Exploring the potential of tocopherols: mechanisms of action and perspectives in the prevention and treatment of breast cancer.

Currently, breast cancer is the most common cause of mortality caused by neoplasia in women worldwide. The unmet challenges of conventional cancer therapy are chemoresistance and lack of selectivity, which can lead to serious side effects in patients; therefore, new treatments based on natural compounds that serve as adjuvants in breast cancer therapy are urgently needed. Tocopherols are naturally occurring antioxidant compounds that have shown antitumor activity against several types of cancer, including breast cancer. This review summarizes the antitumoral activity of tocopherols, such as the antiproliferative, apoptotic, anti-invasive, and antioxidant effects of tocopherols, through different molecular mechanisms. According to the studies described, α-T, δ-T and γ-T are the most studied in breast tumor cells; however, α-T and γ-T show a more critical antitumor activity and significant potential as a complements to chemotherapeutic drugs against breast cancer, enhancing toxicity against tumor cells and preventing cytotoxicity in nontumor cells. However, the possible relationship between tocopherol intake, related to concentration, and the promotion of cancer in particular cases should not be ruled out, so additional studies are required to determine the correct dose to obtain the desired antitumor effect. Moreover, nanomicelles of D-α-tocopherol have promising potential as pharmaceutical excipients for drug delivery to improve the cytotoxicity and selectivity of first-line chemotherapeutics against breast cancer.

Is the use of Pentoxifylline and Tocopherol effective in the treatment of Osteoradionecrosis of the jaws or for the treatment of medicationosteonecrosis of the jaw? An overview.

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.

Comparative efficacy of tocotrienol and tocopherol (vitamin E) on atherosclerotic cardiovascular diseases in humans.

Objective: To compare the efficacy of tocotrienol and tocopherol in the management of patients with atherosclerotic cardiovascular diseases. METHODS: The systematic review was conducted in line with Preferred Reporting Items for Systematic Reviews and Meta- Analyses guidelines 2020, and comprised literature search from 2002 till January 5, 2023, on PubMed, Google Scholar, Cochrane Library, Google, Wiley-Inter Science Library, Medline, SpringerLink, Taylor and Francis databases. The search was conducted using key words, such as: "tocopherol", "tocotrienol", "vitamin E", "dyslipidaemia", "cardiovascular diseases" "cardioprotective", "hypercholesterolemia" and "atherosclerosis" along with Boolean operators. Human clinical studies regarding the use of tocotrienol or tocopherol or comparison of its efficacy in patients having atherosclerosis, dyslipidaemia leading to cardiovascular diseases, and studies including details of efficacy of any of the four alpha, beta, gamma, delta isomers of tocopherol or tocotrienol were included. Pertinent data from the eligible studies was retrieved and reviewed. RESULTS: Of the 516 articles identified, 26 (5%) articles met eligibility criteria. Of them 5(19%) were subjected to detailed analysis. Tocotrienol showed significant anti-oxidant efficacy at (250 mg/d) by decreasing cholesterol and serum inflammatory biomarkers i.e C-reactive protein (40%), malondialdehyde (34%), gamma-glutamyl transferase (22%) (p<0.001). Total anti-oxidant status (TAS) levels raised 22% (p<0.001) and Inflammatory cytokines i.e resistin, interleukin (IL)-1, IL-12, Interferon-gamma were decreased 15-17% (p<0.05-0.01) respectively by tocotrienol. Several microRNA (miRNA-133a, miRNA-223, miRNA-214, miRNA-155) were modulated by δ-tocotrienol. Whereas, tocopherol showed heterogeneity of results by either decreasing or increasing the risk of mortality in atherosclerotic cardiovascular diseases. Conclusion: Compared to tocopherol, tocotrienol was found to be safe and potential candidate for improving cardiovascular health in the management of atherosclerotic cardiovascular diseases.

Different Roles of Tocopherols and Tocotrienols in Chemoprevention and Treatment of Prostate Cancer.

The vitamin E family contains α-tocopherol (αT), ßT, γT, and δT and α-tocotrienol (TE), ßTE, γTE, and δTE. Research has revealed distinct roles of these vitamin E forms in prostate cancer (PCa). The ATBC trial showed that αT at a modest dose significantly decreased PCa mortality among heavy smokers. However, other randomized controlled trials including the Selenium and Vitamin E Cancer Prevention Trial (SELECT) indicate that supplementation of high-dose αT (≥400 IU) does not prevent PCa among nonsmokers. Preclinical cell and animal studies also do not support chemopreventive roles of high-dose αT and offer explanations for increased incidence of early-stage PCa reported in the SELECT. In contrast, accumulating animal studies have demonstrated that γT, δT, γTE, and δTE appear to be effective for preventing early-stage PCa from progression to adenocarcinoma in various PCa models. Existing evidence also support therapeutic roles of γTE and its related combinations against advanced PCa. Mechanistic and cell-based studies show that different forms of vitamin E display varied efficacy, that is, δTE ≥ γTE > δT ≥ γT >> αT, in inhibiting cancer hallmarks and enabling characteristics, including uncontrolled cell proliferation, angiogenesis, and inflammation possibly via blocking 5-lipoxygenase, nuclear factor κB, hypoxia-inducible factor-1α, modulating sphingolipids, and targeting PCa stem cells. Overall, existing evidence suggests that modest αT supplement may be beneficial to smokers and γT, δT, γTE, and δTE are promising agents for PCa prevention for modest-risk to relatively high-risk population. Despite encouraging preclinical evidence, clinical research testing γT, δT, γTE, and δTE for PCa prevention is sparse and should be considered.

Efficacy of adjunctive modalities during tooth extraction for the prevention of osteoradionecrosis: A systematic review and meta-analysis.

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.

Pentoxifylline and tocopherol as prophylaxis for osteonecrosis of the jaw due to bone-modifying agents in patients with cancer submitted to tooth extraction: a case series.

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.

Can the prophylactic use of pentoxifylline and tocopherol before dental extractions prevent osteoradionecrosis? A systematic review.

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.

Pentoxifylline and tocopherol for the treatment of osteoradionecrosis of the jaws. A systematic review.

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.

Effect of tocopherol conjugation on polycation-mediated siRNA delivery to orthotopic pancreatic tumors.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of cancer with a five-year survival rate of around 10 %. CXCR4 and STAT3 display crucial effects on proliferation, metastasis, angiogenesis, and formation of immunosuppressive microenvironment in pancreatic tumors. Here, we have tested the hypothesis that conjugation of α-tocopherol (TOC) to a polycation (PAMD), synthesized from CXCR4-antagonist AMD3100, will improve delivery of therapeutic siRNA to silence STAT3 in PDAC tumors. PAMD-TOC/siSTAT3 nanoparticles showed superior anti-cancer and anti-migration performance compared to the parent PAMD/siSTAT3 nanoparticles in both murine and human PDAC cell lines. The biodistribution of the nanoparticles in orthotropic mouse KPC8060 and human PANC-1 models, indicated that tumor accumulation of PAMD-TOC/siRNA nanoparticles was improved greatly as compared to PAMD/siRNA nanoparticles. This improved cellular uptake, penetration, and tumor accumulation of PAMD-TOC/siSTAT3 nanoparticles, also contributed to the suppression of tumor growth, metastasis and improved survival. Overall, this study presents a prospective treatment strategy for PDAC.

Pentoxifylline and tocopherol for prevention of osteoradionecrosis in patients who underwent oral surgery: A clinical audit.

PURPOSE: Osteoradionecrosis (ORN) of the jaw is a severe and debilitating complication of the head and neck radiotherapy which frequently occurrs after oral surgery. This clinical audit aims aevaluate the effectiveness of combined use of pentoxifylline and tocopherol (PENTO) in prevention ORN onset in patient who underwent oral surgery after head and neck radiotherapy (RT). MATERIAL METHOD: In this clinical audit Pentoxifylline 400 mg, twice a day, and Tocopherol 800 IU once a day (PENTO protocol) have been prescribed. Patients started the protocol 1 week before the surgical procedure and continued for 8 weeks after. RESULTS: Twenty-nine patients were included. They received 75 surgical interventions under PENTO protocol: 71 surgical procedures of dental extraction (single or multiple dental extractions in each session) and four implant placements. A total of 152 dental extractions were carried out: 64 surgical extractions which required the raising of mucoperiosteal flap, and 88 simple extractions. Four out of 29 patients developed ORN after surgical procedures: four cases of ORN occurred after dental extractions (5.6%) and one case of ORN after implant placement (25%). CONCLUSION: PENTO is a useful ORN preventive protocol, low-cost and clinically feasible, safe and well tolerated by patients. Further studies should focus on better defining the effectiveness PENTO, independently from the antibiotic therapy.

Pentoxifylline and tocopherol (vitamin E) with/without clodronate for the management of osteoradionecrosis: A scoping review.

BACKGROUND: Treatment of osteoradionecrosis (ORN) is not a straightforward task, and it is unpredictable. However, a combination of pentoxifylline; an antioxidant drug, and tocopherol (vitamin E) works as a potent antifibrotic agent and have shown recently both significant and impressive results. AIMS: This scoping review aims to investigate the most prescribed regimen of pentoxifylline and tocopherol with/without clodronate for the management of ORN. METHODS: Ovid MEDLINE and EMBASE databases were used to retrieve eligible studies using planned search keywords. PROSPERO and Cohcarne library were also searched for ongoing or published systematic reviews, respectively. Included articles were grouped thematically according to the type of studies and accordingly they were summarized. RESULTS: A total of 27 articles met the inclusion criteria and included in the data analyses. All the included articles were published between 1997 and 2020. Of these 27 included studies, two were randomized control trials, two were systematic reviews, six were retrospective studies, five were observational studies, seven were narrative reviews, four were case reports, and lastly one was an in-vitro study. CONCLUSIONS: Treatment by PENTO (800 mg of pentoxifylline + 1000 IU of tocopherol) once daily for an early established ORN or PENTOCLO (PENTO regimen + 1600 mg of clodronate) once daily for the refractory/severe cases of ORN appears to be the most prescribed regimen used for the treatment of ORN using these drugs. These drugs appear safe, effective and inexpensive for the treatment of ORN.

Resolution of radiation necrosis with bevacizumab following radiation therapy for primary CNS lymphoma.

IMPORTANCE: Radiation necrosis (RN) is a rare but serious adverse effect following treatment with radiation therapy. No standard of care exists for the management of RN, and efforts to prevent and treat RN are limited by a lack of insight into the pathomechanics and molecular drivers of RN. This case series describes the outcomes of treatment with bevacizumab (BV) in two primary CNS lymphoma (PCNSL) patients who developed symptomatic biopsy-proven RN after whole brain radiation (WBRT) with a stereotactic radiosurgery (SRS) boost. OBSERVATIONS: Patient 1 is a 52 year-old female with PCNSL treated with WBRT followed by an SRS boost. She developed symptomatic biopsy-proven RN, and initial treatment with tocopherol and pentoxifylline was unsuccessful. A 100% clinical and radiographic response was achieved with 4 cycles of BV. Patient 2, a 48 year-old male with PCNSL, presented with seizures and biopsy-proven RN after radiation therapy. Initial empiric treatment with tocopherol and pentoxifylline was unsuccessful. A 100% clinical and radiographic response was achieved with 3 cycles of BV. CONCLUSIONS AND RELEVANCE: Monitoring for RN in patients with PCNSL treated with radiation therapy is warranted. BV is an efficacious treatment and a viable alternative to corticosteroids or surgical intervention.

Patients' experience and perceived concerns regarding obtaining and taking prescriptions for head and neck osteoradionecrosis.

The main components of the medical management of osteoradionecrosis (ORN) are combinations of clodronate, pentoxifylline, tocopherol, sometimes with antibiotics or chlorhexidine rinses. Anecdotally in the Cheshire and Merseyside network, patients report having difficulties getting and taking their prescription, hence the aim was to survey patient experience of obtaining prescriptions, administration of the medications, and side effects. Patients prescribed tocopherol and pentoxifylline from the pharmacy department's record database from the period of January 2019 to June 2020 were invited to take part in a semi-structured telephone survey. Sixteen patients out of a total 33 (48%) responded. 11 patients (69%) reported some issue collecting their repeat prescriptions, commonly low stock of medicines in community or unwillingness of GPs to prescribe. One patient permanently stopped treatment owing to difficulties obtaining medication, whilst for three there were temporary gaps in treatment. Difficulty in administration of the medications was reported in 7 patients (44%) patients, most commonly in those with pre-existing dysphagia. Issues related to difficulties in swallowing the large pentoxifylline tablet or with the vitamin E capsules. Patients crushed the medications, but this was associated with gastrointestinal side-effects in one patient who had to stop treatment. One patient stopped chlorhexidine mouthwash due to oral soreness. In conclusion, medical management of ORN is well tolerated by patients. There is difficulty for patients getting prescriptions in primary care. Few patients need to stop taking the medication due to difficulty in administration or side-effects. More patient information would be useful for all concerned.

Nanocarrier-Based Delivery of SN22 as a Tocopheryl Oxamate Prodrug Achieves Rapid Tumor Regression and Extends Survival in High-Risk Neuroblastoma Models.

Despite the use of intensive multimodality therapy, the majority of high-risk neuroblastoma (NB) patients do not survive. Without significant improvements in delivery strategies, anticancer agents used as a first-line treatment for high-risk tumors often fail to provide clinically meaningful results in the settings of disseminated, recurrent, or refractory disease. By enhancing pharmacological selectivity, favorably shifting biodistribution, strengthening tumor cell killing potency, and overcoming drug resistance, nanocarrier-mediated delivery of topoisomerase I inhibitors of the camptothecin family has the potential to dramatically improve treatment efficacy and minimize side effects. In this study, a structurally enhanced camptothecin analog, SN22, reversibly coupled with a redox-silent tocol derivative (tocopheryl oxamate) to allow its optimally stable encapsulation and controlled release from PEGylated sub-100 nm nanoparticles (NP), exhibited strong NB cell growth inhibitory activity, translating into rapid regression and durably suppressed regrowth of orthotopic, MYCN-amplified NB tumors. The robust antitumor effects and markedly extended survival achieved in preclinical models recapitulating different phases of high-risk disease (at diagnosis vs. at relapse with an acquired loss of p53 function after intensive multiagent chemotherapy) demonstrate remarkable potential of SN22 delivered in the form of a hydrolytically cleavable superhydrophobic prodrug encapsulated in biodegradable nanocarriers as an experimental strategy for treating refractory solid tumors in high-risk cancer patients.

iPS-derived neural stem cells for disease modeling and evaluation of therapeutics for mucopolysaccharidosis type II.

Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is a rare, lysosomal disorder caused by mutations in a gene encoding iduronate-2-sulfatase (IDS). IDS deficiency results in an accumulation of glycosaminoglycans (GAGs) and secondary accumulations of other lipids in lysosomes. Symptoms of MPS II include a variety of soft and hard tissue problems, developmental delay, and deterioration of multiple organs. Enzyme replacement therapy is an approved treatment for MPS II, but fails to improve neuronal symptoms. Cell-based neuronal models of MPS II disease are needed for compound screening and drug development for the treatment of the neuronal symptoms in MPS II. In this study, three induced pluripotent stem cell (iPSC) lines were generated from three MPS II patient-derived dermal fibroblast cell lines that were differentiated into neural stem cells and neurons. The disease phenotypes were measured using immunofluorescence staining and Nile red dye staining. In addition, the therapeutic effects of recombinant human IDS enzyme, delta-tocopherol (DT), and hydroxypropyl-beta-cyclodextrin (HPBCD) were determined in the MPS II disease cells. Finally, the neural stem cells from two of the MPS II iPSC lines exhibited typical disease features including a deficiency of IDS activity, abnormal glycosaminoglycan storage, and secondary lipid accumulation. Enzyme replacement therapy partially rescued the disease phenotypes in these cells. DT showed a significant effect in reducing the secondary accumulation of lipids in the MPS II neural stem cells. In contrast, HPBCD displayed limited or no effect in these cells. Our data indicate that these MPS II cells can be used as a cell-based disease model to study disease pathogenesis, evaluate drug efficacy, and screen compounds for drug development.

18F-FDG PET/CT for early response assessment of jaw osteoradionecrosis after the PENTOCLO protocol: A promising imaging modality.

INTRODUCTION: The Pentoxifylline, Tocopherol and Clodronate protocol (PENTOCLO) showed promising results for jaw osteoradionecrosis (ORN) management. However, the clinical and radiological improvements are often delayed, leading to unwanted long-term treatment, with potential loss of opportunity for more radical surgical treatments. Our objective was to assess the diagnosis performance of 18F-FDG PET/CT to early predict ORN response to the PENTOCLO protocol. MATERIALS AND METHODS: All patients from our center who were treated with the PENTOCLO protocol and with a 18F-FDG PET/CT performed at diagnosis and three months after the end of antibiotherapy were retrospectively included. The PENTOCLO protocol was always combined with prior appropriate antibiotherapy for six weeks. The healing endpoint was divided into healing, stability or worsening, according to the combination of clinical and radiological assessments at the date of last follow-up. For each patient, the difference between the maximal standardized uptake value (ΔSUVmax) of the ORN lesion at three months and baseline were computed. Diagnostic performance of 18F-FDG PET/CT was evaluated by sensitivity, specificity and the area under the receiver operating characteristic curve (ROC-AUC) of ΔSUVmax. RESULTS: 24 patients were included with an average follow-up of 29.3 months. The healing, stability and worsening rate were 25%, 62.5% and 12.5% respectively. The AUC for discriminating worsening vs stability or healing was 0.92 (IC95 [0.81-1.00]). A ΔSUVmax greater than or equal to 0 was predictive of a worsening with a sensitivity and specificity of 84 and 66% respectively. CONCLUSION: 18F-FDG PET/CT imaging could be useful for early prediction of PENTOCLO treatment resistance with appropriate antibiotherapy.

[Pentoxifylline and tocopherol - The importance in the treatment of osteoradionecrosis - Literature review and case report]. / Pentoxifyllin und Tocopherol. Die Bedeutung in der Behandlung der Osteoradionekrose ­ Literaturreview und Fallbericht.

Osteoradionecrosis (ORN) is a serious complication after radiotherapy for head and neck cancer and is a challenging condition for both the therapist and the patient because of its difficult treatment. Different non-invasive approaches have been published for the treatment of low-grade ORN cases without establishing a standard regimen for treatment. Based on the approach of ORN pathogenesis, the so-called radiatio-induced fibroathrophic process (RIF), a new treatment concept with pentoxifylline and tocopherol (PENTO) has been published. The results of PENTO therapy seem promising as a conservative treatment approach for mild ORN or as an alternative when surgical intervention is not possible or desired. The present study summarizes the current state of the literature and shows the effectiveness of PENTO therapy based on a case report.

Cilostazol and Tocopherol in the Management of Medication-Related Osteonecrosis of the Jaw: New Insights From a Case Report.

Several treatment protocols for medication-related osteonecrosis of the jaw (MRONJ) have been published. Despite the efficacy of surgical therapy of approximately 90% as primary therapy, the role of other agents, such as drug administration, should not be underestimated. Based on previous experience with osteoradionecrosis, the association of pentoxifylline and tocopherol has shown encouraging results in MRONJ patients. Despite the need for long-term use of the combination, compliance has been good. However, studies in breast cancer patients revealed that pentoxifylline can require dose reduction or discontinuation due to nausea and epigastric pain. Cilostazol has been used as a substitute for pentoxifylline in peripheral artery disease. Herein we report a case in which cilostazol replaced pentoxifylline at a dose of 100mg, 2 times/day with tocopherol 500UI, 2 times/day, in a 77-year-old female patient that could not tolerate pentoxifylline for the management of MRONJ. After an uneventful 22 months of follow-up, a cone-beam computed tomography revealed complete bone formation and no signs of recurrence. Cilostazol may be a useful and safe alternative to pentoxifylline as part of MRONJ management protocols.

Effect of δ-Tocopherol on Mice Adipose Tissues and Mice Adipocytes Induced Inflammation.

The study aim was to evaluate the potential anti-inflammatory effects of vitamin E analogs, especially α-tocopherol and δ-tocopherol. We used male C57BL/6JJcl mice, which were divided into four groups: the control (C), high-fat and high-sucrose diet (H), high-fat and high-sucrose diet+α-tocopherol (Ha) and high-fat and high-sucrose diet+δ-tocopherol (Hd) groups. The mice were fed for 16 weeks. To the high-fat and high-sucrose diet, 800 mg/kg of α-tocopherol or δ-tocopherol was added more. The final body weight was significantly higher in the H group than in the C group. On the other hand, the final body weight was drastically lower in the Ha group and Hd group than in the H group. However, the energy intake was not significantly different among all groups. Therefore, we assumed that α-tocopherol and δ-tocopherol have potential anti-obesity effect. Besides, inflammatory cytokine gene expression was significantly higher in the epididymal fat of the H group than in the C group. These results showed that inflammation was induced by epididymal fat of mice fed a high-fat and high-sucrose diet for 16 weeks. Unfortunately, addition of α-tocopherol or δ-tocopherol to the diet did not restrain inflammation of epididymal fat. Investigation of the anti-inflammatory effects of α-tocopherol or δ-tocopherol in co-cultured 3T3-L1 cells and RAW264.7 cells showed that δ-tocopherol inhibited increased gene expression of the inflammatory cytokines, IL-1ß, IL-6, and iNOS. These results suggest that an anti-inflammatory effect in the δ-tocopherol is stronger than that in the α-tocopherol in vitro. We intend to perform an experiment by in vivo sequentially in the future.