RESUMO
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.
Assuntos
Neoplasias da Mama , Tocoferóis , Humanos , Neoplasias da Mama/tratamento farmacológico , Tocoferóis/farmacologia , Tocoferóis/uso terapêutico , Feminino , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacosRESUMO
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.
Assuntos
Neoplasias da Próstata , Tocoferóis , Tocotrienóis , Masculino , Humanos , Neoplasias da Próstata/prevenção & controle , Tocotrienóis/farmacologia , Tocotrienóis/uso terapêutico , Tocoferóis/farmacologia , Tocoferóis/uso terapêutico , Animais , Suplementos Nutricionais , Quimioprevenção/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Vitamina E/farmacologia , Vitamina E/uso terapêutico , Anticarcinógenos/farmacologia , Anticarcinógenos/uso terapêuticoRESUMO
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.
Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Conservadores da Densidade Óssea , Neoplasias da Mama , Pentoxifilina , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Adolescente , Masculino , Pentoxifilina/uso terapêutico , Tocoferóis/uso terapêutico , Conservadores da Densidade Óssea/efeitos adversos , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/prevenção & controle , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Extração Dentária/efeitos adversos , Extração Dentária/métodos , Difosfonatos/efeitos adversosRESUMO
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.
Assuntos
Neoplasias de Cabeça e Pescoço , Osteorradionecrose , Pentoxifilina , Humanos , Tocoferóis/uso terapêutico , Pentoxifilina/uso terapêutico , Osteorradionecrose/prevenção & controle , Osteorradionecrose/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Extração Dentária , Estudos RetrospectivosRESUMO
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.
Assuntos
Neoplasias de Cabeça e Pescoço , Osteorradionecrose , Pentoxifilina , Humanos , Tocoferóis/uso terapêutico , Pentoxifilina/uso terapêutico , Osteorradionecrose/tratamento farmacológico , Osteorradionecrose/etiologia , Neoplasias de Cabeça e Pescoço/complicações , Arcada OsseodentáriaRESUMO
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.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Camundongos , Animais , RNA Interferente Pequeno/genética , Tocoferóis/farmacologia , Tocoferóis/uso terapêutico , Distribuição Tecidual , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Microambiente TumoralRESUMO
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.
Assuntos
Neoplasias de Cabeça e Pescoço , Procedimentos Cirúrgicos Bucais , Osteorradionecrose , Pentoxifilina , Humanos , Tocoferóis/uso terapêutico , Pentoxifilina/uso terapêutico , Osteorradionecrose/prevenção & controle , Osteorradionecrose/tratamento farmacológico , Osteorradionecrose/etiologia , Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias de Cabeça e Pescoço/cirurgia , Procedimentos Cirúrgicos Bucais/efeitos adversosRESUMO
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.
Assuntos
Osteorradionecrose , Humanos , Ácido Clodrônico/uso terapêutico , Estudos Observacionais como Assunto , Osteorradionecrose/tratamento farmacológico , Pentoxifilina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Tocoferóis/uso terapêutico , Vitamina E/uso terapêutico , Quimioterapia Combinada/efeitos adversosRESUMO
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.
Assuntos
Neoplasias Encefálicas , Linfoma , Pentoxifilina , Lesões por Radiação , Radiocirurgia , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Feminino , Humanos , Linfoma/etiologia , Masculino , Pessoa de Meia-Idade , Necrose , Pentoxifilina/uso terapêutico , Lesões por Radiação/patologia , Radiocirurgia/efeitos adversos , Estudos Retrospectivos , Tocoferóis/uso terapêuticoRESUMO
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.
Assuntos
Neoplasias de Cabeça e Pescoço , Osteorradionecrose , Pentoxifilina , Clorexidina/uso terapêutico , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Osteorradionecrose/tratamento farmacológico , Pentoxifilina/uso terapêutico , Prescrições , Tocoferóis/uso terapêuticoRESUMO
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.
Assuntos
Camptotecina/análogos & derivados , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Neuroblastoma/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Tocoferóis/uso terapêutico , Camptotecina/química , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neuroblastoma/patologia , Fatores de Risco , Análise de Sobrevida , Tocoferóis/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
Osteorradionecrose , Pentoxifilina , Ácido Clodrônico/uso terapêutico , Combinação de Medicamentos , Fluordesoxiglucose F18/uso terapêutico , Humanos , Osteorradionecrose/diagnóstico por imagem , Osteorradionecrose/terapia , Pentoxifilina/uso terapêutico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Estudos Retrospectivos , Tocoferóis/uso terapêuticoRESUMO
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.
Assuntos
Neoplasias de Cabeça e Pescoço , Osteorradionecrose , Pentoxifilina , Humanos , Osteorradionecrose/tratamento farmacológico , Pentoxifilina/uso terapêutico , Tocoferóis/uso terapêuticoRESUMO
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.
Assuntos
Adipócitos/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Inflamação/tratamento farmacológico , Tocoferóis/farmacologia , Células 3T3-L1 , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Animais , Anti-Inflamatórios , Fármacos Antiobesidade , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Sacarose Alimentar/efeitos adversos , Expressão Gênica/efeitos dos fármacos , Inflamação/etiologia , Inflamação/genética , Mediadores da Inflamação/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Tocoferóis/uso terapêutico , alfa-Tocoferol/farmacologia , alfa-Tocoferol/uso terapêuticoRESUMO
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.
Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Conservadores da Densidade Óssea , Osteonecrose , Osteorradionecrose , Preparações Farmacêuticas , Idoso , Cilostazol , Feminino , Humanos , Osteonecrose/induzido quimicamente , Osteonecrose/diagnóstico por imagem , Osteonecrose/tratamento farmacológico , Tocoferóis/uso terapêuticoRESUMO
The identification of the different risk factors for mandibular osteoradionecrosis (ORN) must be done before and after the management of patients with head and neck cancer. Various clinical criteria for this severe radiation-induced complication are related to the patient (intrinsic radiosensitivity, malnutrition associated with thin weight loss, active smoking intoxication, microcapillary involvement, precarious oral status, hyposalivation) and/or related to the disease (oral cavity, large tumor size, tumor mandibular invasion). Therapeutic risk factors are also associated with a higher risk of ORN (primary tumor surgery, concomitant radio-chemotherapy, post-irradiation dental avulsion, preventive non-observance with the absence of stomatological follow-up and daily installation of gutters fluoride and, non-observance curative healing treatments). Finally, various dosimetric studies have specified the parameters in order to target the dose values distributed in the mandible, which increases the risk of ORN. An mean mandibular dose greater than 48-54Gy and high percentages of mandibular volume receiving 40 to 60Gy appear to be discriminating in the risk of developing an ORN.
Assuntos
Neoplasias de Cabeça e Pescoço/radioterapia , Doenças Mandibulares/etiologia , Doenças Mandibulares/terapia , Osteorradionecrose/etiologia , Osteorradionecrose/terapia , Conservadores da Densidade Óssea/uso terapêutico , Ácido Clodrônico/uso terapêutico , Quimioterapia Combinada , Humanos , Oxigenoterapia Hiperbárica , Osteorradionecrose/classificação , Osteorradionecrose/diagnóstico , Pentoxifilina/uso terapêutico , Dosagem Radioterapêutica , Fatores de Risco , Tocoferóis/uso terapêuticoRESUMO
AIMS: Medical management of osteoradionecrosis (ORN) via pentoxifylline, tocopherol (PENTO) and clodronate (PENTOCLO) has shown both promise and early positive outcomes. We aimed to determine clinical outcomes for patients with established ORN managed solely via PENTO or PENTOCLO. METHODS: The study retrospectively reviewed and collected data from the medical records of 169 patients diagnosed with ORN and treated via medical management. Patients that received any additional interventions such as surgery or hyperbaric oxygen were not included. RESULTS: Medical management led to healed ORN in 54.4% (n = 92/169) of patients after an average of 12.9 months. Outcome comparison between PENTO and PENTOCLO identified the former regime to be significantly superior (p = 0.0001). There is an inverse relationship with increasing ORN severity and healing with medical management (p < 0.0001) with oropharyngeal cancer (p = 0.0347) patients responding favourably via this approach. Infection had a critical role in the final outcome with those healing requiring 1.3 antibiotic prescriptions, while those that had disease progression requiring 4.3 prescriptions. CONCLUSION: Medical management is a viable treatment option for ORN. It appears to be most effective in Notani I and non-infected ORN. When healing was not achieved the regime was able to stabilise the condition.
Assuntos
Neoplasias de Cabeça e Pescoço , Osteorradionecrose , Pentoxifilina , Ácido Clodrônico/uso terapêutico , Humanos , Arcada Osseodentária , Osteorradionecrose/tratamento farmacológico , Pentoxifilina/uso terapêutico , Estudos Retrospectivos , Tocoferóis/uso terapêuticoRESUMO
BACKGROUND: The aim of the present study was to evaluate the efficacy of pentoxifylline and tocopherol for the management of osteoradionecrosis of the jaws. METHODS: Twenty-five patients diagnosed with osteoradionecrosis of the jaws treated with pentoxifylline 400 mg + tocopherol 400 mg three times daily (tid) were evaluated. Clinical records and image tests were reviewed. All patients were previously submitted to head and neck radiation therapy and presented with a clinical and radiographic diagnosis of osteoradionecrosis of the jaws. RESULTS: Following therapy with pentoxifylline and tocopherol, 76% (19/25) of the patients showed complete mucosal healing, in which 47.3% (9/19) did not undergo sequestrectomy. From this particular group, 77.7% (7/9) were in stage I and 33.3% (3/9) used the protocol for up to 3 months. Among those who underwent to sequestrectomy, complete mucosal healing was observed in 52.7% (10/19). Among these, 60% (6/10) were in stage I and 100% of the patients were using the protocol for more than 3 months. In all other patients, partial healing of the mucosa was observed since they presented advanced disease. These represented 24% of the sample (6/25), 66.6% (4/6) were in stage III, and 60% (4/6) used the protocol for over 6 months. CONCLUSION: Pentoxifylline and tocopherol may provide effective management of osteoradionecrosis of the jaws, and the association with sequestrectomy may avoid major surgical procedures.
Assuntos
Antioxidantes/uso terapêutico , Arcada Osseodentária/patologia , Osteorradionecrose/tratamento farmacológico , Osteorradionecrose/cirurgia , Pentoxifilina/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Tocoferóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antioxidantes/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteorradionecrose/patologia , Pentoxifilina/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Tocoferóis/farmacologiaRESUMO
PURPOSE: Medication-related osteonecrosis of the jaw (MRONJ) is a previously described debilitating condition in which patients experience progressive bone destruction in the maxilla and/or mandible after exposure to certain drugs. Clinical management of MRONJ remains controversial, with no established guidelines. The aim of our study was to conduct a literature review on the effectiveness of pentoxifylline (PTX) and tocopherol (PENTO protocol) on MRONJ. STUDY DESIGN: A literature review was conducted, using two different scientific databases, to evaluate the effects of PTX and tocopherol on MRONJ. DISCUSSION: PENTO protocol prescription to treat MRONJ was reported to be well tolerated, with minimal side-effects, and non-expensive when compared with other non-surgical treatment modalities. It was shown to relieve painful symptoms in all patients, and significant new bone formation was observed at final follow-up. CONCLUSION: Observational and case-series studies have demonstrated that pentoxifylline and tocopherol are potentially useful in the non-surgical management of MRONJ.
Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Conservadores da Densidade Óssea , Osteonecrose , Pentoxifilina , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/tratamento farmacológico , Difosfonatos , Humanos , Mandíbula , Osteonecrose/induzido quimicamente , Osteonecrose/tratamento farmacológico , Pentoxifilina/uso terapêutico , Tocoferóis/uso terapêuticoRESUMO
OBJECTIVE: Temporal bone osteoradionecrosis (TBORN) is a rare, chronic complication of head and neck radiation. Initial treatment consists of conservative management, with surgical resection of necrotic bone indicated for cases of severe, symptomatic, or progressive disease. Pentoxifylline-tocopherol (PENTO) has demonstrated usefulness for osteoradionecrosis of other head and neck subsites. Herein, we report five TBORN cases utilizing this protocol. STUDY DESIGN: Retrospective case series. SETTING: Tertiary referral center. PATIENTS: This case series describes five TBORN cases in which the PENTO protocol was used in conjunction with conservative management. All patients were women and average age was 61â±â8 years. INTERVENTION: All patients received a daily dose of 800âmg of pentoxifylline and 1âg of tocopherol. Four of the five patients received systemic and/or ototopical antibiotics as an antimicrobial regimen before and/or during the PENTO protocol. MAIN OUTCOME MEASURES: Details regarding the total duration of protocol, improvement in symptoms, exposed bone and radiographic changes, and duration until first improvement of exposed bone were collected retrospectively. RESULTS: The average duration of PENTO protocol was 302â±â166 days. Four of the five (80%) patients demonstrated a decrease in exposed ear canal bone. Three of the five (60%) patients had stable or improvement in otologic symptoms of TBORN. One patient progressed to diffuse TBORN. The average duration until first improvement in exposed bone was 193â±â137 days. CONCLUSIONS: The PENTO protocol may be a useful adjunct to conservative measures in the management of localized TBORN. We recommend trialing the protocol for at least 12 months.