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This study aimed to evaluate the ability of pentoxifylline when compared to lovastatin and chlorpromazine as nephroprotective substances in cases of renal ischemia and reperfusion syndrome (IRI). A total of 36 adult male animals were randomly allocated into four groups (untreated control group, pentoxifylline group, lovastatin group, and chlorpromazine group), each consisting of nine animals. All groups were submitted to experimental ischemia and reperfusion procedures. The animals were evaluated 24, 72 and 120 hours after IRI, including physical examinations, serum urea and creatinine measurements, as well as histopathological, morphometric, and stereological analyses of the renal tissue. Results indicated that 24 hours after IRI, only chlorpromazine was effective in controlling azotemia. At the 72-hour mark, both chlorpromazine and pentoxifylline exhibited efficacy. After 120 hours, all three substances demonstrated renal protective qualities. Pentoxifylline was the most effective in preserving the structural integrity of kidney tissue, followed by chlorpromazine. In conclusion, all three treatments (pentoxifylline, chlorpromazine, and lovastatin) were effective. Pentoxifylline proved to be promising in the response against acute tubular necrosis, although chlorpromazine presented earlier renoprotective effects in terms of maintaining renal function., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Pereira et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Immune dysregulation can play a role in depression pathophysiology, and immunological antagonists can improve depressive symptoms in treatment-resistant bipolar depression (TRD) patients according to studies., Objective: To evaluate the anti-depressant effects of the anti-inflammatory drug, pentoxifylline (PTX) in TRD bipolar I/II adult subjects., Methods: This 12-week, randomized, double-blind, placebo-controlled, parallel-group trial of 60 participants was conducted at Hawler Psychiatric Hospital and Private Clinic in Erbil, Iraq. Participants were confirmed as being qualified for bipolar I/II depression based on DSM-5 criteria. Data were analyzed using modified intent-to-treat analysis., Results: There were no significant differences between the two groups in Hamilton Rating Scale for Depression-17 (HAM-D-17) scores (χ 2 =1.9, P =.48) or a significant time × treatment interaction (χ 2 =7.1, P=.54). Nevertheless, a significant effect of time was observed with both groups' reduction in HAM-D-17 scores from the start to the endpoint (χ 2 = 2.11, P=.002). Besides, a significant time × treatment × CRP interaction was found (χ 2 =3.1, P=0.016), where there was more reduction in HAM-D-17 score in PTX-treated subjects with CRP> 7.1 mg/L. The response rate difference between PTX and the placebo group did not reach a significance level (χ 2 =0.84, p=0.43). Furthermore, serum concentrations of TNF-α, CRP, and IL-6 significantly reduced at week 12 in the PTX group (P=.007,.04, and <.001, respectively)., Conclusion: The current proof of concept study found that in terms of overall anti-depressant effectiveness in bipolar patients with TRD, PTX is not superior to placebo. However, it may improve depressive mood in a subpopulation of subjects with a higher pretreatment inflammatory profile., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The combination of oral pentoxifylline (Ptx) and vitamin E (VitE) has been used to treat radiation-induced fibrosis and soft tissue injury. Here, we review outcomes and perform a radiomic analysis of treatment effects in patients prescribed Ptx + VitE at our institution for the treatment of radiation necrosis (RN)., Methods: A total of 48 patients treated with stereotactic radiosurgery (SRS) had evidence of RN and had MRI before and after starting Ptx + VitE. The radiation oncologist's impression of the imaging in the electronic medical record was used to score response to treatment. Support Vector Machine (SVM) was used to train a model of radiomics features derived from radiation necrosis on pre- and 1st post-treatment T1 post-contrast MRIs that can classify the ultimate response to treatment with Ptx + VitE., Results: A total of 43.8% of patients showed evidence of improvement, 18.8% showed no change, and 25% showed worsening RN upon imaging after starting Ptx + VitE. The median time-to-response assessment was 3.17 months. Nine patients progressed significantly and required Bevacizumab, hyperbaric oxygen therapy, or surgery. Patients who had multiple lesions treated with SRS were less likely to show improvement ( p = 0.037). A total of 34 patients were also prescribed dexamethasone, either before (7), with (16), or after starting (11) treatment. The use of dexamethasone was not associated with an improved response to Ptx + VitE ( p = 0.471). Three patients stopped treatment due to side effects. Finally, we were able to develop a machine learning (SVM) model of radiomic features derived from pre- and 1st post-treatment MRIs that was able to predict the ultimate treatment response to Ptx + VitE with receiver operating characteristic (ROC) area under curve (AUC) of 0.69., Conclusions: Ptx + VitE appears safe for the treatment of RN, but randomized data are needed to assess efficacy and validate radiomic models, which may assist with prognostication.

Background: Jaw osteoradionecrosis (ORN) is a complication in patients with previous head and neck radiotherapy. Its incidence increases with dental extractions. Hence, this review aimed to evaluate the efficacy of adjunctive treatment modalities undertaken at the time of extraction in previous head and neck radiotherapy patients in preventing ORN., Methods: A systematic review was conducted, where studies with data on ORN incidence after extraction with or without adjunctive interventions were included. Meta-analyses were conducted to estimate the pooled prevalence of ORN per intervention and the pooled odds ratio for incidence of ORN between interventions., Results: In total, 1520 patients in 29 studies were included. Interventions identified were hyperbaric oxygen (HBO), pentoxifylline-tocopherol (PENTO), antibiotics (ABX), platelet-rich fibrin and photobiomodulation. The pooled prevalence of ORN for HBO (4.6%), PENTO (3.4%) and ABX (3.8%) was significantly lower than the Control (17.6%). For studies with direct comparisons between groups, HBO had lower but not significant odds of developing ORN than the Control (OR 0.27) and ABX (OR 0.57)., Conclusions: HBO, PENTO and ABX may reduce the incidence of ORN compared to no intervention. Given that all three have similar incidences of ORN, ABX may be the most cost-effective and accessible adjunctive modality., (© 2024 The Authors. Oral Diseases published by Wiley Periodicals LLC.)

Although the Achilles tendon is the largest and strongest tendon in the body, healing of the Achilles tendon is the most common injury, and this process is difficult due to poor tendon circulation; moreover, the underlying mechanism has not been fully elucidated. In our study, we aimed to investigate the effects of pentoxifylline and alpha-tocopherol administered separately or in combination on rats with Achilles tendon injury. Forty-eight male Wistar rats weighing 230 ± 30 g were used in the study. The rats were randomly divided into eight groups of six animals each. Tendons were evaluated histopathologically and biomechanically. According to the statistical analysis, the vascularity density in the pentoxifylline group on day 14 was significantly greater than that in the other groups (p < 0.05). The collagen arrangement in the pentoxifylline and alpha-tocopherol groups on day 14 was found to be firmer and smoother than that in the control group (p < 0.05). The collagen arrangement in the pentoxifylline group on day 28 was greater than that in the other groups (p < 0.05). The biomechanical results were significantly greater in all groups (p < 0.05). Pentoxifylline contributed to tendon healing both through neovascularization in the early period and by improving collagen orientation in the late period, while alpha-tocopherol had a positive effect on collagen orientation in the early period. No beneficial effects were observed when pentoxifylline and alpha-tocopherol were used together. We believe that further research is needed to understand the effects of this combination therapy on tendon healing., (© 2024 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Purpose: The aim of the present study was to determine the methodological quality of systematic reviews that evaluated the effectiveness of pentoxifylline and tocopherol (PENTO) in the treatment of osteoradionecrosis of the jaw (ORNJ) and medication-related osteonecrosis of the jaw (MRONJ)., Methods: Searches were performed in Databases including PubMed, Scopus, LILACS, DARE, Cochrane Library, and SIGLE through OpenGrey until March 2024, were evaluated by two independent reviewers to answer the following question: Is the use of PENTO protocol effective in the treatment of ORNJ or for the treatment of MRONJ?, Results: A total of 256 articles were initially identified; however, following the use of appropriate inclusion and exclusion criteria, five systematic reviews were identified for detailed analysis. The final study sample comprised 588 patients: 397 patients with ORN and 197 patients with MRONJ who were treated with PENTO. The total recovery of individuals who used the PENTO protocol was 62,2 % for ORN and 100 % for MRONJ, with a follow-up period of 1 month to 10 years. The methodological quality of the studies was assessed using the AMSTAR 2 tool, in which four were of low quality and 1 moderate quality., Conclusion: The treatment of ORN and MRONJ with pentoxifylline and tocopherol has shown good results in the studies presented, with a partial or total reduction in bone exposure. However, the low quality of the relevant reports highlights the need for primary and secondary studies with better methodological rigor to reduce bias and provide reassurance for this treatment option., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Diabetic kidney disease (DKD) is associated with a higher risk of cardiovascular disease (CVD). Pentoxifylline (PTF), a nonselective phosphodiesterase inhibitor with anti-inflammatory, antiproliferative, and antifibrotic actions, has demonstrated renal benefits in both clinical trials and meta-analyses. The present work aimed to study the effects of PTF on the progression of subclinical atherosclerosis (SA) in a population of patients with diabetes and moderate to severe chronic kidney disease (CKD)., Methods: In this open-label, randomized controlled, prospective single-center pilot study the evolution of carotid intima-media thickness (CIMT) and ankle-brachial index (ABI) were determined in 102 patients with type 2 diabetes mellitus and CKD assigned to PTF, aspirin or control groups during 18 months. We also determined the variations in the levels of inflammatory markers and Klotho (KL), a protein involved in maintaining cardiovascular health, and their relationship with the progression of SA., Results: Patients treated with PTF presented a better evolution of CIMT, increased KL mRNA levels in peripheral blood cells (PBCs) and reduced the inflammatory state. The progression of CIMT values was inversely related to variations in KL both in serum and mRNA expression levels in PBCs. Multiple regression analysis demonstrated that PTF treatment and variations in mRNA KL expression in PBCs, together with changes in HDL, were significant determinants for the progression of CIMT (adjusted R 2  = 0.24, P < 0.001) independently of traditional risk factors. Moreover, both variables constituted protective factors against a worst progression of CIMT [OR: 0.103 (P = 0.001) and 0.001 (P = 0.005), respectively]., Conclusions: PTF reduced SA progression assessed by CIMT variation, a beneficial effect related to KL gene expression in PBCs., Trial Registration: The study protocol code is PTF-AA-TR-2009 and the trial was registered on the European Union Drug Regulating Authorities Clinical Trials (EudraCT #2009-016595-77). The validation date was 2010-03-09., (© 2024. The Author(s).)

This study aimed to estimate the cost-effectiveness of four therapeutic approaches available for mucosal leishmaniasis in Brazil: miltefosine, meglumine antimoniate, combined with and without pentoxifylline, and liposomal amphotericin B. The perspective adopted was that of the Brazilian Unified National Health System (SUS). The outcome of interest was "cured patient", which was analyzed using a decision tree model. Estimates of direct costs and effectiveness were obtained from the scientific literature. Meglumine antimoniate alone was the base comparator strategy; liposomal amphotericin B showed an incremental cost-effectiveness ratio (ICER) of USD 7,409.13 per cured patient, and the combination of meglumine antimoniate with pentoxifylline presented an ICER of USD 85.13. Miltefosine was absolutely dominated, with higher cost and similar effectiveness when compared to meglumine antimoniate. Sensitivity analyses, varying the cost by ±25%, did not change the results. However, when the cost of miltefosine was estimated at less than USD 171.23, this strategy was dominant over meglumine antimoniate alone. The results confirm that treatment with liposomal amphotericin B remains the option with the highest ICER among the approaches analyzed. Miltefosine may be cost-effective based on the variation in the acquisition price, which deserves attention because it is the only available oral option. The non-accounting of other aspects prevent the use of these results immediately to support decision-making, but they point out the need to negotiate the prices of drugs available for mucosal leishmaniasis and indicates the need of encouraging technology transfer or other actions aimed at expanding the performance of the Brazilian national industrial complex.

Ethnopharmacological Relevance: Phoenix dactylifera L. pollen is the male reproductive dust of palm flowers known as a natural product that is considered a strong stimulant of sexual potency and fertility in Iranian traditional medicine (ITM). In this regard, no evidence-based medications are empirically prescribed to treat IMI. However, applying traditional medicine for the treatment of male infertility has attracted more attention in recent years., Aim of the Study: Phoenix dactylifera L. pollen was compared with pentoxifylline (PTX) to evaluate its efficacy on sperm parameters., Materials and Methods: During this parallel randomized controlled trial, 80 adult men with asthenozoospermia, oligozoospermia, or teratozoospermia (age 20-35 years) were enrolled. In two separate groups of participants with a 1:1 ratio, participants received either 6 g of Phoenix dactylifera L. pollen powder daily or 400 mg of PTX tablets daily for 90 days. We measured the sperm parameters as well as the serum sex hormones in the sample. ANCOVA and t-tests were used to compare groups., Results: There was no significant difference between the study groups in terms of baseline characteristics or demographic characteristics. According to the results, participants who took Phoenix dactylifera L. pollen powder had significantly improved sperm concentration (p = 0.016), morphology (p = 0.029), sperm counts (p = 0.012), progressive motility (p = 0.016), total motility (p = 0.018), and reduced immotile sperms (p = 0.014) compared to those who took PTX., Conclusions: In light of these results, Phoenix dactylifera L. pollen is recommended as a treatment factor for ameliorating IMI by enhancing sperm functional capacity and semen parameters., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hidradenitis Suppurativa (HS) is a chronic inflammatory skin disease that may have profound effects on the patient's quality of life. A personalized HS combination therapy treatment was prescribed to a 54-year-old female suffering from multiple painful sores, as follows: naltrexone capsules titrated from 0.5 mg up to 4.5 mg; pentoxifylline 5%, rifampin 2%, clindamycin 1%, and glycolic acid topical cream. Clinical improvements were observed using two disease-specific outcome measures: Hurley Staging System and HS Score. The patient's HS improved from Stage II (moderate) to Stage I (mild), and the HS score decreased from 103 points with five anatomical regions reported, to 19 points with only three regions affected. Furthermore, the before and after treatment photographs showed a visible reduction in the number of boils/skin abscesses and an overall recovery. Improvements were also observed across all domains of the patient's self-reported quality of life (Hidradenitis Suppurativa Quality of Life Assessment). The patient did not experience any undesirable effects. Compounded medications may be customized to meet the patient's special needs and may be adjusted throughout the course of treatment to match the patient's individual progress. Although further studies are necessary, this personalized, combination therapy may be a key treatment option in HS., Competing Interests: The authors Nat Jones, Fabiana Banov and Maria Carvalho are affiliated with PCCA, the manufacturer of the proprietary compounding bases (Loxoral and Clarifying). Funding statement: none., (Copyright© by International Journal of Pharmaceutical Compounding, Inc.)

Background: Evidence indicates an association between immune dysregulation and major depressive disorder (MDD). Pentoxifylline (PTX), a phosphodiesterase inhibitor, has been shown to reduce pro-inflammatory activities. The aim of this study was to evaluate changes in depressive symptoms and pro-inflammatory markers after administration of PTX as an adjunctive agent to citalopram in patients with MDD., Methods: One hundred patients were randomly assigned to either citalopram (20 mg/day) plus placebo (twice daily) (n=50) or citalopram (20 mg/day) plus PTX (400 mg) (twice daily) (n=50). The Hamilton Depression Rating Scale-17 (HAM-D-17) scores at baseline, weeks 2, 4, 6, 8, 10, and 12 and serum levels of interleukin1-β (IL-1-β), tumor necrosis factor-α, C-reactive protein, IL-6, serotonin, IL-10, and brain-derived neurotrophic factor (BDNF) at baseline and week 12 were evaluated., Results: HAM-D-17 score in the PTX group significantly reduced in comparison to the control group after weeks 4, 6, 8,10, and 12 ((LSMD): - 2.193, p=0.021; - 2.597, p=0.036; - 2.916, p=0.019; - 4.336, p=0.005; and - 4.087, p=0.008, respectively). Patients who received PTX had a better response (83%) and remission rate (79%) compared to the placebo group (49% and 40%, p=0.006 and p=0.01, respectively). Moreover, the reduction in serum concentrations of pro-inflammatory factors and increase in serotonin and BDNF in the PTX group was significantly greater than in the placebo group (p<0.001)., Conclusion: These findings support the safety and efficacy of PTX as an adjunctive antidepressant agent with anti-inflammatory effects in patients with MDD., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Ischemic heart diseases such as myocardial infarction (MI) are a global health problem and a leading cause of mortality worldwide. Angiogenesis is an important approach for myocardial healing following ischemia. Thus, this study aimed to explore the potential cardiac angiogenic effects of selenium (Se), alone and in combination with the tumor necrosis factor-alpha inhibitor, pentoxifylline (PTXF), via Akt/HIF-1α signaling. MI was induced in rats using two subcutaneous doses of isoprenaline (ISP) at a 24-h interval (150 mg/kg). One week later, rats were orally given Se (150 µg/kg/day), PTXF (50 mg/kg/day), or Se/PTXF combination. ISP-induced myocardial damage was evident by increased HW/TL ratios, ST segment elevation, and increased serum levels of CK-MB, LDH, and troponin-I. ISP increased the cardiac levels of the lipid peroxidation marker MDA; the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α; and the pro-apoptotic protein Bax and caspase-3. In contrast, the cardiac levels of the antioxidant markers GSH and SOD and the anti-apoptotic marker Bcl-2 were reduced. Furthermore, ISP markedly increased the cardiac levels of p-Akt and HIF-1α proteins and the cardiac gene expression of ANGPT-1, VEGF, and FGF-2. Treatment with Se both alone and in combination with PTXF ameliorated the ISP-induced myocardial damage and further increased cardiac angiogenesis via Akt/HIF-1α signaling. Se/PTXF combined therapy was more beneficial than individual treatments. Our study revealed for the first time the cardiac angiogenic effects of Se both alone and in combination with PTXF in myocardial infarction, suggesting that both may be promising candidates for clinical studies., (© 2023. The Author(s).)

Pentoxifylline (PTX), a non-selective phosphodiesterase inhibitor, has demonstrated protective effects against lung injury in animal models. Given the significance of pulmonary toxicity resulting from paraquat (PQ) exposure, the present investigation was designed to explore the impact of PTX on PQ-induced pulmonary oxidative impairment in male mice.Following preliminary studies, thirty-six mice were divided into six groups. Group 1 received normal saline, group 2 received a single dose of PQ (20 mg/kg; i.p.), and group 3 received PTX (100 mg/kg/day; i.p.). Additionally, treatment groups 4-6 were received various doses of PTX (25, 50, and 100 mg/kg/day; respectively) one hour after a single dose of PQ. After 72 hours, the animals were sacrificed, and lung tissue was collected.PQ administration caused a significant decrease in hematocrit and an increase in blood potassium levels. Moreover, a notable increase was found in the lipid peroxidation (LPO), nitric oxide (NO), and myeloperoxidase (MPO) levels, along with a notable decrease in total thiol (TTM) and total antioxidant capacity (TAC) contents, catalase (CAT) and superoxide dismutase (SOD) enzymes activity in lung tissue. PTX demonstrated the ability to improve hematocrit levels; enhance SOD activity and TTM content; and decrease MPO activity, LPO and NO levels in PQ-induced pulmonary toxicity. Furthermore, these findings were well-correlated with the observed lung histopathological changes.In conclusion, our results suggest that the high dose of PTX may ameliorate lung injury by improving the oxidant/antioxidant balance in animals exposed to PQ., Competing Interests: The authors declare that they have no conflicts of interest., (Thieme. All rights reserved.)

Introduction: Although the effectiveness of pentoxifylline (PF) as a selective inhibitor of phosphodiesterase to enhance sperm motility through increasing cyclic nucleotide in cases of absolute asthenozoospermia has been demonstrated for ICSI, data related to babies born from the PF-ICSI are still severely lacking. Concerns have been raised regarding the potential embryotoxicity of PF due to the controversial results obtained from the analysis of this compound on animal embryo development. This study aimed to determine whether the application of PF to trigger frozen-thawed TESA (testicular sperm aspiration) spermatozoa increases the risk of adverse obstetric and neonatal outcomes compared with non-PF frozen-thawed TESA ICSI and conventional ICSI using fresh ejaculation., Materials and Methods: A total of 5438 patients were analyzed in this study, including 240 patients underwent PF-TESA ICSI (ICSI using PF triggered frozen-thawed testicular spermatozoa), 101 patients underwent non-PF TESA ICSI (ICSI using frozen-thawed testicular spermatozoa) and 5097 patients underwent conventional ICSI using fresh ejaculation. Propensity score matching was executed to control the various characteristics of patients., Results: No significant differences in pregnancy outcomes were observed among the three groups (PF-TESA ICSI, non-PF TESA ICSI and conventional ICSI), including biochemical pregnancy, clinical pregnancy, implantation, miscarriage, ectopic pregnancy, multiple pregnancy, and live birth, following propensity score matching. Additionally, neonatal outcomes were found to be similar among the three groups, with no statistical differences observed in the birth defect, birth weight, gestational age, preterm birth, and early-neonatal death., Discussion and Conclusion: PF-ICSI may be an alternative treatment in patients using frozen-thawed testicular spermatozoa, resulting in comparable pregnancy and neonatal outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dong, Yin, Wu, Wang, Li, Zhang, Ma and Li.)

Phalangeal microgeodic syndrome (PMS) is a rare osteolytic disorder of unknown etiology that typically affects children up to 15 years old during colder months. Transient peripheral circulatory impairment probably underlines its pathogenesis. Conservative treatment with eviction of cold exposure is often successful. We report the case of a young woman presenting with joint pain in her feet, along with toe discoloration and redness, where a diagnosis of PMS was established based on magnetic resonance imaging findings and exclusion of other differential diagnostic entities. Pharmacological treatment was deemed necessary for symptomatic relief, but a trial of calcium channel blocker (CCB) was not tolerated by the patient. The patient was then started on pentoxifylline, with significant clinical improvement., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Aims: Evaluate the existing evidence of osteoradionecrosis (ORN) treatment in adults with head and neck cancer, the methodological quality and the evidence grade within systematic reviews (SRs)., Methods: An extensive systematic literature search of SRs that addressed ORN in head and neck cancer patients was conducted with screening of eligible studies, data extraction, methodological (AMSTAR 2) and evidence quality assessment (GRADE) of the SRs by independent and calibrated authors., Results: A total of six SRs were enrolled. Based primarily on studies from the 1990s, there is critically low- or moderate-quality evidence that hyperbaric oxygen therapy (HBO) improves ORN healing. From 2005 onward, evidence has been discovered in relation to treatment with pentoxifylline and tocopherol (PENTO). The SRs indicate that the management of ORN with PENTO appears to be promising. The greatest rates of healing are seen in mild and moderate stages of ORN. However, the quality of evidence regarding PENTO, surgery and other treatments remains critically low., Conclusion: There is no standardized protocol to treat ORN. PENTO appears to be the most promising conservative treatment; however, the current level of evidence regarding PENTO is still critically low. More robust clinical studies are needed to establish the best treatment for ORN., (© 2023 Special Care Dentistry Association and Wiley Periodicals LLC.)

This meta-analysis aimed to comprehensively evaluate the efficacy and safety of pentoxifylline (PTF) in the treatment of diabetic nephropathy (DN) and to offer fresh perspectives and evidence-based references for this condition. Meta-analysis. Relevant randomized controlled trials (RCTs) were searched from PubMed, Embase, Cochrane Library, China Knowledge Network (CNKI), Wanfang, and China Biomedical Literature Database. All trials were screened for compliance with the inclusion and exclusion criteria, and relevant data were extracted after quality evaluation. Eighteen studies with a total of 1280 patients were finally included. Compared to the control group, high sensitivity C-reactive protein (hsCRP) was improved (MD = - 0.23. 95% CI = [- 0.41, - 0.05], P = 0.01); urinary albumin excretion (UAE) rate was reduced (MD = - 16.50, 95% CI = [- 18.87, - 14.13], P<0.00001); the change of serum creatinine (Scr) from baseline was reduced (MD = - 0.05, 95%CI = [- 0.08, - 0.01], P = 0.009); fasting plasma glucose (FPG) was decreased (MD = - 5.66, 95% CI = [- 9.79, - 1.53], P = 0.007); and the improvement of glomerular filtration rate (eGFR) from baseline was increased (MD = 4.38, 95% CI = [3.28, 5.48], P<0.00001) in the treatment group. No significant difference was observed between the two groups concerning systolic blood pressure, diastolic blood pressure, total cholesterol, and triglycerides. And in terms of safety, the use of PTF was relatively safe with some self-limiting adverse events. FPG was decreased by PTF more effectively, but there was no effect of PTF on glycated hemoglobin (HbA1c). PTF could improve hsCRP, decrease UAE and Scr, and raise eGFR in the treatment of DN., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Radiation-induced renal fibrosis (RIRF) is a progressive, irreversible condition causing chronic kidney disease. Pentoxifylline (PTX) and vitamin E may mitigate radiation-induced damage and fibrosis. This study assesses their effectiveness. We used four groups, each with six rats: radiation therapy alone (RT-only), radiation therapy plus drug treatment (RT + drug), drug treatment alone (drug-only), and a control group. Rats were monitored for three months, with weight measurements every four weeks. Afterward, rats were analyzed biochemically and histologically, with blood and tissue samples taken for statistical comparison. No significant differences in serum creatinine levels and body weight were observed. RT-only group had more severe kidney tubule effects. Histomorphological, immunohistochemical, and TUNEL analyses showed significant RIRF mitigation in the RT + drug group. Our study highlighted molecular pathways (SMAD, TGF-beta, VEGF) and histological markers (collagens, a-SMA, fibronectin, metalloproteinases) associated with RIRF. PTX and vitamin E reduced ionizing radiation's impact on renal cells and mitigated radiation-induced kidney fibrosis. Further human studies are needed to confirm these findings., (© 2024. The Author(s).)

Objective: To investigate whether pentoxifylline (PTX) attenuates cerebral ischaemia-reperfusion injury (IRI) in rats by inhibiting ferroptosis and to explore the underlying molecular mechanisms., Methods: Cerebral IRI was induced in male Sprague-Dawley (SD) rats using middle cerebral artery occlusion (MCAO). The effects of PTX on cerebral ischaemia-reperfusion brain samples were detected through neurological deficit score, staining and electron microscopy; levels of ferroptosis biomarkers from brain samples were detected using kits. Additionally, the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), transferrin receptor protein 1, divalent metal transporter 1, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) were determined by immunohistochemistry, real-time quantitative polymerase chain reaction and western blotting., Results: Pre-treatment with PTX was found to improve neurological function, evidenced by reduced neurological deficit scores, decreased infarct volume and alleviated pathological features post-MCAO. This improvement was accompanied by reduced lipid peroxidation levels and mitigated mitochondrial damage. Notably, PTX's inhibitory effect on ferroptosis was characterised by enhanced Nrf2 nuclear translocation and regulation of ferroptosis-related proteins. Moreover, inhibition of Nrf2 using ML385 (an Nrf2-specific inhibitor) reversed PTX's neuroprotective effect on MCAO-induced ferroptosis via the SLC7A11/GPX4 signalling pathway., Conclusions: Ferroptosis is evident following cerebral ischaemia-reperfusion in rats. Pentoxifylline confers protection against IRI in rats by inhibiting ferroptosis through the Nrf2/SLC7A11/GPX4 signalling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Second Hospital of Hebei Medical University. Published by Elsevier B.V. All rights reserved.)

Background: Optimal treatments for severe alcoholic hepatitis (SAH) remain controversial. Previous network meta-analysis showed that corticosteroid (CS) combined with N-acetylcysteine (NAC) was superior in reducing short-term mortality of patients with SAH. Recently, granulocyte colony-stimulating factor (G-CSF) treatments for SAH yielded promising results. Objectives: To determine how currently available treatments affect the survival and complications of patients with SAH. Methods: The study was conducted following the guidelines of PRISMA. The data from PubMed, Embase, MEDLINE, Cochrane Library, and clinicaltrials.gov to October 2022 were searched, and patients with SAH with pharmacotherapy were included in our study. The primary outcome was short-term survival, and the other outcomes were medium- (3/6 months) or long-term (12 months) survival and complications after treatment. R software was used to establish network meta-analysis models and the result was expressed by the odd ratio (OR) value and 95% credible interval (Crls). Results: A total of 31 randomized controlled trials, including 19 treatment regimens, were enrolled in our study. As the primary outcome, G-CSF+ pentoxifylline (PTX) ranked first in one-month survival and showed significant superiority when compared with the placebo (OR 8.60, 95% Crls 1.92-45.10) and CS (OR 4.95, 95% Crls 1.11-25.53). Also, G-CSF+PTX ranked first in improving three-month survival and reducing the occurrence of infection. PTX+MTD ranked first in six-month survival, and G-CSF ranked first in twelve-month survival. CS+MTD ranked first in the occurrence of gastrointestinal bleeding and hepatorenal syndrome. Conclusions: The combination of G-CSF and PTX showed a significant benefit in improving the short-term survival of SAH patients.

Pentoxifylline is a nonselective phosphodiesterase inhibitor used for the treatment of peripheral artery disease. Pentoxifylline acts through cyclic adenosine monophosphate, thereby enhancing red blood cell deformability, causing vasodilation and decreasing inflammation, and potentially stimulating ventilation. We conducted a double-blind, placebo-controlled, crossover, counter-balanced study to test the hypothesis that pentoxifylline could lower blood viscosity, enhance cerebral blood flow, and decrease pulmonary artery pressure in lowlanders following 11-14 days at 3,800 m. Participants (6 males/10 females; age, 27 ± 4 yr old) received either a placebo or 400 mg of pentoxifylline orally the night before and again 2 h before testing. We assessed arterial blood gases, venous hemorheology (blood viscosity, red blood cell deformability, and aggregation), and inflammation (TNF-α) in room air (end-tidal oxygen partial pressure, ∼52 mmHg). Global cerebral blood flow (gCBF), ventilation, and pulmonary artery systolic pressure (PASP) were measured in room air and again after 8-10 min of isocapnic hypoxia (end-tidal oxygen partial pressure, 40 mmHg). Pentoxifylline did not alter arterial blood gases, TNF-α, or hemorheology compared with placebo. Pentoxifylline did not affect gCBF or ventilation during room air or isocapnic hypoxia compared with placebo. However, in females, PASP was reduced with pentoxifylline during room air (placebo, 19 ± 3; pentoxifylline, 16 ± 3 mmHg; P = 0.021) and isocapnic hypoxia (placebo, 22 ± 5; pentoxifylline, 20 ± 4 mmHg; P = 0.029), but not in males. Acute pentoxifylline administration in lowlanders at 3,800 m had no impact on arterial blood gases, hemorheology, inflammation, gCBF, or ventilation. Unexpectedly, however, pentoxifylline reduced PASP in female participants, indicating a potential effect of sex on the pulmonary vascular responses to pentoxifylline. NEW & NOTEWORTHY We conducted a double-blind, placebo-controlled study on the rheological, cardiorespiratory and cerebrovascular effects of acute pentoxifylline in healthy lowlanders after 11-14 days at 3,800 m. Although red blood cell deformability was reduced and blood viscosity increased compared with low altitude, acute pentoxifylline administration had no impact on arterial blood gases, hemorheology, inflammation, cerebral blood flow, or ventilation. Pentoxifylline decreased pulmonary artery systolic pressure in female, but not male, participants.

The COVID-19 pandemic has become an unprecedented global medical emergency, resulting in more than 5 million deaths. Acute respiratory distress syndrome (ARDS) caused by COVID-19, characterized by the release of a large number of pro-inflammatory cytokines and the production of excessive toxic ROS, is the most common serious complication leading to death. To develop new strategies for treating ARDS caused by COVID-19, a mouse model of ARDS was established by using lipopolysaccharide (LPS). Subsequently, we have constructed a novel nanospray with anti-inflammatory and antioxidant capacity by loading pentoxifylline (PTX) and edaravone (Eda) on zeolite imidazolate frameworks-8 (ZIF-8). This nanospray was endowed with synergetic therapy, which could kill two birds with one stone: (1) the loaded PTX played a powerful anti-inflammatory role by inhibiting the activation of inflammatory cells and the synthesis of pro-inflammatory cytokines; (2) Eda served as a free radical scavenger in ARDS. Furthermore, compared with the traditional intravenous administration, nanosprays can be administered directly and inhaled efficiently and reduce the risk of systemic adverse reactions greatly. This nanospray could not only coload two drugs efficiently but also realize acid-responsive release on local lung tissue. Importantly, ZIF8-EP nanospray showed an excellent therapeutic effect on ARDS in vitro and in vivo, which provided a new direction for the treatment of ARDS.

Background: Treatment of diabetic neuropathic pain does not change the natural history of neuropathy. Improved glycemic control is the recommended treatment in these cases, given that no specific treatment for the underlying nerve damage is available, so far. In the present study, the potential neuroprotective effect of pentoxifylline in streptozotocin (50 mg/kg) induced diabetic neuropathy in rats was investigated., Methods: Pentoxifylline was administered at doses equivalent to 50, 100 & 200 mg/kg, in drinking water, starting one week after streptozotocin injection and for 7 weeks. Mechanical allodynia, body weight and blood glucose level were assessed weekly. Epidermal thickness of the footpad skin, and neuroinflammation and vascular alterations markers were assessed., Results: Tactile allodynia was less in rats that received pentoxifylline at doses of 100 and 200 mg/kg (60 % mechanical threshold increased by 48 % and 60 %, respectively). The decrease in epidermal thickness of footpad skin was almost completely prevented by the same doses. This was associated with a decrease in spinal tumor necrosis factor alpha (TNFα) and nuclear factor kappa B levels and a decrease in microglial ionized calcium binding adaptor molecule 1 immunoreactivity, compared to the control diabetic group. In sciatic nerve, there was decrease in TNF-α and vascular endothelial growth factor levels and intercellular adhesion molecule immunoreactivity., Conclusion: Pentoxifylline showed a neuroprotective effect in streptozotocin-induced diabetic neuropathy, which was associated with a suppression of both the inflammatory and vascular pathogenic pathways that was not associated with a hypoglycemic effect. Thus, it may represent a potential neuroprotective drug for diabetics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Infertility is an inability to conceive after a reasonable period of time (12 months) without the use of contraception or due to a person's incapacity to procreate, whether independently or with a spouse. Problems with the production and maturation of sperm are the most common causes of male infertility additionally; the motility is the major functional character that determines the fertilizing ability of spermatozoa. Therefore the goal of this study is to get better certain sperm function parameters in vitro of asthenozoospermic patient., Objective: The World Health Organization (WHO) and many studies considered the infertility as a disease and so many couples complaining from unsuccessful assisted reproductive technologies (ART) procedures to overcome their problem. The goal of this study is to improve certain sperm function feature in vitro of asthenozoospermic semen patients by using combination of motility inducing namely; Maca, L-carnitine and Pentoxifylline that enhance the medium to improve certain sperm characters that might be utilized for ART centers., Methodology: Semen aliquots were collected from ninety patients with asthenozoospermia who participated in present study, the volume of semen samples with normal ejaculate when was ranged between 1.4-6ml and can be measured by using a measure pipette or conical graduated tube; Inclusion criteria was Asthenozoospermia, oligozoospermia and teratozoospermia men, Infertile idiopathic men also, fertile normozoospermic men. While Exclusion criteria was Azoospermic men, Alcoholic, Patients under treatment with antibiotics and men with Varicocele.The samples split into two equal groups at random. Using Ham's F12 medium, one portion served as the control group, and the other was the treatment group, which was mixing by combining the following ingredients, Maca powder extracts (Lepidium meyenii) (M) 1 mg/ml, 0.5 mg/ml of L-Carnitine (LC), and 10 mg/ml of Pentoxifylline (PTX). The data were analyzed using Statistical Package for Social Sciences (SPSS) version 23.0. The descriptive statistics including frequency, range, mean and standard error, Data from treated and control groups were expressed as mean ± SEM and to compare value between experimental and control groups using Students t-test. Layering approach is used to investigate sperm parameters before and after in vitro activation., Results: The information showed a very large (p< 0.001) increase in active sperm motility grade A, percentage of progressive motility with significant increase in morphologically normal sperm (MNS) with decreased in DNA fragmentation index after activation by layering technique with novel combination medium compared to Hams F12 medium and before activation., Conclusion: The present work stated that novel combination medium (LC, maca and PXT) have potential effects to improve sperm characters in male infertility factors and suggested to be used for sperm preparation and activation in ART programs.

Background: Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria and progressive impairment in renal function. Pentoxifylline is a non-specific inhibitor of phosphodiesterase with anti-inflammatory properties which may have therapeutic potency in patients with diabetic kidney disease., Objective: The present study is aimed at evaluating the efficacy of pentoxifylline as a treatment strategy for alleviating the microalbuminuria in type-2 diabetic patients with nephropathy., Methods: This double-blind randomized clinical trial was performed on outpatients with type 2 diabetic nephropathy who presented urine albumin excretion of 30-300 mg per 24 hours on at least three consecutive occasions. A total of 58 patients were randomly assigned to the treatment and control groups. The treatment group (n=29) received pentoxifylline (400 mg/day) for 3 months in addition to the standard drugs for diabetic nephropathy (Raas blockers), while the control group (n=29) received placebo as add-on therapy. Finally, urine albumin test was measured before and after 3 months of treatment and compared between the two groups., Results: Before the intervention, no significant difference in the levels of albuminuria was observed between the two groups (153.21±130.80 mg/day vs. 159.93 ±130.45; p=0.845); but after 12 weeks of treatment, albuminuria in the treatment group was significantly reduced compared to the placebo group (29.59 ±27.88 mg/day vs. 160.48±129.53 mg/day; p<0.0001). At the end of the study, the response rate to treatment (more than 50% reduction in albuminuria) was 89.7% in the pentoxifylline group, while no response to treatment was observed in the placebo group (p<0.0001)., Conclusions: Pentoxifylline as add-on therapy to the conventional treatment (Raas blockers) may reduce the microalbuminuria in patients with diabetic nephropathy without any side effects.

Background: In older adults, bladder outlet obstruction (BOO) is prevalent, primarily due to benign prostatic hyperplasia (BPH). These patients' lower urinary tract symptoms can be treated surgically and with medical therapy. Compared to standard treatment with tamsulosin, Pentoxifylline, a phosphodiesterase inhibitor, could benefit patients with BOO due to its properties on microcirculatory blood flow and oxygenation of ischemic tissues. Hence, this trial intended to study the efficacy of Pentoxifylline combined with tamsulosin in treating BOO patients., Materials and Methods: This randomized, double-blind clinical trial recruited 60 patients with BPH from a single center in 2022. Upon consent of patients meeting the eligibility criteria, they were randomly allocated to intervention (Pentoxifylline + tamsulosin) and control (placebo + tamsulosin) groups. The patients were evaluated for international prostate symptom score (IPSS), quality of life (QoL), maximum urinary flow rate (Q max ) by uroflowmetry, and post-void residual volume (PVR) by abdominal sonography at the onset of the study and after the 12th week., Results: Patients who used the combination therapy had significantly better results of prostate symptoms and quality of life improvement (IPSS: -36.6%, QoL: -45.3%) compared to patients who received tamsulosin alone (IPSS: -21.2%, QoL: -27.7%) (p < .001). Also, this study shows that the improvement in maximum urinary flow rate and residual volume by combination therapy is significantly higher (Q max : +42.5%, PVR: -42.6%) compared to monotherapy (Q max : +25.1%, PVR: -26.1%) (p < .001)., Conclusion: When combined with tamsulosin, Pentoxifylline could significantly improve the lower urinary symptoms of BPH patients. It is well tolerated, and the treatment outcomes are better in patients who receive the combination of Pentoxifylline and tamsulosin than those who only receive tamsulosin., (© 2024 John Wiley & Sons Australia, Ltd.)

Objective: Aim: To study changes of dental biofilm microbiota composition during experimental opioid exposure, after its withdrawal and when using of complex drug correction.., Patients and Methods: Materials and Methods: Microbiological studies (48 rats) included microscopic and bacteriological methods, as well as determination of antibiotic susceptibility of microbial isolates. Ceftriaxone and pentoxifylline were used to correction the changes., Results: Results: The action of opioid for 10 weeks caused considerable changes in the microbiocenosis, which was illustrated by a significant increasing of the opportunistic pathogens quantitative indicators and the emergence of pathogenic microbiota. Changes in the microbiocenosis at 6 weeks of opioid exposure and after its withdrawal for 4 weeks were expressed in the appearance of pathogenic microbiota and the absence of significant differences in quantitative indicators of saprophytic and opportunistic microflora compared to similar indicators in animals with 10 weeks opioid exposure. This indicated a slow progression of dysbiotic changes and the inflammatory process in the oral cavity of rats., Conclusion: Conclusions: After 10 weeks of experiment with opioid administration for 6 weeks and the use of ceftriaxone and pentoxifylline on the background of 4-week opioid withdrawal, a significant reduction of quantitative indicators of opportunistic bacteria and elimination of pathogenic species of microorganisms was determined. The use of complex drug correction on the background of 10 weeks of opioid exposure led to a significant reduction in the quantitative indicators of opportunistic pathogens and contributed to the elimination of most pathogenic species of microbiota under the action of ceftriaxone.

Livedoid vasculopathy (LV) is a chronic, recurrent thrombotic vasculopathy characterized by painful ulcerations on the lower extremities, which heal slowly and leave atrophic white scars known as "atrophie blanche." This report presents the case of a 31-year-old woman with a 4-year history of recurrent painful ulcerations on her legs and feet. A skin biopsy revealed findings consistent with LV, and an exhaustive laboratory workup ruled out secondary causes such as thrombophilia, malignancies, autoimmune diseases, and peripheral arterial disease. The patient showed remarkable improvement with a treatment regimen of pentoxifylline, nifedipine, and warfarin, resulting in complete ulcer resolution and sustained remission over 5 months. Our case highlights the importance of a comprehensive diagnostic approach and a multidisciplinary treatment strategy in managing primary LV to achieve remission and prevent recurrence of skin ulcerations., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Lichen planopilaris (LPP) is a primary chronic lymphocytic cutaneous disorder that selectively destroys the hair follicles, resulting in scarring alopecia. Unfortunately, current available treatments are not fully effective to stop hair loss, and the level of evidence for medical interventions is weak., Objectives: The present article aimed to determine the efficacy of the different medical interventions in LPP through a network meta-analysis (NMA)., Methods: A systematic review and meta-analysis were performed including randomized trials that report the outcomes of lichen planopilaris activity index (LPPAI). These articles were pooled and a NMA was conducted., Results: A total of seven studies were identified and included in meta-analysis, comprising 251 LPP patients. The NMA showed the mean difference in LLPAI was significantly superior with the combination of clobetasol plus N-acetylcysteine (mean difference: -2.0, 95% CI = -3.43 to -0.51) and the combination of clobetasol plus pentoxifylline (mean difference: -1.62, 95% CI = -3.0 to -0.25) compared to the treatment of reference (clobetasol). The NMA showed cyclosporine (mean difference: 2.05 95% CI = 0.68-3.49), methotrexate (mean difference: 1.95 95% CI = 1.23-3.17), the combination of methotrexate plus prednisolone (mean difference: 1.56 95% CI = 0.25-2.96) were significantly worse than hydroxychloroquine according to the differences in LLPAI., Conclusion: This work is the first NMA in LPP and hence, it can be helpful in serving as an initial step toward better evidence-based decisions in the treatment of this challenging condition. We propose a triple-combined approach consisting of topical clobetasol, hydroxychloroquine, and N-acetylcysteine as resulted in the most effective approach. Considering the poor outcomes observed with pioglitazone, mycophenolate mofetil, and cyclosporine, it is advisable to contemplate the use of these medications in patients who have not responded adequately to more efficacious alternatives., (© 2023 S. Karger AG, Basel.)

Background: Myocardial perfusion defect (MPD) is common in chronic Chagas cardiomyopathy (CCC) and is associated with inflammation and development of left ventricular systolic dysfunction. We tested the hypothesis that pentoxifylline (PTX) could reduce inflammation and prevent the development of MPD in a model of CCC in hamsters., Methods and Results: We investigated with echocardiogram and rest myocardial perfusion scintigraphy at baseline (6-months after T. cruzi infection/saline) and post-treatment (after additional 2-months of PTX/saline administration), female Syrian hamsters assigned to 3 groups: T. cruzi-infected animals treated with PTX (CH + PTX) or saline (CH + SLN); and uninfected control animals (CO). At the baseline, all groups showed similar left ventricular ejection fraction (LVEF) and MPD areas. At post-treatment evaluation, there was a significant increase of MPD in CH + SLN group (0.8 ± 1.6 to 9.4 ± 9.7%), but not in CH + PTX (1.9 ± 3.0% to 2.7 ± 2.7%) that exhibited MPD area similar to CO (0.0 ± 0.0% to 0.0 ± 0.0%). The LVEF decreased in both infected groups. Histological analysis showed a reduced inflammatory infiltrate in CH + PTX group (395.7 ± 88.3 cell/mm 2 ), as compared to CH + SLN (515.1 ± 133.0 cell/mm 2 ), but larger than CO (193.0 ± 25.7 cell/mm 2 ). The fibrosis and TNF-α expression was higher in both infected groups., Conclusions: The prolonged use of PTX is associated with positive effects, including prevention of MPD development and reduction of inflammation in the chronic hamster model of CCC., (© 2023. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

Inhalation of high concentrations of phosgene often causes pulmonary edema, which obstructs the airway and causes tissue hypoxia. There is currently no specific antidote. This study was performed to investigate the effect behind pentoxifylline (PTX) treatment for phosgene-induced lung injury in rat models. Rats were exposed to phosgene. The protein levels of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and occludin proteins in lung tissue were determined. The effect of both prophylactic and therapeutic administration of PTX (50 mg/kg and 100 mg/kg) was evaluated. The lung permeability index and HIF-1α protein level increased, the arterial blood oxygenation index (PaO 2 /FIO 2 ratio) and occludin protein level decreased significantly 6 h after phosgene exposure ( P < 0.05). PTX exerted protective effects by HIF-1α-VEGF-occludin signaling pathway to some extent. Moreover, prophylactic, but not therapeutic administration of PTX (100 mg/kg), exhibited a significant protective effect. Pretreatment with PTX protected against phosgene-induced lung injury, possibly by inhibiting differential expression of HIF-1α, VEGF, and occludin.

Objective: Radiation necrosis (RN) is a long-term side effect of Gamma Knife stereotactic radiosurgery that may require surgical intervention. Pentoxifylline and vitamin E have previously been shown to be effective in the treatment of RN in the published literature, but there are no data on the prophylactic use of these molecules or, more importantly, whether prophylaxis is required., Methods: The iatrogenic RN model included 50 Sprague-Dawley rats of both sexes. There were 7 treatment subgroups established. Gamma-Plan 8.32 was used to plan after magnetic resonance scans were performed in a specially designed frame. The injection doses used in the treatment groups were vitamin E (30 mg/kg/day in a single dose) and pentoxifylline (50 mg/kg/day in 2 doses). Control magnetic resonance scans were performed at the end of a 16-week treatment, and the subjects were decapitated for pathological evaluations., Results: The intensity of hypoxia - inducible factor 1α immunoreactivity is statistically significantly lower in the therapeutic vitamin E, prophylactic pentoxifylline and vitamin E, and therapeutic pentoxifylline and vitamin E groups than in the other groups. Similarly, the intensity of vascular endothelial growth factor immunoreactivity was reduced in the therapeutic vitamin E and prophylactic pentoxifylline and vitamin E treatment modality groups. When compared with other groups, the therapeutic pentoxifylline group had significantly fewer vascular endothelial growth factor-immunoreactive cells in the perinecrotic area, with an accompanying decreased contrast enhancement pattern., Conclusions: Both vitamin E and pentoxifylline are effective for the treatment and/or restriction of RN, either alone or in combination. The use of these molecules as a preventive measure did not outperform the therapeutic treatment., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Diabetic neuropathy (DN) is the most prevalent complication of diabetes. Pharmacological treatments for DN are often limited in efficacy, so the development of new agents to alleviate DN is essential. The aim of this study was to evaluate the effects of rolipram, a selective phosphodiesterase-4 inhibitor (PDE-4I), and pentoxifylline, a general PDE inhibitor, using a rat model of DN. In this study, a diabetic rat model was established by i.p. injection of STZ (55 mg/kg). Rats were treated with rolipram (1 mg/kg), pentoxifylline (100 mg/kg), and combination of rolipram (0.5 mg/kg) and pentoxifylline (50 mg/kg), orally for 5 weeks. After treatments, sensory function was assessed by hot plate test. Then rats were anesthetized and dorsal root ganglion (DRG) neurons isolated. Cyclic adenosine monophosphate (cAMP), adenosine triphosphate (ATP, adenosine diphosphate and mitochondrial membrane potential (MMP) levels, Cytochrome c release, Bax, Bcl-2, caspase-3 proteins expression in DRG neurons were assessed by biochemical and ELISA methods, and western blot analysis. DRG neurons were histologically examined using hematoxylin and eosin (H&E) staining method. Rolipram and/or pentoxifylline significantly attenuated sensory dysfunction by modulating nociceptive threshold. Rolipram and/or pentoxifylline treatment dramatically increased the cAMP level, prevented mitochondrial dysfunction, apoptosis and degeneration of DRG neurons, which appears to be mediated by inducing ATP and MMP, improving cytochrome c release, as well as regulating the expression of Bax, Bcl-2, and caspase-3 proteins, and improving morphological abnormalities of DRG neurons. We found maximum effectiveness with rolipram and pentoxifylline combination on mentioned factors. These findings encourage the use of rolipram and pentoxifylline combination as a novel experimental evidence for further clinical investigations in the treatment of DN., (© 2023 Wiley Periodicals LLC.)

Objective: The aim of this review is to evaluate the different medicinal interventions available for the management of oral submucous fibrosis (OSF)., Materials and Methods: We conducted a comprehensive electronic search on PubMed, Web of Science, and Cochrane Library databases for articles related to OSF patients treated with medications from December 2011 to September 2022. GRADE system was used to evaluate the evidence quality. The reporting of the systematic review is in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. The main outcomes were the improvement of maximum mouth opening, burning sensation, cheek flexibility, and tongue protrusion., Results: Twenty-nine randomized controlled trials (RCTs), five clinical trials (CCTs) were included, and the use of drugs for OSF treatment were evaluated. Drugs like steroids, hyaluronidase, pentoxifylline, lycopene, curcumin, dpirulina, aloe vera, omega3, oxitard, allicin, colchicine have been used. It was found that drugs with evidence high quality were salvia miltiorrhiza combined with triamcinolone acetonide, lycopene, pentoxifylline, curcumin, and aloe vera, and those with evidence moderate quality were allicin, colchicine, omega 3, and oxitard., Conclusion: Based on the results of our comprehensive analysis, for long-term treatment, we found lycopene with low side effects, whereas for relieving the symptoms of severe burning sensation, aloe vera is the most effective. Although the recent review has made some progress, drug therapy for OSF remains unclear, and more high-quality RCTs are needed to identify better treatments for OSF., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Due to the inflammatory factors in the pathophysiology of schizophrenia, Pentoxifylline, as anti-inflammatory medication, seems to improve the symptoms of schizophrenia. This study aims to evaluate the efficacy of Pentoxifylline as an adjunctive therapy on cognitive deficits and symptoms of schizophrenia., Methods: This randomized double-blind placebo-controlled clinical trial was conducted on 52 patients diagnosed with chronic schizophrenia. All patients were divided into two, treatment and control groups. They received a 400 mg dose of Pentoxifylline and the placebo in the treatment and control groups, respectively, twice a day for 8 weeks. Then, they were tested with the Positive and Negative Syndrome Scale (PANSS), Wisconsin Card Sorting Test (WCST), digit span, Stroop test, and Rey Auditory and Verbal Learning Test at baseline and the end of the weeks 4 and 8. Data analysis was done by Kolmogorov-Smirnov test, t -test, Mann-Whitney test, chi-square test, and generalized estimating equation model., Results: After analyzing the data, it was revealed that the positive symptoms of PANSS, the number of errors in the incongruent Stroop test, and reaction time in the congruent Stroop test were significantly lower in the treatment group ( p  < 0.05). Moreover, the number of categories of WCST was significantly higher in the treatment group ( p  < 0.05). There was no statistically significant difference in other parameters between the control and treatment groups ( p  > 0.05)., Conclusions: As evidenced by the results of this study, Pentoxifylline can help alleviate schizophrenia cognitive deficits and can reduce psychotic symptoms. Therefore, it can potentially be useful for schizophrenia treatment., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Osteoradionecrosis (ORN) of the jaws remains one of the most debilitating complications of radiotherapy (RT) in patients with head and neck cancer (HNC). Liquid pentoxifylline and vitamin E (PVe) presents an alternative formulation to tablets for patients with dysphagia or enteric feeding., Objective: This study aimed to assess the clinical outcomes of using a liquid formulation of PVe for both established ORN and as a prophylaxis to avoid its occurrence after dental extractions. A secondary objective was to determine patient-reported side effects in relation to the liquid formulation of PVe., Study Design: The clinical records of 111 patients with HNC who were prescribed liquid PVe were reviewed retrospectively (66 with established ORN and 45 as prophylaxis before an invasive dental procedure)., Results: In established ORN, 44% healed, and 41% were stable. In the prophylaxis group, 96% of surgical sites healed completely, with 4% (n = 2) developing ORN. Most patients (89%) were able to tolerate liquid PVe. Of the 11% (n = 12) who could not tolerate this regime, the most commonly reported side effect was gastric irritation (n = 5/12), whereas no more than 1 patient reported dizziness, malaise, and bleeding., Conclusions: This retrospective review suggests that liquid PVe is efficacious for both established ORN and as a prophylaxis. Side effects reported were similar to those recognized for the tablet formulation., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aim: To investigate the impact of pentoxifylline (PTX, 3 × 400 mg per day) and ursodeoxycholic acid (UDCA, 3 × 250 mg per day) administered for 12 weeks on radiation-induced liver toxicity., Materials and Methods: Inclusion criteria were liver metastases of extrahepatic malignancies undergoing HDR-BT. 36 patients were prospectively randomized to the medication (N = 18) or control arm (N = 18) and follow-up by hepatobiliary magnetic resonance imaging (MRI) was scheduled 6 and 12 weeks after local ablation by HDR-BT. We determined the threshold doses of fRILI by image fusion of MRI with the dosimetry data., Results: 32 patients completed the study schedule. Per-protocol treatment was limited to 8 patients in the medication group and 16 patients in the control group. 22 adverse events of any grade likely or certainly related to PTX were recorded in 12 patients leading to the discontinuation of the study medication in 7 patients and to a dose reduction of PTX in 2 patients. In the per-protocol population, statistical analysis failed to prove a reduction of fRILI 6 and 12 weeks after HDR-BT. The incidence of adverse effects attributed to PTX (70.6%) was well above the data found in the literature for its approved indication., Conclusion: The study endpoint was not met mainly attributed to the low statistical power of the small per-protocol cohort. Independently, PTX cannot be recommended for the reduction of radiation-induced liver toxicity in oncologic patients undergoing HDR-BT of liver metastases. Further studies might focus on a combination of UDCA with other potential drugs to help establish a preventive and tolerable regimen., (© 2023. The Author(s).)

Background: Chronic radiation proctitis (CRP) is a long-term complication of pelvic radiotherapy that manifests as rectal bleeding, diarrhoea, fistula formation and obstruction. Treatments such as endoscopic argon plasma coagulation, hyperbaric oxygen therapy and rectal topical formalin have imposed a significant medical burden on CRP patients. In contrast, oral therapies offer a more accessible and acceptable option for managing CRP. Here, we conducted a systematic review of the efficacy of oral treatments for CRP to assess their potential as an effective and convenient treatment option for this condition., Methods: We searched the Cochrane Central Register of Controlled Trials, PubMed, Web of Science, China National Knowledge Infrastructure and Chinese VIP in February 2021. We included post-radiotherapy participants with CRP that compared oral medicine alone or in combination with other treatments versus control treatments. The primary outcomes were bleeding, diarrhoea and symptom score. Heterogeneity between studies was checked using Cochrane Q test statistics and I 2 test statistics. The Cochrane risk-of-bias tool was used to assess the quality of the included studies., Results: We included 10 randomised controlled trials (RCTs) and 1 retrospective study with 898 participants. Three placebo-controlled trials evaluated the effects of oral sucralfate on CRP, with meta-analysis showing no significant different with placebo arm. Four trials on TCM demonstrated significant improvement of symptoms, especially for the 3 trials on oral TCM drinks. Retinyl palmitate and high-fibre diet were found to reduce rectal bleeding. The combination of oral pentoxifylline and tocopherol did not significantly change the process of CRP., Conclusions: Our study implies that oral TCM drinks, retinyl palmitate and a high-fiber diet showed significant improvement in CRP symptoms, but not with the combination of oral pentoxifylline and tocopherol. Further multicentre, larger-scale RCTs are needed to confirm the efficacy and safety of these treatments and optimize treatment strategies, ultimately improving the quality of life for patients with CRP., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Approximately 20-50% of patients presenting with localized colorectal cancer progress to stage IV metastatic disease (mCRC) following initial treatment and this is a major prognostic determinant. Here, we have interrogated a heterogeneous set of primary colorectal cancer (CRC), liver CRC metastases and adjacent liver tissue to identify molecular determinants of the colon to liver spreading. Screening Food and Drug Administration (FDA) approved drugs for their ability to interfere with an identified colon to liver metastasis signature may help filling an unmet therapeutic need., Methods: RNA sequencing of primary colorectal cancer specimens vs adjacent liver tissue vs synchronous and asynchronous liver metastases. Pathways enrichment analyses. The Library of Integrated Network-based Cellular Signatures (LINCS)-based and Connectivity Map (CMAP)-mediated identification of FDA-approved compounds capable to interfere with a 22 gene signature from primary CRC and liver metastases. Testing the identified compounds on CRC-Patient Derived Organoid (PDO) cultures. Microscopy and Fluorescence Activated Cell Sorting (FACS) based analysis of the treated PDOs., Results: We have found that liver metastases acquire features of the adjacent liver tissue while partially losing those of the primary tumors they derived from. We have identified a 22-gene signature differentially expressed among primary tumors and metastases and validated in public databases. A pharmacogenomic screening for FDA-approved compounds capable of interfering with this signature has been performed. We have validated some of the identified representative compounds in CRC-Patient Derived Organoid cultures (PDOs) and found that pentoxyfilline and, to a minor extent, dexketoprofen and desloratadine, can variably interfere with number, size and viability of the CRC -PDOs in a patient-specific way. We explored the pentoxifylline mechanism of action and found that pentoxifylline treatment attenuated the 5-FU elicited increase of ALDHhigh cells by attenuating the IL-6 mediated STAT3 (tyr705) phosphorylation., Conclusions: Pentoxifylline synergizes with 5-Fluorouracil (5-FU) in attenuating organoid formation. It does so by interfering with an IL-6-STAT3 axis leading to the emergence of chemoresistant ALDHhigh cell subpopulations in 5-FU treated PDOs. A larger cohort of CRC-PDOs will be required to validate and expand on the findings of this proof-of-concept study., (© 2023. The Author(s).)

Background: Post-circumcision penile ischemia is a devastating complication. We will present our experience in managing children with various forms of penile ischemia., Materials and Methods: This cohort prospective observational and interventional study was performed on all male children with post-circumcision penile ischemia between April 2017 and October 2021. A designed and approved protocol includes a combination of early pentoxifylline infusion, hyperbaric oxygen inhalation, early catheterization, and appropriate surgical debridement were applied for patients with deep ischemia 11/23, mainly the necrotic skin and subcutaneous tissues. Data of patient age, anesthesia method, monopolar diathermy usage, early presentation and positive wound culture were collected and analyzed statistically., Results: During the study period 3,382 children were circumcised for non-medical reasons; 23 children were diagnosed with penile ischemia (0.7%), among other complications (9%). Most of the penile ischemia is associated with the use of monopolar diathermy (74%). The use of compressive wound dressing to control post-circumcision bleeding and infections is also responsible for ischemia in 52.2% and 43.5% of the cases. Inexperienced physicians were commonly responsible for ischemia (73.9%). Patients managed at first 24 h had better outcomes than those who were presented later (p = 0.001)., Conclusion: In children with post-circumcision penile ischemia, a combination of hyperbaric oxygen therapy and pentoxifylline is especially effective for patients with skin and facial necrosis, this management reduces penile tissue loss., (© 2023. The Author(s).)

Purpose: To assess the prophylaxis effect of pentoxifylline and tocopherol (PENTO) on the frequency and severity of medication-related osteonecrosis of the jaw (MRONJ) diagnosed at three months in patients with cancer submitted to tooth extractions during the treatment with bone-modifying agents., Methods: This case series was conducted at the outpatient dental clinic of the Instituto de Medicina Integral Prof. Fernando Figueira (IMIP) between April 2021 and April 2022. Patients ≥ 18 years old were included; those with maxillary metastasis or who performed head or neck radiotherapy were excluded. The PENTO protocol was prescribed two weeks before and two weeks after the tooth extraction, and patients were reassessed one week, one month, and three months after the extraction. The main outcome was the development of MRONJ., Results: Of the 114 screened patients, 17 were included; they were aged between 43 and 73 years and were mostly female (88.2%). Thirty-two tooth extractions were performed (22 in the maxilla and 10 in the mandible). Breast cancer was the most predominant neoplasm (70.6%), being metastatic in 35.3% of patients. Also, all patients used intravenous bisphosphonates. Stage 1 MRONJ was diagnosed in three patients (17.6%), representing three (9.4%) of all tooth extractions. The repair of MRONJ was achieved 30 days after the PENTO protocol., Conclusion: The prophylaxis use of PENTO reduced the severity of injuries, was well-tolerated, and showed patient compliance., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: This systematic review aimed to determine whether the pentoxifylline and tocopherol (PENTO) protocol effectively reduce the risk of osteoradionecrosis (ORN) in patients undergoing tooth extraction after head and neck radiotherapy., Methods: We searched PubMed, SCOPUS, LILACS, EMBASE, Web of Science, and Cochrane databases up to August 2022. We considered only studies that included patients diagnosed with head and neck cancer undergoing tooth extraction with PENTO prophylaxis after radiotherapy., Results: Of the 642 studies identified, 4 were included. Across the included studies, 387 patients had 1871 teeth extracted while on PENTO prophylaxis. The interval of the PENTO protocol differed among the studies included. Overall, a total of 12 (3.1%) patients had ORN, whereas at the individual tooth level analysis the ORN rate was 0.9%., Conclusions: Insufficient evidence exists to promote using the PENTO protocol before dental extractions to prevent ORN., Competing Interests: DISCLOSURE None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Osteoradionecrosis of the jaws (ORNJ) is a severe and challenging complication of head and neck radiation therapy. Despite its aggressiveness and controversy respect to its efficacy, surgical intervention remains the main treatment modality. Nevertheless, due to advances in the understanding of ORNJ physiopathology, new treatment alternatives such as the combination of pentoxifylline with tocopherol (PENTO) have emerged. The aim of this systematic review was to assess the reported efficacy of PENTO for the treatment of ORNJ.  Material and Methods: Studies were search using Pubmed, The Cochrane Library, Scopus, and Web of Science data bases following the PRISMA guidelines. Inclusion criteria were cohort, case series, randomized or non-randomized clinical studies published in English including human subjects who received PENTO as treatment for ORN of the jaws.  Results: Eleven articles met the inclusion criteria and were included for data analysis. All studies reported patients with complete mucosal coverage with no exposed bone (considered healthy) after PENTO treatment, ranging from 16.6% to 100% of the patients, depending on the study. Clinical improvement or disease stabilization was reported between 7.6% and 66.6% of studied individuals, while disease progression was seen in only 5 studies involving 7.6 - 32% of patients., Conclusions: PENTO treatment achieved a complete disease control in a significant number of patients in all studies. However, there is no standardized protocol for administering the therapy. It is necessary to determine the pharmacological doses and to evaluate the benefits of adding antibiotics and clodronate. Good quality clinical trials are needed to develop a successful algorithm for the management of ORN of the jaws.