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1.
Bioorg Med Chem Lett ; 20(22): 6370-4, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-20934331

RESUMO

A backup molecule to compound 2 was sought by targeting the most likely metabolically vulnerable site in this molecule. Compound 18 was subsequently identified as a potent P2X(7) antagonist with very low in vivo clearance and high oral bioavailability in all species examined. Some evidence to support the role of P2X(7) in the etiology of pain is also presented.


Assuntos
Imidazolinas/farmacologia , Antagonistas Purinérgicos/farmacologia , Receptores Purinérgicos P2X7/efeitos dos fármacos , Administração Oral , Animais , Disponibilidade Biológica , Meia-Vida , Haplorrinos , Imidazolinas/administração & dosagem , Imidazolinas/química , Imidazolinas/farmacocinética , Antagonistas Purinérgicos/administração & dosagem , Antagonistas Purinérgicos/química , Antagonistas Purinérgicos/farmacocinética , Ratos
2.
Bioorg Med Chem Lett ; 20(17): 5080-4, 2010 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-20673717

RESUMO

A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X(7) receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X(7) antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies.


Assuntos
Amidas/farmacologia , Antagonistas do Receptor Purinérgico P2/farmacologia , Ácido Pirrolidonocarboxílico/química , Receptores Purinérgicos P2X7/efeitos dos fármacos , Amidas/química , Descoberta de Drogas , Modelos Moleculares , Antagonistas do Receptor Purinérgico P2/química , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 20(15): 4653-6, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20579878

RESUMO

Structure-activity relationships (SAR) of analogues of lead compound 1 were investigated and compound 16 was selected for further study in animal models of pain. Compound 16 was shown to be a potent antihyperalgesic agent in both the rat acute complete Freund's adjuvant (CFA) model of inflammatory pain [Iadarola, M. J.; Douglass, J.; Civelli, O.; Naranjo, J. R. rain Res.1988, 455, 205] and the knee joint model of chronic inflammatory pain [Wilson, A. W.; Medhurst, S. J.; Dixon, C. I.; Bontoft, N. C.; Winyard, L. A.; Brackenborough, K. T.; De Alba, J.; Clarke, C. J.; Gunthorpe, M. J.; Hicks, G. A.; Bountra, C.; McQueen, D. S.; Chessell, I. P. Eur. J. Pain2006, 10, 537].


Assuntos
Acetamidas/química , Antagonistas do Receptor Purinérgico P2X , Pirazóis/química , Acetamidas/síntese química , Acetamidas/uso terapêutico , Administração Oral , Animais , Modelos Animais de Doenças , Humanos , Dor/tratamento farmacológico , Pirazóis/síntese química , Ratos , Receptores Purinérgicos P2X7/metabolismo , Relação Estrutura-Atividade
4.
Bioorg Med Chem Lett ; 18(20): 5609-13, 2008 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-18809327

RESUMO

6-Phenylnicotinamide (2) was previously identified as a potent TRPV1 antagonist with activity in an in vivo model of inflammatory pain. Optimization of this lead through modification of both the biaryl and heteroaryl components has resulted in the discovery of 6-(4-fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide (32; SB-782443) which possesses an excellent overall profile and has been progressed into pre-clinical development.


Assuntos
Benzotiazóis/síntese química , Química Farmacêutica/métodos , Niacinamida/análogos & derivados , Niacinamida/síntese química , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/química , Administração Oral , Animais , Benzotiazóis/farmacologia , Capsaicina/química , Linhagem Celular , Desenho de Fármacos , Cobaias , Humanos , Inflamação , Concentração Inibidora 50 , Modelos Químicos , Niacinamida/química , Niacinamida/farmacologia , Ratos
5.
J Pain ; 9(7): 580-7, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18420461

RESUMO

UNLABELLED: The role of specific nicotinic receptor (nAChR) subtypes in antinociception has not been fully elucidated because of the lack, until recently, of selective tool compounds. (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiopene-2-carboxamide) (compound B) is reported to be an agonist selective for the alpha(7)nAChR and in the present study was found to be efficacious in inflammatory pain models in 2 species. Compound B reversed complete Freund adjuvant-induced reductions in paw withdrawal thresholds in rat and mouse in a dose-related manner, producing maximum reversals of 65% +/- 4% at 10 mg/kg and 87% +/- 15% at 20 mg/kg. When rats and mice were predosed with the centrally penetrant, broad-spectrum nicotinic receptor antagonist mecamylamine, the efficacy of the agonist was significantly inhibited, producing reversals of only 11% +/- 5% at 10 mg/kg and 5% +/- 13% at 20 mg/kg, confirming activity via nicotinic receptors. Rats were also predosed systemically with the selective low-brain penetrant alpha(7)-antagonist methyllycaconitine, which had no effect on agonist activity (90% +/- 18% at 10 mg/kg), suggesting a central involvement. This hypothesis was further established with methyllycaconitine completely inhibited the agonist effect when dosed intrathecally (1% +/- 7%). PERSPECTIVE: These studies provide good rationale for the utility of selective, central nervous system penetrant agonists at the alpha(7)-nicotinic receptor for the treatment of inflammatory pain.


Assuntos
Benzofuranos/farmacologia , Hiperalgesia/tratamento farmacológico , Quinuclidinas/farmacologia , Receptores Nicotínicos/fisiologia , Aconitina/administração & dosagem , Aconitina/análogos & derivados , Aconitina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Benzofuranos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Adjuvante de Freund , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/fisiopatologia , Injeções Intraperitoneais , Masculino , Mecamilamina/administração & dosagem , Mecamilamina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Antagonistas Nicotínicos/administração & dosagem , Antagonistas Nicotínicos/farmacologia , Dor/tratamento farmacológico , Dor/metabolismo , Dor/fisiopatologia , Medição da Dor/métodos , Quinuclidinas/administração & dosagem , Ratos , Suporte de Carga/fisiologia , Receptor Nicotínico de Acetilcolina alfa7
6.
Pain ; 138(1): 61-69, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18164820

RESUMO

Several studies have implicated a potential role for histamine H(3) receptors in pain processing, although the data are somewhat conflicting. In the present study we investigated the effects of the novel potent and highly selective H(3) receptor antagonists GSK189254 (6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride) and GSK334429 (1-(1-methylethyl)-4-([1-[6-(trifluoromethyl)-3-pyridinyl]-4-piperidinyl]carbonyl)hexahydro-1H-1,4-diazepine) in two rat models of neuropathic pain, namely the chronic constriction injury (CCI) model and the varicella-zoster virus (VZV) model. Both GSK189254 (0.3, 3 and/or 10mg/kg p.o.) and GSK334429 (1, 3 and 10mg/kg p.o.) significantly reversed the CCI-induced decrease in paw withdrawal threshold (PWT) measured using an analgesymeter and/or von Frey hairs. In addition, GSK189254 (3mg/kg p.o.) and GSK334429 (10mg/kg p.o.) both reversed the VZV-induced decrease in PWT using von Frey hairs. We also investigated the potential site of action of this analgesic effect of H(3) antagonists using autoradiography. Specific binding to H(3) receptors was demonstrated with [(3)H]-GSK189254 in the dorsal horn of the human and rat spinal cord, and in human dorsal root ganglion (DRG), consistent with the potential involvement of H(3) receptors in pain processing. In conclusion, we have shown for the first time that chronic oral administration of selective H(3) antagonists is effective in reversing neuropathic hypersensitivity in disease-related models, and that specific H(3) receptor binding sites are present in the human DRG and dorsal horn of the spinal cord. These data suggest that H(3) antagonists such as GSK189254 and GSK334429 may be useful for the treatment of neuropathic pain.


Assuntos
Azepinas/administração & dosagem , Benzazepinas/administração & dosagem , Modelos Animais de Doenças , Antagonistas dos Receptores Histamínicos H3/administração & dosagem , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Niacinamida/análogos & derivados , Medição da Dor/efeitos dos fármacos , Piridinas/administração & dosagem , Receptores Histamínicos H3/metabolismo , Medula Espinal/metabolismo , Animais , Herpes Zoster/complicações , Herpes Zoster/tratamento farmacológico , Herpes Zoster/metabolismo , Humanos , Masculino , Neuralgia/etiologia , Niacinamida/administração & dosagem , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/metabolismo , Ratos , Distribuição Tecidual
7.
Biochem Pharmacol ; 73(8): 1182-94, 2007 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-17276409

RESUMO

GSK207040 (5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-2-pyrazinecarboxamide) and GSK334429 (1-(1-methylethyl)-4-({1-[6-(trifluoromethyl)-3-pyridinyl]-4-piperidinyl}carbonyl)hexahydro-1H-1,4-diazepine) are novel and selective non-imidazole histamine H(3) receptor antagonists from distinct chemical series with high affinity for human (pK(i)=9.67+/-0.06 and 9.49+/-0.09, respectively) and rat (pK(i)=9.08+/-0.16 and 9.12+/-0.14, respectively) H(3) receptors expressed in cerebral cortex. At the human recombinant H(3) receptor, GSK207040 and GSK334429 were potent functional antagonists (pA(2)=9.26+/-0.04 and 8.84+/-0.04, respectively versus H(3) agonist-induced changes in cAMP) and exhibited inverse agonist properties (pIC(50)=9.20+/-0.36 and 8.59+/-0.04 versus basal GTPgammaS binding). Following oral administration, GSK207040 and GSK334429 potently inhibited cortical ex vivo [(3)H]-R-alpha-methylhistamine binding (ED(50)=0.03 and 0.35 mg/kg, respectively). Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50)=0.02 and 0.11 mg/kg p.o. for GSK207040 and GSK334429, respectively). In more pathophysiologically relevant pharmacodynamic models, GSK207040 (0.1, 0.3, 1 and 3mg/kg p.o.) and GSK334429 (0.3, 1 and 3mg/kg p.o.) significantly reversed amnesia induced by the cholinergic antagonist scopolamine in a passive avoidance paradigm. In addition, GSK207040 (0.1, 0.3 and 1mg/kg p.o.) and GSK334429 (3 and 10mg/kg p.o.) significantly reversed capsaicin-induced reductions in paw withdrawal threshold, suggesting for the first time that blockade of H(3) receptors may be able to reduce tactile allodynia. Novel H(3) receptor antagonists such as GSK207040 and GSK334429 may therefore have therapeutic potential not only in dementia but also in neuropathic pain.


Assuntos
Azepinas/uso terapêutico , Benzazepinas/uso terapêutico , Capsaicina , Antagonistas dos Receptores Histamínicos/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Neuralgia/tratamento farmacológico , Pirazinas/uso terapêutico , Piridinas/uso terapêutico , Receptores Histamínicos H3/metabolismo , Escopolamina , Analgésicos/farmacocinética , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Azepinas/administração & dosagem , Azepinas/farmacocinética , Benzazepinas/farmacocinética , Benzazepinas/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Ingestão de Líquidos/efeitos dos fármacos , Agonistas dos Receptores Histamínicos/farmacocinética , Agonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacocinética , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Masculino , Transtornos da Memória/induzido quimicamente , Neuralgia/induzido quimicamente , Pirazinas/farmacocinética , Pirazinas/farmacologia , Piridinas/administração & dosagem , Piridinas/farmacocinética , Ratos , Ratos Sprague-Dawley
8.
Bioorg Med Chem Lett ; 16(17): 4533-6, 2006 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-16806913

RESUMO

Starting from the high throughput screening hit (3), novel N-tetrahydroquinolinyl, N-quinolinyl and N-isoquinolinyl carboxamides have been identified as potent antagonists of the ion channel TRPV1. The N-quinolinylnicotinamide (46) showed excellent potency at human, guinea pig and rat TRPV1, a favourable in vitro DMPK profile and activity in an in vivo model of inflammatory pain.


Assuntos
Benzamidas/química , Benzamidas/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Benzamidas/síntese química , Capsaicina/farmacologia , Cobaias , Humanos , Isoquinolinas/síntese química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Estrutura Molecular , Quinolinas/síntese química , Ratos , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismo
9.
Eur J Pain ; 10(6): 537-49, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16199187

RESUMO

Clinically, inflammatory pain is far more persistent than that typically modelled pre-clinically, with the majority of animal models focussing on short-term effects of the inflammatory pain response. The large attrition rate of compounds in the clinic which show pre-clinical efficacy suggests the need for novel models of, or approaches to, chronic inflammatory pain if novel mechanisms are to make it to the market. A model in which a more chronic inflammatory hypersensitivity phenotype is profiled may allow for a more clinically predictive tool. The aims of these studies were to characterise and validate a chronic model of inflammatory pain. We have shown that injection of a large volume of adjuvant to the intra-articular space of the rat knee results in a prolonged inflammatory pain response, compared to the response in an acute adjuvant model. Additionally, this model also results in a hypersensitive state in the presence and absence of inflammation. A range of clinically effective analgesics demonstrate activity in this chronic model, including morphine (3mg/kg, t.i.d.), dexamethasone (1mg/kg, b.i.d.), ibuprofen (30mg/kg, t.i.d.), etoricoxib (5mg/kg, b.i.d.) and rofecoxib (0.3-10mg/kg, b.i.d.). A further aim was to exemplify the utility of this chronic model over the more acute intra-plantar adjuvant model using two novel therapeutic approaches; NR2B selective NMDA receptor antagonism and iNOS inhibition. Our data shows that different effects were observed with these therapies when comparing the acute model with the model of chronic inflammatory joint pain. These data suggest that the chronic model may be more relevant to identifying mechanisms for the treatment of chronic inflammatory pain states in the clinic.


Assuntos
Artrite/tratamento farmacológico , Artrite/patologia , Modelos Animais de Doenças , Dor/tratamento farmacológico , Dor/patologia , Animais , Artrite/induzido quimicamente , Doença Crônica , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Adjuvante de Freund , Lactonas/uso terapêutico , Masculino , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Dor/induzido quimicamente , Fenóis/uso terapêutico , Piperidinas/uso terapêutico , Ratos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Joelho de Quadrúpedes/fisiologia , Sulfetos/uso terapêutico , Sulfonas/uso terapêutico , Fatores de Tempo , Suporte de Carga
10.
Pain ; 118(3): 327-335, 2005 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-16289798

RESUMO

The aim of the present study was to investigate the effects of cannabinoid agonists on established inflammatory hyperalgesia. We have compared the effects of pre-administration versus post-administration of a potent non-selective cannabinoid agonist HU210 and a selective CB2 receptor agonist JWH-133 on hindpaw weight bearing and paw oedema in the carrageenan model of inflammatory hyperalgesia. For comparative purposes we also determined the effects of the mu-opioid receptor agonist morphine and the COX2 inhibitor rofecoxib in this model. At 3 h following intraplantar injection of carrageenan (2%, 100 microl) there was a significant (P < 0.001) reduction in weight bearing on the ipsilateral hindpaw, compared to vehicle treated rats and a concomitant increase in ipsilateral hindpaw volume (P < 0.001), compared to vehicle treated rats. Systemic administration of HU210 (10 microg/kg) and JWH-133 (10 mg/kg) at 3 h following injection of carrageenan, significantly attenuated decreases in ipsilateral hindpaw weight bearing (P < 0.05 for both) and paw volume (P < 0.001 for both). Pre-administration of HU210 and JWH-133 had similar effects on weight bearing in this model. Pre-administered HU210 also significantly decreased carrageenan-induced changes in paw volume (P < 0.001), this was not the case for JWH-133. Effects of post-administered HU210 and JWH-133 on ipsilateral hindpaw weight bearing and paw volume were comparable to the effect of systemic post-administration of morphine and rofecoxib (3 mg/kg for both). In summary, both HU210 and JWH-133 attenuated established inflammatory hypersensitivity and swelling, suggesting that cannabinoid-based drugs have clinical potential for the treatment of established inflammatory pain responses.


Assuntos
Canabinoides/administração & dosagem , Dronabinol/análogos & derivados , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Inflamação/tratamento farmacológico , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistas , Analgésicos/administração & dosagem , Animais , Carragenina , Dronabinol/administração & dosagem , Combinação de Medicamentos , Hiperalgesia/etiologia , Hiperalgesia/prevenção & controle , Inflamação/induzido quimicamente , Inflamação/complicações , Inflamação/fisiopatologia , Masculino , Ratos , Resultado do Tratamento , Suporte de Carga
11.
J Pharmacol Exp Ther ; 304(1): 56-62, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12490575

RESUMO

Vanilloid receptor type 1 (VR1) (TRPV1) is a ligand-gated ion channel expressed on sensory nerves that responds to noxious heat, protons, and chemical stimuli such as capsaicin. Herein, we have examined the activity of the VR1 antagonist capsazepine in models of inflammatory and neuropathic pain in the rat, mouse, and guinea pig. In naïve animals, subcutaneous administration of capsazepine (10-100 mg/kg s.c.) did not affect withdrawal thresholds to noxious thermal or mechanical stimuli. However, pretreatment with capsazepine prevented the development of mechanical hyperalgesia induced by intraplantar injection of capsaicin, with a similar potency in all three species. Capsazepine (up to 100 mg/kg s.c.) did not affect mechanical hyperalgesia in the Freund's complete adjuvant (FCA)-inflamed hind paw of the rat or mouse. Strikingly, capsazepine (3-30 mg/kg s.c.) produced up to 44% reversal of FCA-induced mechanical hyperalgesia in the guinea pig. Capsazepine also produced significant reversal of carageenan-induced thermal hyperalgesia in the guinea pig at 30 mg/kg s.c., but was ineffective in the rat. Similarly, in the partial sciatic nerve ligation model of neuropathic pain, capsazepine was surprisingly effective in the guinea pig, producing up to 80% reversal of mechanical hyperalgesia (1-30 mg/kg s.c.) but had no effect in the rat or mouse. These data show that VR1 antagonists have antihyperalgesic activity in animal models of chronic inflammatory and neuropathic pain, and illustrate species differences in the in vivo pharmacology of VR1 that correlate with differences in pharmacology previously seen in vitro.


Assuntos
Capsaicina/análogos & derivados , Capsaicina/farmacologia , Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Receptores de Droga/antagonistas & inibidores , Algoritmos , Animais , Anticonvulsivantes/farmacologia , Carbamazepina/farmacologia , Relação Dose-Resposta a Droga , Cobaias , Hiperalgesia/etiologia , Hiperalgesia/patologia , Inflamação/etiologia , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doenças do Sistema Nervoso Periférico/complicações , Doenças do Sistema Nervoso Periférico/patologia , Ratos , Ratos Wistar , Nervo Isquiático/patologia
12.
Pain ; 100(3): 219-229, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12467993

RESUMO

Inoculation of syngeneic MRMT-1 mammary tumour cells into one tibia of female rats produced tumour growth within the bone associated with a reduction in bone mineral density (BMD) and bone mineral content (BMC), severe radiological signs of bone destruction, together with the development of behavioural mechanical allodynia and hyperalgesia. Histological and radiological examination showed that chronic treatment with the bisphosphonate, zoledronic acid (30 microg/kg, s.c.), for 19 days significantly inhibited tumour proliferation and preserved the cortical and trabecular bone structure. In addition, BMD and BMC were preserved and a dramatic reduction of tartrate resistant acid phosphatase-positive polykaryocytes (osteoclasts) was observed. In behavioural tests, chronic treatment with zoledronic acid but not the significantly less effective bisphosphonate, pamidronate, or the selective COX-2 inhibitor, celebrex, attenuated mechanical allodynia and hyperalgesia in the affected hind paw. Zoledronic acid also attenuated mechanical hyperalgesia associated with chronic peripheral neuropathy and inflammation in the rat. In contrast, pamidronate or clodronate did not have any anti-hyperalgesic effect on mechanical hyperalgesia in the neuropathic and inflammatory pain models. We conclude that zoledronic acid, in addition to, or independent from, its anti-metastatic and bone preserving therapeutic effects, is an anti-nociceptive agent in a rat model of metastatic cancer pain. This unique property of zoledronic acid amongst the bisphosphonate class of compounds could make this drug a preferred choice for the treatment of painful bone metastases in the clinic.


Assuntos
Neoplasias Ósseas/complicações , Neoplasias Ósseas/tratamento farmacológico , Difosfonatos/administração & dosagem , Imidazóis/administração & dosagem , Dor/tratamento farmacológico , Dor/etiologia , Animais , Densidade Óssea/efeitos dos fármacos , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/patologia , Ácido Clodrônico/administração & dosagem , Feminino , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Hiperestesia/tratamento farmacológico , Hiperestesia/etiologia , Modelos Animais , Transplante de Neoplasias , Variações Dependentes do Observador , Medição da Dor/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Pamidronato , Radiografia , Ratos , Ratos Sprague-Dawley , Valores de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tíbia/efeitos dos fármacos , Tíbia/patologia , Tíbia/cirurgia , Tato/efeitos dos fármacos , Resultado do Tratamento , Ácido Zoledrônico
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