suspected late‐onset sepsis or necrotizing enterocolitis: a pilot study incorporating clinical outcomes

Infection-induced inflammation is associated with adverse long-term outcomes in preterm infants. Pentoxifylline (PTX) is a candidate for adjunct immunomodulatory therapy in preterm infants with late-onset sepsis (LOS) and necrotizing enterocolitis (NEC), but pharmacokinetic data in this population are extremely limited. This study aims to characterize the pharmacokinetic properties of intravenous PTX and its metabolites in preterm infants. An open label pilot clinical study of intravenous PTX as an adjunct therapy in preterm infants (gestation <32 weeks) with suspected LOS or NEC was undertaken. PTX was infused for 12h for two days (60mgkg-1 per 12h), and in infants with confirmed diagnosis of LOS or NEC, for 6h for another 4 days (30mgkg-1 per 6h). Plasma concentrations of PTX and its principal metabolites from collected blood samples were measured using a validated LCMS assay. NONMEM was used to analyse the data using population pharmacokinetic modelling. The preterm infants (n=26) had a median (range) gestation of 24.8 weeks (23.3-30.4) and birthweight of 689g (370-1285). PTX was well tolerated and without treatment-limiting adverse effects. Changes in size (weight) and maturation were successfully modelled for PTX and metabolites. After allometric scaling, clearance increased with postmenstrual age, increasing by approximately 30% per week for PTX and M1 (lisofylline) and simulations of current dosing demonstrated a six-fold difference in exposure between 24 and 35 weeks postmenstrual age. The developed model can be used to explore dosing strategies based on size and maturation for preterm infants.

Pharmacokinetics of pentoxifylline and its 5-hydroxyhexyl metabolite following intravenous administration in cattle.

This study investigated the pharmacokinetics of pentoxifylline (PTX) and its 5-hydroxyhexyl metabolite (M-I) after single-dose intravenous (IV) administration (10mg/kg) of PTX in six healthy cattle. The safety of PTX was evaluated by clinical observation and biochemical analysis. Plasma concentrations of PTX and M-I were simultaneously determined by reverse-phase high performance liquid chromatography. Pharmacokinetic parameters were calculated using non-compartmental methods. Salivation and discomfort were observed for 2h following the drug administration. Serum direct bilirubin, total bilirubin, and phosphorus levels at 24h following the drug administration were significantly different from the control values (0h) (P < 0.05). Pharmacokinetic variables of PTX were characterized by a short terminal elimination half-life (1.05 ± 0.19h), a large volume of distribution (6.30 ± 1.76L/kg), and high total body clearance (5.31 ± 1.27L/h/kg). The mean ratio between the area under the concentration-time curves of M-I and PTX was 1.34. These results indicate that single-dose administration of PTX at 10mg/kg IV in cattle resulted in therapeutic concentrations similar to those observed in humans and horse. However, further studies are necessary to determine the safety and pharmacokinetics following repeated administrations of PTX.

Effect of Pentoxifylline Concentration on Sperm Quality in Jeju Crossbred Horses

Effect of Pentoxifylline Concentration on Sperm Quality in Jeju Crossbred Horses

Degradation kinetics and mechanism of pentoxifylline by ultraviolet activated peroxydisulfate.

Degradation of pentoxifylline (PTX) by sodium peroxydisulfate (SPDS) assisted by UV irradiation has been investigated in deionized water. The treatment was more favorable over direct photolysis or peroxydisulfate oxidation alone. The effects of various parameters, including different dosage of oxidant agent, PTX concentration, initial solution pH levels, and the presence of inorganic ions like chloride, nitrate and carbonate have been evaluated. The rate of PTX decomposition depends on the oxidant agent dose. The highest degradation was determined at pH 10.5, which can be explained by the generation of additional hydroxyl radicals (HO˙) in the reaction between sulfate radicals and hydroxide ions. The presence of inorganic ions, especially the carbonate ions quench valuable sulfate radicals and have successfully retarded the PTX decomposition. Six PTX oxidation products were identified using UPLC-QTOF-MS for trials in a basic environment. The main degradation product (3,7-dimethyl-6-(5-oxohexyloxy)-3,7-dihydro-2H-purin-2-one) was isolated by column chromatography and identified by 1HNMR and LC MS analyzes.

Concentration-Dependant Antioxidant Activity of Pentoxifylline in Nitrite-induced Hemoglobin Oxidation Model

Free radical formation in heme proteins is recognized as a factor in mediating the toxicity of many chemicals. The present study was designed to evaluate the dose-response relationship of the free radical scavenging properties of pentoxifylline in nitrite-induced Hb oxidation. Different concentrations of pentoxifylline were added at different time intervals of Hb oxidation in erythrocytes lysate, and formation of methemoglobin (MetHb) was monitored spectrophotometrically. The results showed that in this model, pentoxifylline successfully attenuates Hb oxidation after challenge with sodium nitrite; this protective effect was found to be not related to the catalytic stage of Hb oxidation, though such effect was reported to be more prominent when the compound was at the same time of induction of Hb oxidation with nitrite. In conclusion, pentoxifylline can effectively, in concentration-dependent pattern, attenuate sodium nitrite-induced Hb oxidation in vitro.&#x0D; Key words: pentoxifylline, radical scavenging, hemoglobin oxidation

Bioequivalence and Pharmacokinetics Comparison of Two Formulations of Extended-Release Pentoxifylline Tablets in Healthy Subjects after Fasting and Fed Conditions

The pharmacokinetics and bioequivalence of a newly developed extended-released (ER) tablet containing 400 mg pentoxifylline as a test product was compared with the reference brand product Trental® 400 mg ER tablet produced by Sanofi-Aventis. Two separate studies were conducted simultaneously. The first study was conducted under fasting condition, whereas, the second study was conducted under fed condition; using the same batches of the test and reference products in both studies. In each study, both products were administered to 32 healthy male adult volunteers applying a single-dose, two-treatment, two-period, two-sequence, randomized crossover design with one-week washout period between dosing. Twenty two blood samples were withdrawn from each volunteer over 24 hours period. Pentoxifylline concentrations were determined in plasma by a validated HPLC method according to FDA Bioanalytical Method Validation Guidance using UV detection and chloramphenicol as internal standard. The lower limit of quantitation of the drug in plasma was 5 ng/ml and the upper limit of quantitation was 500 ng/ml. From the plasma concentration-time data of each individual, the pharmacokinetic parameters; Cmax, AUC0-t, AUC0-¥, Cmax/AUC0-¥, Tmax, lZ &amp; T0.5; were calculated applying non-compartmental analysis. Data of the test and reference products were statistically analyzed to test for bioequivalence of the two products, using criteria of FDA and EMEA Guidance. The pharmacokinetic parameters mentioned above were statistically analyzed by descriptive statistics, ANOVA test and 90% Confidence Interval (CI). ANOVA test involved the calculation of the effects of: treatment, period, sequence and subjects nested in sequence. According to the above guidance, the primary pharmacokinetic parameters used for bioequivalence testing, namely Cmax, AUC0-t and AUC0-¥ were also statistically analyzed by ANOVA &amp; CI tests using the corresponding Ln-transformed values. The mean values Cmax, AUC0-t , AUC0-¥ , Cmax/AUC0-¥ , Tmax, lZ &amp; T0.5 for the test formula obtained from the fasting study were; 144.4 ng/ml, 845.4 ng.hr/ml, 868.4 ng.hr/ml, 0.186 hr-1, 3.29 hr, 0.561 hr-1 and 1.65 hr, respectively; and the mean values of these parameters for the reference formula were; 150.0 ng/ml, 871.1 ng.hr/ml, 893.7 ng.hr/ml, 0.177 hr-1, 3.70 hr, 0.558 hr-1 and 1.59 hr, respectively. The mean values of the above mentioned parameters for the test formula obtained from the fed study were; 157.8 ng/ml, 826.5 ng.hr/ml, 853.8 ng.hr/ml, 0.198 hr-1, 5.4 hr, 0.458 hr-1 and 2.06 hr, respectively; and the mean values of these parameters for the reference formula were; 162.1 ng/ml, 869.7 ng.hr/ml, 894.8 ng.hr/ml, 0.196 hr-1, 4.1 hr, 0.525 hr-1 and 1.80 hr, respectively. Based on criteria of FDA and EMEA Guidance on Bioavailability and Bioequivalence, the results of the fasting and fed studies demonstrated bioequivalence of the two products under either condition. Accordingly, it is concluded that the newly developed ER tablet containing 400 mg pentoxifylline is bioequivalent to Trental® 400 mg ER tablet produced by Sanofi-Aventis.&#x0D; Keywords: Pentoxifylline, Pharmacokinetics, Bioequivalence.

Activation of the mobility of human spermatozoa with the use of pentoxifylline: effects on spermal DNA

Introduction: 50% of pregnancy failure is due male factors. One of these factors is the absence of spermatozoa in the ejaculate; in these cases the patient is submitted to epididymal or testicular sperm aspiration. The spermatozoa acquired from these technics usually are immobile, what makes necessary the use of pentoxifylline, which activates sperm movement, to distinction of viable spermatozoa to ICSI. Objectives: To analyze if a low concentration of pentoxifylline causes spermatic chromatin damages. Materials and Methods: Sperm motility activation was tested in different concentrations of pentoxifylline. After the screening of doses, the lowest effective concentration was choose to analyze the chromatin damage rate. 15 samples of fresh sperm were tested for DNA damage with HALOSPERM Kit. Blades’ analyses were made in bright field microscopy. The fragmented DNA was settle by the absence of chromatin dispersion halo or small halo. Results: The lowest and effective pentoxifylline dose was 1.5 mM. There was no significant difference on chromatin damage rate between study and control groups (p = 0.55). Conclusion: The use of pentoxifylline at 1.5 mM does not affect the sperm DNA.