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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.

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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.

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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.

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Cervical cancer (CC) is one of the most common and deadly types of female cancer worldwide. Late diagnosis in CC increases the risk of tumor cells spreading to distant organs (metastasis). The epithelial-mesenchymal transition (EMT) is a fundamental process of cancer metastasis. Inflammation can lead to tumor progression, EMT induction, and metastasis. The inflammatory microenvironment is a potent inducer of EMT; inflammatory cytokines such as Tumor Necrosis Factor-alpha (TNF-α) and Transforming growth factor-beta (TGF-ß1) activate transcriptional factors such as STAT3, Snail, Smad, and the Nuclear Factor kappa light-chain-enhancer of activated beta cells (NF-κΒ), which drive EMT. Anti-inflammatory compounds may be an option in the disruption of EMT. PenToXifylline (PTX) possesses potent anti-inflammatory effects by inhibiting NF-κB activity. In addition, PTX exerts an anti-fibrotic effect by decreasing Smad2/3/4. We hypothesize that PTX could exert anti-EMT effects. CaSki human cervical tumor cells were exposed to TNF-α 10 ng/mL and TGF-ß1 alone or in combination for 5 days. Our results revealed that TNF-α and TGF-ß1 induced N-cadherin and Vimentin, confirming the induction of EMT. Furthermore, the combination of cytokines synergized the expression of mesenchymal proteins, enhanced IκBα and p65 phosphorylation, and upregulated Serpin family E member 1 (SERPINE1) mRNA. PTX pretreatment prior to the addition of TNF-α and TGF-ß1 significantly reduced N-cadherin and Vimentin levels. To our knowledge, this is the first time that this effect of PTX has been reported. Additionally, PTX reduced the phosphorylation of IκB-α and p65 and significantly decreased SERPINE1 expression, cell proliferation, migration, and invasion. In conclusion, PTX may counteract EMT in cervical cancer cells by decreasing the NF-κB and SERPINE1.

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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.

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BACKGROUND: Experimental reports have demonstrated that florfenicol (FFC) exerts potent anti-inflammatory effects, improving survival in a murine endotoxemia model. Considering the anti-inflammatory and immunomodulatory properties of pentoxifylline (PTX) as an adjuvant to enhance the efficacy of antibiotics, the anti-inflammatory effects of the interaction FFC/PTX over the E. coli Lipopolysaccharide (LPS)-induced acute inflammatory response was evaluated in rabbits. METHODS: Twenty-five clinically healthy New Zealand rabbits (3.8 ± 0.2 kg body weight: bw), were distributed into five experimental groups. Group 1 (control): treated with 1 mL/4 kg bw of 0.9% saline solution (SS) intravenously (IV). Group 2 (LPS): treated with an IV dose of 5 µg/kg of LPS. Group 3 (pentoxifylline (PTX) + LPS): treated with an oral dose of 30 mg/kg PTX, followed by an IV dose of 5 µg/kg of LPS 45 min after PTX. Group 4 (Florfenicol (FFC) + LPS): treated with an IM dose of 20 mg/kg of FFC, followed by an IV dose of 5 µg/kg of LPS 45 min after FFC administration. Group 5 (PTX + FFC + LPS): treated with an oral dose of 30 mg/kg of PTX, followed by an IM dose of 20 mg/kg of FFC, and, 45 min after an IV dose of 5 µg/kg of LPS was administered. The anti-inflammatory response was evaluated through changes in plasma levels of interleukins (TNF-α, IL-1ß and IL-6), C-reactive protein (CRP), and body temperature. RESULTS: It has been shown that each drug produced a partial inhibition over the LPS-induced increase in TNF-α, IL-1ß, and CRP. When both drugs were co-administered, a synergistic inhibitory effect on the IL-1ß and CRP plasma concentrations was observed, associated with a synergic antipyretic effect. However, the co-administration of PTX/FFC failed to modify the LPS-induced increase in the TNF-α plasma concentrations. CONCLUSIONS: We concluded that the combination of FFC and PTX in our LPS sepsis models demonstrates immunomodulatory effects. An apparent synergistic effect was observed for the IL-1ß inhibition, which peaks at three hours and then decreases. At the same time, each drug alone was superior in reducing TNF-α levels, while the combination was inferior. However, the peak of TNF-α in this sepsis model was at 12 h. Therefore, in rabbits plasma IL-1ß and TNF-α could be regulated independently, thus, further research is needed to explore the effects of this combination over a more prolonged period.

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This work aimed to assess the effects of the coadministration of pentoxifylline (PTX) on the pharmacokinetic profile of florfenicol (FFC) after intramuscular administration in rabbits. Ten New Zealand white rabbits, 1 year of age and 3.9 ± 0.1 kg body weight, were assigned according to a randomized block design to Group 1 (FFC): treated with 30 mg/kg of FFC intramuscularly, and Group 2 (PTX + FFC) treated with an oral dose of 30 mg/kg PTX 45 min before the intramuscular injection of 30 mg/kg FFC. Blood samples were collected before and at different times between 0.5 and 12.0 h after drug administration. FFC plasma concentrations were determined by high-performance liquid chromatography. Results showed that IM injection of the long-acting formulation of FFC in rabbits resulted in a slow increase in mean plasma concentrations reaching a Cmax of 3.09 ± 0.52 ug/mL at 2.8 ± 0.45 h (Tmax ) after drug administration. While coadministration of PTX and FFC decreased the time to achieve the maximal concentration by modifying the absorption of FFC without changes in the other pharmacokinetic parameters.

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Mucosal leishmaniasis (ML) is a severe form of tegumentary leishmaniasis associated with a persistent inflammatory response. High levels of TNF, IFN-γ, CXCL9 and CXCL10 are found in ML patients, and the association of pentoxifylline with antimony is more effective in decreasing the healing time in ML patients when compared to antimony alone. The present study aimed to investigate the existence of a correlation between cytokine and chemokine production and ML severity and evaluate the potential value of cytokine and chemokine production as marker of therapeutic response in ML patients. This prospective study included 86 subjects in an area of endemic Leishmania braziliensis transmission. Patients diagnosed with ML were classified into clinical stages ranging from I to V according to disease severity. TNF, IFN-γ, CXCL9 and CXCL10 levels were quantified in the supernatant of the mononuclear cell cultures by ELISA before and after treatment with antimony alone or antimony plus pentoxifylline. The median TNF level in the group with mild disease (Stages I-II) was 1064 pg/mL (142-3738 pg/mL), while, in the group with moderate or severe disease (Stages III-V), it was 1941 pg/mL (529-5294 pg/mL) (p = 0.008). A direct correlation was observed between ML clinical severity and levels of TNF production (r = 0.44, p = 0.007). Patients who were treated with antimony and pentoxifylline healed significantly faster than those treated with antimony alone (52 vs. 77 days, hazard ratio = 0.60; 95% confidence interval = 0.38-0.95, p = 0.013). Therapeutic failure was higher in the group that received antimony alone (25% vs. 7%; p = 0.041). There was a significant decrease in CXCL9 after therapy of ML in both groups (p = 0.013; p = 0.043). TNF levels are associated with the severity of mucosal diseases, and pentoxifylline associated with antimony should be the recommended therapy for ML in countries where liposomal amphotericin B is not available.

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Alcohol-associated liver disease is one of the main causes of chronic liver disease. It comprises a clinical-histologic spectrum of presentations, from steatosis, steatohepatitis, to different degrees of fibrosis, including cirrhosis and severe necroinflammatory disease, called alcohol-associated hepatitis. In this focused update, we aim to present specific therapeutic interventions and strategies for the management of alcohol-associated liver disease. Current evidence for management in all spectra of manifestations is derived from general chronic liver disease recommendations, but with a higher emphasis on abstinence and nutritional support. Abstinence should comprise the treatment of alcohol use disorder as well as withdrawal syndrome. Nutritional assessment should also consider the presence of sarcopenia and its clinical manifestation, frailty. The degree of compensation of the disease should be evaluated, and complications, actively sought. The most severe acute form of this disease is alcohol-associated hepatitis, which has high mortality and morbidity. Current treatment is based on corticosteroids that act by reducing immune activation and blocking cytotoxicity and inflammation pathways. Other aspects of treatment include preventing and treating hepatorenal syndrome as well as preventing infections although there is no clear evidence as to the benefit of probiotics and antibiotics in prophylaxis. Novel therapies for alcohol-associated hepatitis include metadoxine, interleukin-22 analogs, and interleukin-1-beta antagonists. Finally, granulocyte colony-stimulating factor, microbiota transplantation, and gut-liver axis modulation have shown promising results. We also discuss palliative care in advanced alcohol-associated liver disease.