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2.
Drugs R D ; 20(1): 39-45, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32078147

RESUMO

BACKGROUND AND OBJECTIVE: Clodronate is a nitrogen-free bisphosphonate that is widely and effectively used in the treatment of many osteo-metabolic disorders. The objective of our study was to evaluate the effectiveness of clodronate in reducing pain and bone marrow edema in knee osteoarthritis. METHODS: In total, 74 patients were included in the study. Group 1 received intramuscular clodronate 200 mg daily for 15 days and then once weekly for the next 11.5 months; group 2 received intramuscular clodronate 200 mg daily for 15 days and then once weekly for the next 2.5 months. Visual analog scale (VAS) scores were recorded at baseline (T0) and after 30 days (T1), 3 months (T2), 6 months (T3), 9 months (T4), and 12 months (end of study; T5). We also evaluated functional status and use of paracetamol (T0, T1, T2, T3, T4, and T5) and changes in Whole Organ Magnetic Resonance Imaging Score (WORMS; T0, T2, and T5). RESULTS: Both groups had a statistically significant reduction in VAS score until 3 months. Group 1 then experienced further VAS reductions, whereas VAS scores for group 2 progressively increased. Pain, stiffness, and physical function also showed the same trend, as did bone marrow edema extension, which was evaluated with WORMS. CONCLUSION: Our study indicates that intramuscular administration of a therapeutic dose of clodronate followed by a maintenance dose is effective in the management of symptomatic knee osteoarthritis, improving functional outcomes and reducing pain and bone marrow edema. Prolonged treatment increases the long-term efficacy of clodronate compared with the shorter schedule.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Ácido Clodrônico/uso terapêutico , Osteoartrite do Joelho/tratamento farmacológico , Dor/tratamento farmacológico , Idoso , Conservadores da Densidade Óssea/administração & dosagem , Ácido Clodrônico/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Osteoartrite do Joelho/diagnóstico por imagem , Dor/diagnóstico por imagem , Medição da Dor , Fatores de Tempo , Resultado do Tratamento
3.
Yakugaku Zasshi ; 140(1): 63-79, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-31902887

RESUMO

Since the first report in 2003, bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been increasing, without effective clinical strategies. Osteoporosis is common in elderly women, and bisphosphonates (BPs) are typical and widely used anti-osteoporotic or anti-bone-resorptive drugs. BRONJ is now a serious concern in dentistry. As BPs are pyrophosphate analogues and bind strongly to bone hydroxyapatite, and the P-C-P structure of BPs is non-hydrolysable, they accumulate in bones upon repeated administration. During bone-resorption, BPs are taken into osteoclasts and exhibit cytotoxicity, producing a long-lasting anti-bone-resorptive effect. BPs are divided into nitrogen-containing BPs (N-BPs) and non-nitrogen-containing BPs (non-N-BPs). N-BPs have far stronger anti-bone-resorptive effects than non-N-BPs, and BRONJ is caused by N-BPs. Our murine experiments have revealed the following. N-BPs, but not non-N-BPs, exhibit direct and potent inflammatory/necrotic effects on soft-tissues. These effects are augmented by lipopolysaccharide (the inflammatory component of bacterial cell-walls) and the accumulation of N-BPs in jawbones is augmented by inflammation. N-BPs are taken into soft-tissue cells via phosphate-transporters, while the non-N-BPs etidronate and clodronate inhibit this transportation. Etidronate, but not clodronate, has the effect of expelling N-BPs that have accumulated in bones. Moreover, etidronate and clodronate each have an analgesic effect, while clodronate has an anti-inflammatory effect via inhibition of phosphate-transporters. These findings suggest that BRONJ may be induced by phosphate-transporter-mediated and infection-promoted mechanisms, and that etidronate and clodronate may be useful for preventing and treating BRONJ. Our clinical trials support etidronate being useful for treating BRONJ, although additional clinical trials of etidronate and clodronate are needed.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/etiologia , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/prevenção & controle , Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/efeitos adversos , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/tratamento farmacológico , Conservadores da Densidade Óssea/metabolismo , Conservadores da Densidade Óssea/uso terapêutico , Ensaios Clínicos como Assunto , Ácido Clodrônico/química , Ácido Clodrônico/metabolismo , Ácido Clodrônico/farmacologia , Ácido Clodrônico/uso terapêutico , Difosfonatos/química , Difosfonatos/metabolismo , Difosfonatos/uso terapêutico , Ácido Etidrônico/química , Ácido Etidrônico/metabolismo , Ácido Etidrônico/farmacologia , Ácido Etidrônico/uso terapêutico , Humanos , Inflamação , Arcada Osseodentária/metabolismo , Camundongos , Nitrogênio , Proteínas de Transporte de Fosfato/antagonistas & inibidores , Ratos
4.
Int J Radiat Oncol Biol Phys ; 107(1): 154-162, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31987975

RESUMO

PURPOSE: Radiation-induced (RI) plexopathy is a rare peripheral nerve injury after radiation therapy for cancer. No treatment has been shown to slow its progression. A pentoxifylline-vitamin E combination significantly reduced RI fibrosis, and its association with clodronate (PENTOCLO) allowed healing of osteoradionecrosis and reduction of neurologic symptoms in phase 2 trials. METHODS AND MATERIALS: A placebo-controlled, double-blind trial conducted in adults with RI limb plexopathy without cancer recurrence, randomized in 2 arms to PENTOCLO (pentoxifylline 800 mg, tocopherol 1000 mg, clodronate 1600 mg 5 days per week) or triple placebo. The primary outcome measure after 18 months of treatment was the neurologic Subjective Objective Management Analytic (SOMA) score evaluating pain, paresthesia, and motor disability. RESULTS: Between 2011 and 2015, 59 patients were included: 1 false inclusion (neoplastic plexopathy), 29 treated with placebo (group P), and 29 treated with the active drugs (group A); 46 patients presented an upper-limb and 12 a lower-limb plexopathy. The mean delay after irradiation was 26 ± 8 years, for patients with neurologic symptoms for 5 ± 5 years. The median global SOMA scores in the P and A groups, respectively, were 9 (range, 6-11) versus 9 (range, 8-11) at M0 and 9 (range, 5-12) versus 10 (range, 6-11) at M18 without any significant difference. Analysis of the secondary outcomes showed that SOMA score subdomains for pain and paresthesia were more affected in group A (not significant). The frequency of adverse events was similar in the 2 groups (81% of patients): slight expected vascular-gastrointestinal symptoms in A, but a large excess of RI complications (arterial stenosis). CONCLUSIONS: This first randomized drug trial in RI plexopathy failed to show a beneficial effect. More studies are needed in patients with less advanced disease and fewer confounding comorbidities and with a more sensitive measure to detect a therapeutic effect.


Assuntos
Ácido Clodrônico/uso terapêutico , Pentoxifilina/uso terapêutico , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Traumatismos dos Nervos Periféricos/etiologia , Lesões por Radiação/tratamento farmacológico , Tocoferóis/uso terapêutico , Idoso , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Resultado do Tratamento
5.
Digestion ; 101(1): 6-11, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31770754

RESUMO

BACKGROUND: Transient receptor potential vanilloid 4 (TRPV4) is activated by stretch (mechanical), warm temperature, some epoxyeicosatrienoic acids, and lipopolysaccharide. TRPV4 is expressed throughout the gastrointestinal epithelia and its activation induces adenosine triphosphate (ATP) exocytosis that is involved in visceral hypersensitivity. As an ATP transporter, vesicular nucleotide transporter (VNUT) mediates ATP storage in secretory vesicles and ATP release via exocytosis upon stimulation. SUMMARY: TRPV4 is sensitized under inflammatory conditions by a variety of factors, including proteases and serotonin, whereas methylation-dependent silencing of TRPV4 expression is associated with various pathophysiological conditions. Gastrointestinal epithelia also release ATP in response to hypo-osmolality or acid through molecular mechanisms that remain unclear. These synergistically released ATP could be involved in visceral hypersensitivity. Low concentrations of the first generation bisphosphate, clodronate, were recently reported to inhibit VNUT activity and thus clodronate may be a safe and potent therapeutic option to treat visceral pain. Key Messages: This review focuses on: (1) ATP and TRPV4 activities in gastrointestinal epithelia; (2) factors that could modulate TRPV4 activity in gastrointestinal epithelia; and (3) the inhibition of VNUT as a potential novel therapeutic strategy for functional gastrointestinal disorders.


Assuntos
Trifosfato de Adenosina/metabolismo , Trato Gastrointestinal/metabolismo , Proteínas de Transporte de Nucleotídeos/metabolismo , Canais de Cátion TRPV/metabolismo , Dor Abdominal/tratamento farmacológico , Dor Abdominal/etiologia , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Doença Crônica , Ácido Clodrônico/farmacologia , Ácido Clodrônico/uso terapêutico , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/fisiopatologia , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Camundongos , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/metabolismo , Membrana Mucosa/fisiopatologia , Proteínas de Transporte de Nucleotídeos/antagonistas & inibidores , Pressorreceptores/efeitos dos fármacos , Pressorreceptores/metabolismo , Pressorreceptores/fisiopatologia , Receptores Purinérgicos P2/efeitos dos fármacos , Receptores Purinérgicos P2/metabolismo
6.
Int J Colorectal Dis ; 35(2): 333-336, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31820076

RESUMO

PURPOSE: Calcinosis cutis is an anecdotal local injury seen long after irradiation in cancer survivors. Our purpose was to shed light on this little studied and potentially serious ulceration. CASES: We report two cases of severe perineal-sacral infection with hard lesions, one decade after anorectal cancer irradiation. CT-scans showed extensive calcification and soft tissue inflammation, but previous radiation therapy was overlooked and the diagnosis was not made for several months after various tests, including biopsy. The two patients had different comorbidities and were managed by multidisciplinary collaboration between specialists. Surgery of the sacral ulcer was limited by the accessibility of non-irradiated tissues. In the absence of current guidelines, after radiopathological expertise, we used a "draining" procedure followed by antifibrotic pentoxifylline-tocopherol-clodronate treatment. CONCLUSION: Long after pelvic radiotherapy, symptomatic subcutaneous macrocalcification is suggestive of radiation-induced calcinosis. Prolonged antibiotic therapy followed by PENTOCLO treatment led to clinical improvement.


Assuntos
Neoplasias do Ânus/radioterapia , Calcinose/etiologia , Lesões por Radiação/etiologia , Neoplasias Retais/radioterapia , Dermatopatias Bacterianas/etiologia , Antibacterianos/uso terapêutico , Neoplasias do Ânus/patologia , Calcinose/diagnóstico , Calcinose/microbiologia , Calcinose/terapia , Ácido Clodrônico/uso terapêutico , Drenagem , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pentoxifilina/uso terapêutico , Lesões por Radiação/diagnóstico , Lesões por Radiação/microbiologia , Lesões por Radiação/terapia , Radioterapia/efeitos adversos , Neoplasias Retais/patologia , Dermatopatias Bacterianas/diagnóstico , Dermatopatias Bacterianas/microbiologia , Dermatopatias Bacterianas/terapia , Fatores de Tempo , Tocoferóis/uso terapêutico , Resultado do Tratamento
7.
J Biol Regul Homeost Agents ; 33(5): 1315-1320, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31591875

RESUMO

Osteoarthritis (OA) is a chronic rheumatic disease characterized by joint cartilage wear and loss of normal function. Clodronate (CLO) is a first-generation non-nitrogen-containing bisphosphonate that exerts anti-inflammatory and analgesic and modulatory effects on bone and cartilage metabolism. To date, few clinical studies have evaluated the effect of CLO in OA. Current evidence suggests that CLO may represent a new type of analgesic drug as it reduces pain in bone diseases characterized by edema such as Complex Regional Pain Syndrone type-1 and vertebral fractures. Thanks to its anti-inflammatory and analgesic effects, CLO has been shown to afford benefit in knee OA, erosive OA of the hand, painful knee hip prosthesis and veterinary practice. Transforming growth factor ß1 has also been found to play an important role in the pathogenesis of OA. The present review article examines recent evidence on the potential use of CLO in the treatment of OA.


Assuntos
Ácido Clodrônico/uso terapêutico , Difosfonatos/uso terapêutico , Osteoartrite/tratamento farmacológico , Cartilagem Articular/patologia , Humanos
8.
Undersea Hyperb Med ; 46(4): 385-397, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31509895

RESUMO

Over the past four decades, hyperbaric oxygen (HBO2) therapy has played a prominent role in both the prevention and treatment of mandibular osteoradionecrosis (ORN). It has done so on the strength of laboratory observations and clinical reports, yet only limited efficacy data. This dual role has come under increasing scrutiny in the modern radiotherapy (RT) and surgical eras. The ability to spare healthy "non-target" tissue has markedly improved since the two-dimensional planning and delivery techniques in use when HBO2's prophylactic value was first demonstrated. A recent study failed to identify this same benefit in patients who received high-precision imaging and conformal RT. HBO2 therapy is under challenge as preferred treatment for early stage ORN. A recently introduced "fibroatrophic" mechanism contrasts with the hypovascular-hypocellular-hypoxic injury pattern that formed the basis for HBO2's therapeutic use. This alternative pathophysiologic state appears to benefit from an oral antioxidant medication regimen. The continuing necessity of HBO2 in support of mandibular reconstruction for advanced ORN is in question. Microsurgery-based vascularized bone flaps increasingly represent standard care, invariably in the absence of perioperative HBO2. Renewed interest in hyperbaric oxygen as a radiation sensitizer offers some promise. Hypoxia remains a critical radio-resistant factor in many solid tumors. Malignant gliomas have been a primary focus of several small studies, with resulting improvements in local control and median survival. Hyperbaric radiation sensitization has recently addressed oropharyngeal cancer. Preliminary data indicates that addition of HBO2 to chemo-radiation standard of care is technically feasible, well tolerated and safe. A Phase II efficacy trial will investigate the potential for of HBO2 to improve progression-free and relapse-free survival in newly diagnosed locally advanced head and neck cancers. What follows is a review and summary of relevant peer-reviewed literature.


Assuntos
Neoplasias de Cabeça e Pescoço/radioterapia , Oxigenação Hiperbárica , Mandíbula/efeitos da radiação , Osteorradionecrose/terapia , Tolerância a Radiação , Hipóxia Celular/efeitos da radiação , Ensaios Clínicos Fase II como Assunto , Ácido Clodrônico/uso terapêutico , Combinação de Medicamentos , Humanos , Mandíbula/cirurgia , Osteorradionecrose/patologia , Osteorradionecrose/prevenção & controle , Pentoxifilina/uso terapêutico , Radioterapia Conformacional/efeitos adversos , Procedimentos Cirúrgicos Reconstrutivos , Tocoferóis/uso terapêutico , Extração Dentária
9.
Res Vet Sci ; 125: 298-304, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31351199

RESUMO

Navicular syndrome, a common cause of equine forelimb lameness, is associated with pathological changes in the navicular bone. Consequently, administration of bisphosphonates (BPs) has been advocated in order to modify the rate of bone turnover. The present study aimed to assess the clinical efficacy of intramuscularly administered clodronic acid for the treatment of 11 horses with clinical and radiographic findings compatible with navicular syndrome. Magnetic resonance imaging was performed in 5 of the 11 horses. The animals were treated with an intramuscular dose of clodronic acid of 765 mg/horse, administered over three separate injection sites. Before and at 7, 30 and 90 days after treatment, horses were subjected to lameness and accelerometric evaluations. A clinical improvement was observed in 6 of the 11 horses. These 6 horses showed a mean reduction of two degrees in lameness score. Accelerometry in these horses revealed increased velocity, stride length, stride regularity and dorsoventral displacement of the gravity of centre together with a reduction in stride frequency, suggesting a gait improvement. This study demonstrates that intramuscular clodronic acid can be useful for lameness reduction in some horses with navicular syndrome.


Assuntos
Ácido Clodrônico/uso terapêutico , Doenças dos Cavalos/tratamento farmacológico , Coxeadura Animal/tratamento farmacológico , Animais , Membro Anterior/patologia , Marcha , Doenças dos Cavalos/patologia , Cavalos , Coxeadura Animal/patologia , Imagem por Ressonância Magnética/veterinária , Ossos do Tarso/patologia
10.
BMJ Case Rep ; 12(7)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31296627

RESUMO

We present a case of transient osteoporosis of the hip in a 38-year-old recreational trail runner. Shortly after a trail running competition, he developed acute hip pain, functional disability and an antalgic gait. Diagnosis was made with MRI showing bone marrow oedema, plain radiographs demonstrating osseous demineralisation and bone scintigraphy showing uniform radioactive uptake. Treatment included off-loading of the anatomical site for 6 months until symptom resolution, analgaesia, Vitamin D, bisphosphonates and pulsed electromagnetic field therapy. He recovered fully and returned to running activities 8 months after initial presentation. Transient osteoporosis of the hip is rare but benign, self-limiting condition; however, awareness and exact diagnosis are important as runners often present with hip pain and other more serious pathologies such as avascular necrosis or stress fractures need to be excluded.


Assuntos
Dor Aguda/complicações , Artralgia/complicações , Osteoporose/complicações , Osteoporose/diagnóstico por imagem , Corrida , Dor Aguda/terapia , Adulto , Analgesia , Artralgia/terapia , Conservadores da Densidade Óssea/uso terapêutico , Doenças da Medula Óssea/complicações , Doenças da Medula Óssea/diagnóstico por imagem , Doenças da Medula Óssea/terapia , Ácido Clodrônico/uso terapêutico , Edema/complicações , Edema/diagnóstico por imagem , Edema/terapia , Radiação Eletromagnética , Articulação do Quadril/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Osteoporose/terapia , Radiografia , Cintilografia , Vitamina D/uso terapêutico
11.
Clin Exp Metastasis ; 36(3): 199-209, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30963355

RESUMO

Adjuvant therapy with bisphosphonates in prostate cancer is effective in improving bone mineral density and thus reducing fractures and skeletal-related events. We analyzed the effect of bisphosphonates on overall survival (OS) in subgroups of patients with prostate cancer. A systematic literature search was conducted of the PubMed database and the bibliographies of related studies. The long-term OS rates were extracted from every eligible trial. The hazard ratio (HR) was pooled with the fixed effects model, and preplanned subgroup analyses were performed. The search yielded 112 articles, of which 10 articles with 13 patient subgroups met the eligibility criteria. The meta-analysis of all 13 subgroups showed that adjuvant bisphosphonate therapy did not significantly improve OS versus the control group (HR = 0.961, 95% CI 0.899-1.026, p = 0.233) with low heterogeneity (I2 = 13.47%, degrees of freedom = 12, p = 0.336). There was no significant improvement in OS with the addition of bisphosphonates in the major subgroup analyses (metastatic (M1) versus non-metastatic, clodronate versus zoledronic acid, castration-sensitive prostate cancer (CSPC) versus castration-refractory prostate cancer). When the subgroups were further divided, adjuvant bisphosphonate therapy significantly improved OS in patients with CSPC + M1 (HR = 0.874, 95% CI 0.778-0.982, p = 0.023; I2 = 0.0%, degrees of freedom = 3, p = 0.579). Our study demonstrated that bisphosphonates do not significantly improve long-term OS in patients with prostate cancer. However, adjuvant bisphosphonate therapy significantly improves OS in the subgroup of patients with CSPC + M1.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Ácido Clodrônico/uso terapêutico , Fraturas Ósseas/prevenção & controle , Neoplasias da Próstata/patologia , Ácido Zoledrônico/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Quimioterapia Adjuvante/métodos , Humanos , Masculino , Neoplasias da Próstata/mortalidade , Taxa de Sobrevida
12.
BMJ Open ; 9(3): e026662, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30837258

RESUMO

INTRODUCTION: Osteoradionecrosis (ORN) of the mandible is a painful and debilitating condition occurring after radiotherapy to the head and neck to treat cancer. For decades, hyperbaric oxygen (HBO) has formed the mainstay of the early management of ORN. Literature about the efficacy of HBO is contentious. Recently, Oral and Maxillofacial surgical units in France and UK have trialled a combination of medications to treat ORN, also known as PENTOCLO (PENtoxifylline+TOcopherol±CLOdronate). This regime has shown promising results to date however randomised controlled trials in the area comparing HBO against PENTOCLO are lacking and there are no current trials registered in Europe, UK, Australia and the USA. The purpose of this pilot study is to generate a hypothesis that can be tested in large multi-centre controlled trials. METHODS AND ANALYSIS: For this pilot study we will recruit 16 patients who will be randomly allocated to one of either HBO or PENTOCLO. After a 4 week period of uniform 'pre-treatment' medication patients will be commenced on their allocated treatment. Standard follow-up examination, imaging and photographs will be taken and de-identified and then presented to two Oral and Maxillofacial surgeons for allocation of a Notani & Lyons classification score. Data for each patient will be tracked over the 18 months of treatment and follow-up. The results will then be analysed using descriptive statistics and all patients included in an intention to treat analysis. ETHICS AND DISSEMINATION: Ethical approval for this study has been granted by the South Metropolitan Health Service HREC (PRN RGS0000001193). Data generated by conducting this study will be uploaded to an open access repository in a de-identified form. Results from this study will be disseminated at national and international conferences as well as peer reviewed medical publications. TRIAL REGISTRATION NUMBER: ACTRN12618001099213; Pre-results.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Ácido Clodrônico/uso terapêutico , Oxigenação Hiperbárica , Doenças Mandibulares/terapia , Osteorradionecrose/terapia , Pentoxifilina/uso terapêutico , Tocoferóis/uso terapêutico , Adulto , Protocolos Clínicos , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos
13.
Equine Vet J ; 51(3): 356-363, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30153345

RESUMO

BACKGROUND: Clodronate is prescribed to performance horses with lameness. Despite its clinical popularity, little research has been done to understand the effects of clodronate in the horse. OBJECTIVES: Our objective was to determine if a single treatment with clodronate at the clinically approved dose altered bone remodelling, bone cell recruitment or lameness in the horse. STUDY DESIGN: Twelve university-owned equestrian team competition horses with a history of forelimb lameness due to navicular syndrome were randomised to receive either 1.4 mg/kg clodronate (CLOD n = 6) or an equivalent volume of LRS (CONT; n = 6) in a blinded manner. METHODS: Blood was evaluated weekly for 8 weeks before and after drug administration (clodronate or placebo) for bone turnover markers CTX-I and osteocalcin. Lameness evaluations were performed to assess for change in lameness 1 week before and 1, 2, 3 and 8 weeks after drug administration. Coach questionnaires were performed to assess for change in ridden performance 1, 2, 3 and 8 weeks after drug administration. Bone cell recruitment was evaluated in vitro 2 weeks before and after drug administration. RESULTS: There were no differences in in vitro bone cell recruitment from whole bone marrow or in bone turnover markers CTX-I or osteocalcin. A small but significant decrease in forelimb lameness was detected in CLOD treated horses 1 week after treatment (P = 0.005). There were no significant differences in hindlimb lameness. Coaches identified an improvement in performance significantly more often in CLOD vs. CONT (P = 0.01) at week 8. MAIN LIMITATIONS: Two CONT horses received intra-articular anti-inflammatory medication after treatment, which may have altered lameness results. CONCLUSIONS: A single dose of clodronate appears to reduce lameness without producing detectable effects on bone turnover markers. Due to the long half-life of a bisphosphonate drug, the effect of multiple doses on bone remodelling and lameness should be investigated. The Summary is available in Portuguese - see Supporting Information.


Assuntos
Ácido Clodrônico/uso terapêutico , Colágeno Tipo I/sangue , Doenças dos Cavalos/tratamento farmacológico , Coxeadura Animal/tratamento farmacológico , Osteocalcina/sangue , Animais , Biomarcadores/sangue , Colágeno Tipo I/metabolismo , Feminino , Membro Anterior , Doenças dos Cavalos/sangue , Cavalos , Masculino , Osteocalcina/metabolismo
14.
BMC Pediatr ; 18(1): 340, 2018 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-30376845

RESUMO

BACKGROUND: Neonatal severe primary hyperparathyroidism (NSHPT) is a rare autosomal recessive disorder of calcium homeostasis, characterized by striking hyperparathyroidism, marked hypercalcemia and hyperparathyroid bone disease. We report the case of a newborn with a novel homozygous mutation of the CaSR, treated by successful subtotal parathyroidectomy, who had an acute presentation of the disease, i.e. out-of hospital cardiorespiratory arrest. . CASE PRESENTATION: A 8-day-old female newborn was admitted to the NICU of University of Bari "Aldo Moro" (Italy) after a cardiorespiratory arrest occurred at home. Severe hypercalcemia was found and different drug therapies were employed (Furosemide, Cinacalcet and bisphosphonate), as well as hyperhydration, until subtotal parathyroidectomy, was performed at day 32. Our patient's mutation was never described before so that a strict and individualized long-term follow-up was started. CONCLUSIONS: This case of NSHPT suggests that a near-miss event, labelled as a possible case of SIDS, could also be due to severe hypercalcemia and evidentiates the difficulties of the neonatal management of NSHPT. Furthermore, the identification of the specific CaSR mutation provides the substrate for prenatal diagnosis.


Assuntos
Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/genética , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/genética , Mutação , Receptores de Detecção de Cálcio/genética , Conservadores da Densidade Óssea/uso terapêutico , Calcimiméticos/uso terapêutico , Cinacalcete/uso terapêutico , Ácido Clodrônico/uso terapêutico , Difosfonatos/uso terapêutico , Feminino , Hidratação , Furosemida/uso terapêutico , Genes Recessivos , Homozigoto , Humanos , Hiperparatireoidismo Primário/terapia , Recém-Nascido , Doenças do Recém-Nascido/terapia , Paratireoidectomia
15.
Sci Rep ; 8(1): 15855, 2018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30367142

RESUMO

Chronic myelomonocytic leukemia (CMML) is an entity of myelodysplastic syndrome/myeloproliferative neoplasm. Although CMML can be cured with allogeneic stem cell transplantation, its prognosis is generally very poor due to the limited efficacy of chemotherapy and to the patient's age, which is usually not eligible for transplantation. Comprehensive analysis of CMML pathophysiology and the development of therapeutic agents have been limited partly due to the lack of cell lines in CMML and the limited developments of mouse models. After successfully establishing patient's derived disease-specific induced pluripotent stem cells (iPSCs) derived from a patient with CMML, we utilized these CMML-iPSCs to achieve hematopoietic re-differentiation in vitro, created a humanized CMML mouse model via teratomas, and developed a drug-testing system. The clinical characteristics of CMML were recapitulated following hematopoietic re-differentiation in vitro and a humanized CMML mouse model in vivo. The drug-testing system using CMML-iPSCs identified a MEK inhibitor, a Ras inhibitor, and liposomal clodronate as potential drugs for treating CMML. Clodronate is a drug commonly used as a bisphosphonate for osteoporosis. In this study, the liposomalization of clodronate enhanced its effectiveness in these assays, suggesting that this variation of clodronate may be adopted as a repositioned drug for CMML therapy.


Assuntos
Ácido Clodrônico/uso terapêutico , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Lipossomos/química , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Animais , Diferenciação Celular , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/transplante , Leucemia Mielomonocítica Crônica/patologia , Leucemia Mielomonocítica Crônica/terapia , Masculino , Camundongos , Neurofibromina 1/metabolismo , Fosforilação , Fator de Transcrição STAT5/metabolismo , Teratoma/metabolismo , Teratoma/patologia , Transplante Heterólogo
16.
Artigo em Alemão | MEDLINE | ID: mdl-30340242

RESUMO

Systemic administration of tiludronate or clodronate decreases lameness in some horses suffering from navicular syndrome within 2-6 months of treatment. In horses that fail to respond to the first treatment, a follow-up treatment may still improve the lameness. Horses with a lameness duration of less than 6 months have better odds of experiencing improvement in lameness. Bisphosphonate (BP) treatment can result in renal damage, and it is recommended to assess renal function prior to and after treatment. Horses with pre-existing renal compromise should not be treated with BP, as this may promote deterioration of their renal status. Furthermore, BP should not be administered concurrently with non-steroidal antiinflammatory medications or other nephrotoxic drugs. One of the most common side effects of BP treatment in the horse is development of colic signs, which usually resolves with hand walking. In cases where medical treatment is warranted, N-butylscopolamine, xylazine, detomidine or butorphanol should be administered alone or in combination. The treatment with non-steroidal antiinflammatory medications is not recommended. In horses with muscle fasciculations, plasma electrolyte concentrations should be determined. The route of administration for BP should follow manufacturer recommendations, as local applications such as intraarticular injections or administration via regional limb perfusion may not be safe and are thus currently not recommended.


Assuntos
Difosfonatos/uso terapêutico , Doenças dos Cavalos/tratamento farmacológico , Osteoartrite/veterinária , Animais , Ácido Clodrônico/uso terapêutico , Doenças dos Cavalos/fisiopatologia , Cavalos , Osteoartrite/tratamento farmacológico , Osteoartrite/fisiopatologia , Ossos do Tarso/fisiopatologia
17.
Int J Mol Sci ; 19(7)2018 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-29973487

RESUMO

Macrophages, cells belonging to the innate immune system, present a high plasticity grade, being able to change their phenotype in response to environmental stimuli. They play central roles during development, homeostatic tissue processes, tissue repair, and immunity. Furthermore, it is recognized that macrophages are involved in chronic inflammation and that they play central roles in inflammatory diseases and cancer. Due to their large involvement in the pathogenesis of several types of human diseases, macrophages are considered to be relevant therapeutic targets. Nanotechnology-based systems have attracted a lot of attention in this field, gaining a pivotal role as useful moieties to target macrophages in diseased tissues. Among the different approaches that can target macrophages, the most radical is represented by their depletion, commonly obtained by means of clodronate-containing liposomal formulations and/or depleting antibodies. These strategies have produced encouraging results in experimental mouse models. In this review, we focus on macrophage targeting, based on the results so far obtained in preclinical models of inflammatory diseases and cancer. Pros and cons of these therapeutic interventions will be highlighted.


Assuntos
Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Ácido Clodrônico/uso terapêutico , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Humanos , Inflamação/imunologia , Lipossomos , Macrófagos/imunologia , Camundongos , Nanotecnologia , Neoplasias/imunologia
18.
Br J Haematol ; 182(6): 816-829, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29984830

RESUMO

In the Medical Research Council (MRC) Myeloma IX trial (ISRCTN684564111) patients were randomised to sodium clodronate or zoledronic acid and induction treatment: cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) or cyclophosphamide, thalidomide and dexamethasone (CTD) followed by autologous stem cell transplant (ASCT) in the intensive pathway; attenuated CTD or melphalan and prednisolone (MP) in the non-intensive pathway. Subsequent randomisation allocated patients to either thalidomide or observation. The European Organisation for Research and Treatment of Cancer (EORTC) quality of life (QoL) questionnaires, QLQ-C30 and QLQ-MY24, were administered at baseline, 3, 6 and 12 months and annually thereafter, enabling the effect of sequential treatment on patient-reported health-related QoL (HR-QoL) to be investigated. The protocol specified four subscales of interest: Pain, Fatigue, Global Health Status/Quality of Life and Physical Functioning at 3, 6 and 12 months that were compared using linear models. The intensive pathway showed significant differences in favour of CTD for Fatigue at 3 months and Physical Functioning at 12 months. The non-intensive pathway and maintenance phase reported significant differences at 3 months; Pain (improved with attenuated CTD) and Global Health status/Quality of Life (improved with observation). The improved outcomes in MRC Myeloma IX were accompanied by some beneficial and few detrimental effects on HR-QoL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Qualidade de Vida , Adolescente , Adulto , Idoso , Ácido Clodrônico/uso terapêutico , Quimioterapia de Consolidação/métodos , Feminino , Humanos , Estudos Longitudinais , Quimioterapia de Manutenção/métodos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/psicologia , Indução de Remissão/métodos , Autorrelato , Inquéritos e Questionários , Talidomida/uso terapêutico , Transplante Autólogo , Adulto Jovem , Ácido Zoledrônico/uso terapêutico
19.
Minerva Med ; 109(4): 300-325, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29947493

RESUMO

INTRODUCTION: Clodronic acid is a non-nitrogen-containing bisphosphonate largely used from some decades in the prevention and treatment of postmenopausal and secondary osteoporosis. In addition to antiresorptive activity, clodronate has shown anti-inflammatory and analgesic properties, and modulatory effects on bone and cartilage metabolism. EVIDENCE ACQUISITION: A literature review has been conducted to characterize the mechanism of action of clodronate and to retrieve available evidence about the use of clodronate in primary and secondary osteoporosis, and its potential role in other musculoskeletal conditions and orthopedic surgery. EVIDENCE SYNTHESIS: The efficacy and safety of the available clodronate formulations (oral, intravenous and intramuscular) in the prevention and treatment of postmenopausal and secondary osteoporosis, including corticosteroid-induced osteoporosis and bone mass loss secondary to endocrine, gastrointestinal and neoplastic diseases, have been demonstrated in a variety of clinical trials. The analgesic, anti-inflammatory, bone- and chondro-modulating properties of clodronate have allowed to expand its use in other musculoskeletal conditions to those currently approved. Clodronate has proven to be beneficial in the treatment of osteoarthritis of the knee and of the hand, in the management of complex regional pain syndrome, and in the peri- and postoperative phase in subjects undergoing arthroplasty. CONCLUSIONS: The analysis of the available literature has shown that clodronate has relevant musculoskeletal effects beyond the antiresorptive activity. Further research is needed to better position clodronate therapy in the management of these conditions and to define the optimal formulation and dose regimen in any of the tested new indications.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Ácido Clodrônico/uso terapêutico , Doenças Musculoesqueléticas/tratamento farmacológico , Conservadores da Densidade Óssea/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Ácido Clodrônico/farmacologia , Humanos , Neoplasias Musculares/tratamento farmacológico , Procedimentos Ortopédicos , Osteoartrite/tratamento farmacológico , Osteoporose/tratamento farmacológico , Osteoporose/etiologia
20.
Cell Tissue Res ; 374(1): 25-38, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29767277

RESUMO

The oxygen-induced retinopathy (OIR) animal model established in C57 mice and SD rats has been widely used in retinal neovascular disease studies, while Balb/c mice have not been used because Balb/c OIR mice lack neovascular tufts. One study found a substantial difference in the density of retinal microglia between C57 and Balb/c mice; however, no direct evidence could clarify whether the density of retinal microglia in Balb/c mice led to this difference. In our study, intraperitoneal injection of minocycline was used to inhibit the activation of microglia and intravitreal injection of clodronate liposomes was used to decrease the density of microglia in Balb/c OIR model mice. We found that with the decline in microglia induced by the two drugs, the avascular area in treated Balb/c OIR mice was higher than that in untreated Balb/c OIR mice; moreover, a small area of neovascular tufts appeared at P17. After checking the expression of Iba1, a microglial marker and GFAP, an astrocyte and Müller cell marker, we found that minocycline and clodronate could inhibit the activation of microglia or decrease the density of microglia, while they had no significant effect on astrocytes and Müller cells. Therefore, these data suggest that the density of microglia in the retina may determine the result of vasculopathy in OIR mice to some extent. In future studies, predicting the development of retinal neovascular diseases by detecting the density of microglia in living animals or human beings with newly developed instruments and methods may be useful.


Assuntos
Microglia/patologia , Neovascularização Retiniana/patologia , Retinopatia da Prematuridade/patologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Contagem de Células , Ácido Clodrônico/farmacologia , Ácido Clodrônico/uso terapêutico , Células Ependimogliais/efeitos dos fármacos , Células Ependimogliais/patologia , Gliose/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Minociclina/farmacologia , Minociclina/uso terapêutico , Neovascularização Fisiológica/efeitos dos fármacos , Oxigênio , Neovascularização Retiniana/tratamento farmacológico , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/crescimento & desenvolvimento , Vasos Retinianos/patologia , Retinopatia da Prematuridade/tratamento farmacológico
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