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1.
Br J Anaesth ; 121(1): 76-85, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29935598

RESUMO

BACKGROUND: Breast cancer accounts for 7% of female cancer deaths, usually attributable to metastasis. While surgery is a mainstay of treatment, perioperative interventions may influence risk of metastasis during breast tumour resection. Amide local anaesthetics influence cancer cell biology via numerous mechanisms in vitro, but in vivo data is lacking. We aimed to test the hypothesis that perioperative lidocaine reduces pulmonary metastasis after inhalation and i.v. anaesthesia in the 4T1 murine breast cancer model. METHODS: 4T1 Cancer cells were injected into the mammary fat-pad of immunocompetent BALB/c female mice. After 7 days, the resultant tumour was excised under either sevoflurane or ketamine/xylazine anaesthesia with or without perioperative i.v. lidocaine (1.5 mg kg-1 bolus followed by 25 min infusion 2 mg kg-1 h-1). Fourteen days post-surgery, posthumous lung and liver specimens were examined for metastasis. Pro-inflammatory and pro-metastatic cytokines were profiled in post-mortem serum from a small number of the mice. RESULTS: Primary tumour diameter was similar between groups. Lidocaine reduced lung metastatic colony count vs sevoflurane alone; median (inter-quartile range) 0 (0-2) compared with 22.5 (0-481), P=0.02 and reduced the proportion of animals with pulmonary metastasis (28.5% compared with 52.5%, P=0.04). In mice receiving ketamine-xylazine, lidocaine did not decrease the overall colony count: 60 (26-123) compared with 23.5 (0-225), P=0.43, but increased the proportion of animals with pulmonary metastasis (100% compared with 50%, P<0.01). Post-mortem serum analysis demonstrated reduced pro-inflammatory and angiogenic cytokine expression in animals without metastasis which received lidocaine with sevoflurane. CONCLUSIONS: In this 4T1 murine model of breast cancer, lidocaine decreased pulmonary metastasis when combined with sevoflurane anaesthesia, perhaps via anti-inflammatory and anti-angiogenic effects. It had no such effect in mice given ketamine anaesthesia.


Assuntos
Agonistas alfa-Adrenérgicos , Anestésicos Dissociativos , Anestésicos Inalatórios , Anestésicos Locais/farmacologia , Ketamina , Lidocaína/farmacologia , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/cirurgia , Metástase Neoplásica/prevenção & controle , Sevoflurano , Xilazina , Animais , Linhagem Celular Tumoral , Citocinas/sangue , Feminino , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Neovascularização Patológica/patologia , Neovascularização Patológica/prevenção & controle
2.
Br J Anaesth ; 113 Suppl 1: i14-21, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25001620

RESUMO

BACKGROUND: While volatile agents have been implicated in metastasis-enhancing effects on cancer cells, the effects of xenon are unknown. We investigated xenon- and sevoflurane-mediated effects on migration and expression of angiogenesis biomarkers in human breast adenocarcinoma cells. METHODS: MDA-MB-231 and MCF-7 cells were exposed to xenon 70% with O2 25%, CO2 5%; control gas containing O2 25%, CO2 5%, N2 70%; or sevoflurane 2.5 vol% administered in O2 60%, N2 37%, or control gas. Cell viability was determined by the MTT assay. Migration at 24 h was determined using the Oris™ Cell Migration Assay. Secretion of angiogenesis factors was measured using a membrane-based immunoassay array. RESULTS: Xenon reduced MDA-MB-231 migration to 59 (13%) after 1-h exposure (P=0.02), 64 (10%) after 3 h (P=0.01), and 71 (9%) after 5 h (P=0.04) compared with control gas, without affecting viability. Similarly, MCF-7 migration was significantly reduced at all timepoints [to 58 (12%) at 1 h, 65 (12%) at 3 h, and 65% (12%) at 5 h]. Sevoflurane did not affect migration when delivered in control gas. Glycine, an N-methyl-d-aspartate receptor co-agonist, antagonized the effects of xenon on migration. Expression of the pro-angiogenesis factor regulated on activation, normal T cell expressed and secreted (RANTES) was reduced in conditioned medium from xenon-exposed MDA-MB-231 cells compared with cells exposed to either control gas or sevoflurane [mean dot density 2.0 (0.2) compared with 3.0 (0.1) and 3.1 (0.3), respectively (P=0.02)]. CONCLUSION: Xenon, but not sevoflurane, inhibited migration in both oestrogen receptor positive and negative breast adenocarcinoma cells. Furthermore, xenon decreased release of the pro-angiogenic factor RANTES from MDA-MB-231 cells.


Assuntos
Adenocarcinoma/patologia , Anestésicos Inalatórios/farmacologia , Indutores da Angiogênese/farmacologia , Neoplasias da Mama/patologia , Xenônio/farmacologia , Adenocarcinoma/irrigação sanguínea , Adenocarcinoma/metabolismo , Indutores da Angiogênese/metabolismo , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/metabolismo , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Éteres Metílicos/farmacologia , Neovascularização Patológica/induzido quimicamente , Neovascularização Patológica/metabolismo , Sevoflurano , Células Tumorais Cultivadas
3.
J Appl Microbiol ; 117(3): 611-7, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24863842

RESUMO

Clotrimazole is a broad-spectrum antimycotic drug mainly used for the treatment of Candida albicans and other fungal infections. A synthetic, azole antimycotic, clotrimazole is widely used as a topical treatment for tinea pedis (athlete's foot), as well as vulvovaginal and oropharyngeal candidiasis. It displays fungistatic antimycotic activity by targeting the biosynthesis of ergosterol, thereby inhibiting fungal growth. As well as its antimycotic activity, clotrimazole has become a drug of interest against several other diseases such as sickle cell disease, malaria and some cancers. It has also been combined with other molecules, such as the metals, to produce clotrimazole complexes that show improved pharmacological efficacy. Moreover, several new, modified-release pharmaceutical formulations are also undergoing development. Clotrimazole is a very well-tolerated product with few side effects, although there is some drug resistance appearing among immunocompromised patients. Here, we review the pharmaceutical chemistry, application and pharmacology of clotrimazole and discuss future prospects for its further development as a chemotherapeutic agent.


Assuntos
Antifúngicos/farmacologia , Clotrimazol/farmacologia , Antifúngicos/efeitos adversos , Antifúngicos/química , Antifúngicos/uso terapêutico , Clotrimazol/efeitos adversos , Clotrimazol/química , Clotrimazol/uso terapêutico
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