RESUMO
INTRODUCTION AND PURPOSE: The need for aggressive efforts to help tobacco users quit remains a healthcare priority. Brief interventions delivered in the healthcare environment continue to be a valuable component of a comprehensive tobacco control policy. Unfortunately, such treatments are offered less often than desired, and quality is variable. Previous research has demonstrated the value of training experiences in increasing treatment availability, quality, as well as improving clinical outcomes. Less is known about how specific clinical activities and other features are impacted as a function of training. These issues were explored within the context of a standardised 5A's (ASK, ADVISE, ASSESS, ASSIST, ARRANGE) brief intervention training program. METHODS: A variety of healthcare providers participated in this study. Survey methodology was employed to collect Practice Behaviour, Self-Efficacy and Attitude ratings at pretraining, post training and 6-month follow-up. Linear mixed effects models were used to evaluate primary outcomes, and linear regression to explore the relationships among clinical variables. RESULTS: Pretraining data suggested overall modest levels of tobacco treatment activity, with limited direct intervention (ASSIST) or follow-up (ARRANGE) efforts. The training experience was shown to have a substantial and sustained impact on 5A's Practice Behaviour ratings, and other clinical indicators (all Pre vs. Post and Pre vs. Follow-up comparisons p < 0.001). Self-Efficacy at post training predicted practice behaviours at follow-up (for ADVISE, ASSESS, ASSIST and ARRANGE: all p's < 0.05). CONCLUSIONS: The value of a structured training experience was confirmed, and findings served to clarify the specific nature of training program impact.
Assuntos
Pessoal de Saúde/psicologia , Nicotiana/efeitos adversos , Abandono do Hábito de Fumar/psicologia , Fatores de Tempo , Atitude do Pessoal de Saúde , Comportamento , Atenção à Saúde/métodos , Humanos , Autoeficácia , Abandono do Hábito de Fumar/métodos , Inquéritos e QuestionáriosAssuntos
Amiloidose/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Doença de Crohn/complicações , Nefropatias/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Amiloidose/etiologia , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Doença de Crohn/induzido quimicamente , Doença de Crohn/tratamento farmacológico , Quimioterapia Combinada , Humanos , Infliximab , Nefropatias/etiologia , MasculinoRESUMO
BACKGROUND: The incidence of patients starting renal replacement therapy (RRT) for established renal failure (ERF) in Scotland has fallen from 2005 to 2011 due to a reduction in older patients starting RRT; there are significant differences between NHS Health board areas. AIM: To understand the apparent inequality in provision of RRT between NHS board areas in Scotland. DESIGN: Retrospective population analysis of Scottish renal registry (SRR) data, population statistics and quality outcomes framework summary statistics. RESULTS: The incidence of patients starting RRT for ERF in Scotland fell from 123 per million population (pmp) in 2005 to 96 pmp in 2011. The incidence of ≥75 year olds fell from 406 to 274 pmp. There are significant differences between NHS board areas when standardized for age and social deprivation. There is no relationship between the population prevalence of CKD as reported by QOF and the incidence of RRT for ERF. Those areas with high incidence rates of ≥75 year olds have higher 90-day [Spearman's rank correlation: coefficient = 0.662; P = 0.03] and 1-year [Spearman's rank correlation: coefficient = 0.776; P = 0.003] mortality rates. CONCLUSION: The significant variation in provision of RRT for ERF between Scottish NHS Board areas is not explained by age or social deprivation. There is evidence of change in practice towards RRT for patients aged ≥75 years but variation between NHS Board areas. This disparity must be further investigated to ensure equity of access to RRT for those who will benefit from it, and to non-dialytic care for those who would not.
Assuntos
Atenção à Saúde/estatística & dados numéricos , Disparidades em Assistência à Saúde/estatística & dados numéricos , Falência Renal Crônica/terapia , Terapia de Substituição Renal/estatística & dados numéricos , Adulto , Distribuição por Idade , Idoso , Atenção à Saúde/organização & administração , Feminino , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Pesquisa sobre Serviços de Saúde/métodos , Humanos , Falência Renal Crônica/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Sistema de Registros , Terapia de Substituição Renal/tendências , Estudos Retrospectivos , Escócia/epidemiologia , Fatores Socioeconômicos , Medicina Estatal/estatística & dados numéricos , Análise de Sobrevida , Adulto JovemAssuntos
Autoria , Pesquisa em Odontologia , Publicações Periódicas como Assunto , Humanos , Reino UnidoRESUMO
OBJECTIVES: This study investigated blood contamination of artificially and clinically contaminated Siqveland matrix bands and retainers. A modified version of the recognised Kastle-Meyer test for blood was used to compare the efficacy of enzymatic agents, a washer-disinfector and an instrument washer for pre-sterilisation cleaning of Siqveland matrix bands and retainers. METHODS: Assembled Siqveland matrix bands were contaminated either artificially with horse blood or clinically during dental treatment. Contaminated assembled matrix bands and retainers were subjected to immersion in an enzymatic agent, automated processing in a washer-disinfector or instrument washer, or a combination of pre-soaking and automatic cleaning. Residual blood contamination from each band and retainer was measured and compared to the volume of blood recovered from an unprocessed control group of contaminated assembled matrix bands or retainers. RESULTS: Residual blood was recovered from every clinically contaminated assembled Siqveland matrix band and retainer. The volume of blood recovered from assembled Siqveland matrix bands ranged from 0.13-7.1 microl and from retainers, following removal of the matrix band, from 0.001-1.523 microl. The most effective method of pre-sterilisation cleaning for artificially contaminated assembled matrix bands was processing in the washer-disinfector. Conversely, the most effective method for cleaning clinically contaminated assembled matrix bands and retainers was pre-soaking in an enzymatic agent followed by a heavy-duty cycle in an instrument washer. CONCLUSIONS: It is not possible to clean assembled Siqveland matrix bands using any method currently available to dental practitioners. Matrix bands should be discarded after use on one patient. Once the band is removed, all detectable blood can be removed from the retainer by pre-soaking in an enzymatic detergent followed by processing in an instrument washer.
Assuntos
Descontaminação/métodos , Desinfetantes de Equipamento Odontológico , Contaminação de Equipamentos , Controle de Infecções Dentárias/métodos , Braquetes Ortodônticos , Contenções Ortodônticas , Animais , Sangue , Detergentes , Desinfecção/instrumentação , Desinfecção/métodos , Enzimas , Contaminação de Equipamentos/prevenção & controle , CavalosRESUMO
Cisplatin is a widely used chemotherapeutic agent whose dose-limiting side effects include ototoxicity and nephrotoxicity. Recent evidence indicates that cisplatin induces the expression of a novel protein, kidney injury molecule-1, in the renal proximal tubular epithelium to aid in regeneration. In this study, we determined whether kidney injury molecule-1 is expressed in the cochlea and is induced by cisplatin. Using reverse transcriptase polymerase chain reaction techniques, we have now identified kidney injury molecule-1 in the rat cochlea and in three different mouse transformed hair cell lines. Administration of cisplatin to rats produced hearing loss and induced kidney injury molecule-1 mRNA in the rat cochlea. Pretreatment of rats with lipoic acid, a scavenger of reactive oxygen species, significantly reduced cisplatin-induced hearing loss and kidney injury molecule-1 expression. Cisplatin also increased the expression of cochlear NOX3 mRNA, a member of the superoxide generating NADPH oxidase family of proteins recently identified in the cochlea, inhibition of which decreased kidney injury molecule-1 expression. Polymerase chain reaction performed on different regions of the cochlea indicated the presence of kidney injury molecule-1 mRNA in the lateral wall, organ of Corti and spiral ganglion. This distribution was confirmed by immunocytochemistry. Taken together, these data identify kidney injury molecule-1 as a novel cochlear injury molecule, whose expression is regulated by reactive oxygen species generated via the NADPH oxidase pathway.
Assuntos
Antineoplásicos/farmacologia , Moléculas de Adesão Celular/metabolismo , Cisplatino/farmacologia , Cóclea/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Animais , Antioxidantes/uso terapêutico , Northern Blotting/métodos , Moléculas de Adesão Celular/genética , Interações Medicamentosas , Perda Auditiva/tratamento farmacológico , Perda Auditiva/fisiopatologia , Imuno-Histoquímica/métodos , Masculino , Proteínas de Membrana/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Ácido Tióctico/uso terapêutico , Fatores de TempoRESUMO
OBJECTIVES: This study investigated the bacterial and fungal contamination of used dental burs. A novel assay system for comparison of efficacy of pre-sterilisation cleaning techniques for dental burs was used to evaluate manual scrubbing, enzymic agents and washer-disinfectors. METHODS: Thirty dental burs contaminated during cavity preparation were analysed for micro-biological total viable counts and species of bacteria and fungi present. To simulate clinically contaminated burs, a culture of Streptococcus sanguis NCTC 7863 was used to inoculate unused dental burs, alone and combined with blood, saliva or a mixture of blood and saliva. Contaminated burs were subjected to six pre-sterilisation cleaning techniques and the log reduction in contamination achieved by each method was assessed. RESULTS: The microbial count from used dental burs ranged from 0 to 6.92 x 10(4) CFU ml(-1). Many potentially pathogenic species were identified. The decontamination assay demonstrated that autoclaving alone was not sufficient to sterilise dental burs. Manual scrubbing in air was less efficacious than manual scrubbing under water (p<0.001). The most effective method of pre-sterilisation cleaning for dental burs was a washer-disinfector. CONCLUSIONS: Enzymic agents are suitable for soaking contaminated dental burs immediately after use. Washer-disinfectors are recommended as the method of choice for pre-sterilisation cleaning of contaminated dental burs.
Assuntos
Preparo da Cavidade Dentária/instrumentação , Contaminação de Equipamentos/prevenção & controle , Esterilização/métodos , Ar , Sangue , Contagem de Colônia Microbiana , Desinfetantes de Equipamento Odontológico/uso terapêutico , Detergentes/uso terapêutico , Desinfecção/métodos , Terapia Enzimática , Humanos , Saliva , Staphylococcus/classificação , Streptococcus/classificação , Streptococcus sanguis/isolamento & purificação , Água , Leveduras/classificaçãoRESUMO
Calciphylaxis, now better known as Calcific uraemic arteriolopathy (CUA), is an uncommon condition characterised by small vessel calcification and occlusion with resultant painful violaceous skin lesions that typically ulcerate to form non-healing gangrenous ulcers. The syndrome is usually found in patients with renal failure. In this report we describe a 61 year old lady who developed lower limb ulceration secondary to calciphylaxis and discuss the current treatment options for this serious condition.
Assuntos
Calcinose/complicações , Gangrena/complicações , Falência Renal Crônica/complicações , Úlcera Cutânea/patologia , Calcinose/fisiopatologia , Evolução Fatal , Feminino , Gangrena/patologia , Humanos , Falência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/patologia , Pessoa de Meia-IdadeRESUMO
Carboplatin is currently being used as an anticancer drug against human cancers. However, high dose of carboplatin chemotherapy resulted in hearing loss in cancer patients. We have shown that carboplatin-induced hearing loss was related to dose-dependent oxidative injury to the cochlea in rat model. However, the time response of ototoxic dose of carboplatin on hearing loss and oxidative injury to cochlea has not been explored. The aim of the study was to evaluate the time response of carboplatin-induced hearing loss and oxidative injury to the cochlea of the rat. Male Wistar rats were divided into two groups of 30 animals each and treated as follows: (1) control (normal saline, i.p.) and (2) carboplatin (256 mg/kg, a single i.p. bolus injection). Auditory brain-evoked responses (ABRs) were recorded before and 1-5 days after treatments. The animals (n = 6) from each group were sacrificed on day 1, 2, 3, 4, and 5 and cochleae were isolated and analyzed. Carboplatin significantly elevated the hearing thresholds to clicks and to 2, 4, 8, 16, and 32 kHz tone burst stimuli only 3-5 days post-treatment. Carboplatin significantly increased nitric oxide (NO), malondialdehyde (MDA) levels and manganese superoxide dismutase (Mn-SOD) activity in the cochlea 4-5 and 3-5 days post-treatment, respectively, indicating enhanced influx of free radicals and oxidative injury to the cochlea. Carboplatin significantly depressed the reduced to oxidized glutathione (GSH/GSSG) ratio, antioxidant enzyme activities such as copper/zinc-superoxide dismutase (CuZn-SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) as well as enzyme protein expressions in the cochlea 3-5 days after treatment. The data suggest that carboplatin-induced hearing loss involves oxidative injury to the cochlea of the rat in a time-dependent manner.
Assuntos
Antineoplásicos/toxicidade , Carboplatina/toxicidade , Cóclea/efeitos dos fármacos , Perda Auditiva Neurossensorial/induzido quimicamente , Animais , Antineoplásicos/administração & dosagem , Carboplatina/administração & dosagem , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Potenciais Evocados Auditivos do Tronco Encefálico , Glutationa/análise , Dissulfeto de Glutationa/análise , Humanos , Masculino , Malondialdeído/análise , Modelos Animais , Óxido Nítrico/análise , Ratos , Ratos Wistar , Superóxido Dismutase/análiseAssuntos
Ciclosporina/uso terapêutico , Transplante de Rim/fisiologia , Tacrolimo/uso terapêutico , Adolescente , Adulto , Idoso , Azatioprina/uso terapêutico , Creatinina/sangue , Diabetes Mellitus/epidemiologia , Quimioterapia Combinada , Feminino , Seguimentos , Rejeição de Enxerto/epidemiologia , Humanos , Incidência , Transplante de Rim/imunologia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapêutico , Complicações Pós-Operatórias/classificação , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Fatores de Tempo , Transplante HomólogoRESUMO
OBJECTIVES: To determine the diagnostic accuracy of the sperm penetration assay (SPA) and standard semen parameters for subsequent fertilization in in vitro fertilization-embryo transfer (IVF-ET). DESIGN: Prospective study. SETTING: Andrology Laboratory, and university research laboratory. PATIENTS: Two hundred sixteen couples undergoing male-partner screening before IVF-ET (265 cycles). INTERVENTION(S): Male-partner screening (semen analyses [SA] and SPA), standard IVF-ET procedures, follow-up of fertilization in IVF-ET. MAIN OUTCOME MEASURE(S): Diagnostic accuracy of SA and SPA for prediction of fertilization in IVF-ET. RESULT(S): The SPA predicted IVF fertilization with high negative (84%) and positive (98%) predictive rates, and correct prediction in 88% of cycles. In contrast, sperm concentration, motility, morphology, and complete SA showed poor diagnostic accuracy, with correct prediction of IVF fertilization in 64%, 65%, 45%, and 68% of cycles, respectively. CONCLUSION(S): Very low sperm concentration and/or motility were good predictors of poor IVF fertilization, however, low to normal semen parameters were not predictive of successful IVF fertilization. The SPA is a useful screening tool that predicts IVF fertilization with high diagnostic accuracy. The SPA may be useful to discriminate between those couples with a high probability of normal fertilization in IVF and those with a low probability of normal fertilization that may benefit from assisted fertilization by intracytoplasmic sperm injection (ICSI).
Assuntos
Transferência Embrionária , Injeções de Esperma Intracitoplásmicas/métodos , Interações Espermatozoide-Óvulo/fisiologia , Animais , Cricetinae , Reações Falso-Negativas , Reações Falso-Positivas , Feminino , Fertilização/fisiologia , Humanos , Masculino , Mesocricetus , Valor Preditivo dos Testes , Gravidez , Estudos Prospectivos , Análise de Regressão , Sensibilidade e Especificidade , Contagem de Espermatozoides , Motilidade dos EspermatozoidesRESUMO
Carboplatin is currently being used in the clinic against a variety of human cancers. However, high dose carboplatin chemotherapy resulted in ototoxicity in cancer patients. This is the first study to show carboplatin-induced oxidative stress response in the cochlea of rat. Male Wistar rats were divided into two groups of six animals each and treated as follows: (1) control (normal saline, i.p.) and (2) carboplatin (256 mg/kg, i.p.). Animals in both groups were sedated with ketamine/xylazine and auditory brainstem-evoked responses were recorded before and 4 days after treatments. The animals were sacrificed on the fourth day and cochleae were harvested and analyzed. A significant elevation of the hearing threshold shifts was noted at clicks, 8, 16, and 32 kHz tone burst stimuli following carboplatin administration. Carboplatin significantly increased nitric oxide and malondialdehyde levels, xanthine oxidase and manganese-superoxide dismutase activities in the cochlea indicating enhanced flux of free radicals. Cochlear glutathione levels, antioxidant enzyme activities such as copper zinc-superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione S-transferase and enzyme protein levels were significantly depleted 4 days after carboplatin treatment. The data suggest that carboplatin induced free radical generation and antioxidant depletion, and caused oxidative injury in the cochleae of rats.
Assuntos
Antineoplásicos/toxicidade , Carboplatina/toxicidade , Cóclea/efeitos dos fármacos , Cóclea/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Antineoplásicos/administração & dosagem , Antioxidantes/metabolismo , Limiar Auditivo/efeitos dos fármacos , Carboplatina/administração & dosagem , Catalase/antagonistas & inibidores , Cóclea/lesões , Cóclea/fisiopatologia , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Radicais Livres/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/antagonistas & inibidores , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismoRESUMO
The experimental class III antiarrhythmic drug, L-768673, prolongs the refractory period of cardiac myocytes by selectively blocking the slow-activating delayed rectifying potassium (I(Ks)) channel. The I(Ks) channel has also been identified in vestibular dark cells and in the marginal cells of the stria vascularis. In the stria vascularis, the I(Ks) channel plays an important role in cochlear homeostasis. Genetic null deletion of the I(Ks) channel in mice and man results in profound hearing loss and cochlear pathology. Therefore, the purpose of the present study was to investigate the effect of L-768673 on the auditory function and cochlear morphology in rats using auditory brainstem-evoked response and light microscopy. Auditory testing was performed one week prior to dosing, following 14 days of administration and 28 days after the completion of dosing. L-768673 (50 or 250 mg/kg/day for 14 days), had no significant effects on auditory function or cochlear morphology. The results of this study suggest that high doses of L-768673 are not toxic to the inner ear of adult rats treated for 14 consecutive days, and that the ototoxic potential of orally administered L-768673 and similar I(Ks)-selective compounds is unlikely at doses within the therapeutic range.
Assuntos
Acetamidas/farmacologia , Antiarrítmicos/farmacologia , Benzodiazepinonas/farmacologia , Cóclea/efeitos dos fármacos , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Transtornos da Audição/induzido quimicamente , Bloqueadores dos Canais de Potássio , Animais , Audiometria de Resposta Evocada , Limiar Auditivo , Cóclea/patologia , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Carboplatin, a platinum-containing anticancer drug, is currently being used against a variety of cancers. However, a single high dose of carboplatin is ototoxic in cancer patients. This is the first study to show carboplatin-induced hearing loss in a rat model. Male Wistar rats were divided into five groups and treated as follows: (1) control (saline, intraperitoneally (i.p.)); (2) carboplatin (64 mg/kg, i.p.); (3) carboplatin (128 mg/kg i.p.); (4) carboplatin (192 mg/kg, i.p.) and (5) carboplatin (256 mg/kg, i.p.). Animals in all groups were sedated with ketamine/xylazine and auditory brain-evoked responses (ABRs) were recorded before and 4 days after treatments. The animals were sacrificed on the fourth day and cochleae were harvested and analyzed. Carboplatin dose-dependently decreased body weight. However, at higher doses of carboplatin (192 and 256 mg/kg), there was a significant elevation of hearing threshold shifts at clicks, 4, 8, 16 and 32 kHz tone burst stimuli. The higher doses of carboplatin (192 and 256 mg/kg) significantly increased cochlear lipid peroxidation (132 and 146% of control) and depleted cochlear glutathione levels (66 and 63% of control), respectively. The antioxidant enzyme activities such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase (GST) depressed significantly at higher doses of carboplatin. The data suggest that higher doses of carboplatin (above 128 mg/kg) induce hearing loss as evidenced by significant changes in ABRs, lipid peroxidation and antioxidants in the cochlea of rats.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/toxicidade , Antioxidantes/metabolismo , Carboplatina/administração & dosagem , Carboplatina/toxicidade , Surdez/induzido quimicamente , Animais , Limiar Auditivo/efeitos dos fármacos , Catalase/antagonistas & inibidores , Cóclea/efeitos dos fármacos , Cóclea/metabolismo , Cóclea/fisiopatologia , Surdez/metabolismo , Surdez/fisiopatologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/toxicidade , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Peroxidase/antagonistas & inibidores , Glutationa Redutase/antagonistas & inibidores , Glutationa Transferase/antagonistas & inibidores , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/antagonistas & inibidoresRESUMO
The purpose of this study was to investigate how the hair cells and stria vascularis are affected at the onset of cisplatin ototoxicity. The effects on the endocochlear potential (EP) and the cochlear microphonics (CM) were observed simultaneously in two groups of adult chinchillas receiving as follows: (1) 5 microl of cisplatin (1 mg/ml) in normal saline, and (2) 5 microl of normal saline on the round window. The EP and the CM were recorded for 12-14 h after cisplatin application, and morphological changes were assessed using scanning electron microscopy. Both the EP and the CM amplitude demonstrated a profound reduction, and a very strong correlation was observed between these two values during this time period. Although the reduction of the EP and the CM was observed by 12-14 h, only very slight degeneration of outer hair cells was seen at that time. These data suggested that a reduction of the EP which was caused by the alteration of the stria vascularis might be primarily responsible for very early changes in cochlear function after topical cisplatin application, while later changes were the direct result of hair cell damage.
Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Potenciais Microfônicos da Cóclea/efeitos dos fármacos , Animais , Chinchila , Cóclea/efeitos dos fármacos , Cóclea/fisiologia , Cóclea/ultraestrutura , Eletrofisiologia , Masculino , Microscopia Eletrônica de Varredura , Fatores de TempoRESUMO
HYPOTHESIS: The goals of this investigation were to compare the efficacy of three protective agents against cisplatin-induced elevation of auditory brainstem response (ABR) thresholds and to examine whether these protective agents prevent cisplatin-induced alterations of the antioxidant defense system in the cochlea of the rat. BACKGROUND: Cisplatin is an ototoxic antitumor agent. Previous animal studies have shown that cisplatin administration causes an elevation of ABR thresholds. These auditory changes are accompanied by alterations in the concentration of glutathione and the antioxidant enzymes in the cochlea. The authors' previous work has indicated that the protective agent diethyldithiocarbamate (DDTC) prevents decrease in glutathione (GSH), alteration of antioxidant enzyme activity, and disruption of cochlear function with cisplatin administration. METHODS: Wistar rats were sedated and underwent pretreatment ABR testing using clicks and tone burst stimuli at 8, 16, and 32 kHz. Control rats received saline by intraperitoneal (i.p.) injection. Positive control rats were administered cisplatin 16 mg/kg i.p. Three groups of rats received protective agents in combination with cisplatin. The DDTC-protected rats were given 600 mg/kg of DDTC subcutaneously 1 hour after cisplatin. Animals protected by 4-methylthiobenzoic acid (MTBA) were given 250 mg/kg of this agent i.p. 30 minutes before cisplatin. Animals protected with ebselen were given 16 mg/kg i.p. one hour before cisplatin. The ABR thresholds were recorded 72 hours after cisplatin administration in all groups. Cochleas were removed, and extracts of the tissues were analyzed for GSH, activities of antioxidant enzymes (superoxide dismutase [SOD], catalase, glutathione peroxidase, and glutathione reductase) and malondialdehyde (MDA) (as an index of lipid peroxidation). RESULTS: Cisplatin-treated rats had significant ABR threshold shifts, ranging from 27 to 40 dB. Rats administered each of the three protective agents in combination with cisplatin had ABR threshold shifts of <10 dB. The cochleae of rats administered cisplatin alone had nearly a 50% depletion of glutathione and about a 50% reduction in the activities of SOD, glutathione peroxidase, and glutathione reductase, while catalase activity was reduced to 70% of control values. These changes were accompanied by a reciprocal elevation of MDA of 165%. These changes, namely, the depletion of GSH and antioxidant enzyme activity and the elevation of MDA in the cochlea, were largely attenuated by the administration of the protective agents tested. CONCLUSION: These findings suggest that cisplatin ototoxicity is related to lipid peroxidation and that the use of protective agents prevents hearing loss and lipid peroxidation by sparing the antioxidant system in the cochlea. These results suggest the possibility that the clinical use of protective agents could effectively reduce or prevent damage to the inner ear of patients receiving cisplatin chemotherapy, provided that the antitumor effect is not altered.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Antineoplásicos/efeitos adversos , Antioxidantes/uso terapêutico , Azóis/uso terapêutico , Benzoatos/uso terapêutico , Cisplatino/efeitos adversos , Doenças Cocleares/induzido quimicamente , Doenças Cocleares/prevenção & controle , Ditiocarb/uso terapêutico , Transtornos da Audição/induzido quimicamente , Transtornos da Audição/prevenção & controle , Compostos Organosselênicos/uso terapêutico , Animais , Doenças Cocleares/diagnóstico , Doenças Cocleares/enzimologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Glutationa/deficiência , Glutationa/efeitos dos fármacos , Transtornos da Audição/diagnóstico , Transtornos da Audição/enzimologia , Isoindóis , Peroxidação de Lipídeos/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
This study was designed to investigate the role of graded doses of lipoic acid pretreatment against cisplatin-induced nephrotoxicity. Male Wistar rats were divided into six groups and treated as follows: 1) vehicle (saline) control; 2) cisplatin (16 mg/kg, intraperitoneally); 3) lipoic acid (100 mg/kg, intraperitoneally); 4) cisplatin plus lipoic acid (25 mg/kg); 5) cisplatin plus lipoic acid (50 mg/kg) and 6) cisplatin plus lipoic acid (100 mg/kg). Rats were sacrificed three days after treatment, and plasma as well as kidneys were isolated and analyzed. Plasma creatinine increased (677% of control) following cisplatin administration alone which was decreased by lipoic acid in a dose-dependent manner. Cisplatin-treated rats showed a depletion of renal glutathione (GSH), increased oxidized GSH and decreased GSH/GSH oxidized ratio (62%, 166% and 62% of control), respectively which were restored with lipoic acid pretreatment. Renal superoxide dismutase, catalase, glutathione peroxidase (GSH peroxidase) and glutathione reductase activities decreased (62%, 75%, 62% and 80% of control), respectively, and malondialdehyde content increased (204% of control) following cisplatin administration, which were restored with increasing doses of lipoic acid. The renal platinum concentration increased following cisplatin administration, which was possibly decreased by chelation with lipoic acid. The data suggest that the graded doses of lipoic acid effectively prevented a decrease in renal antioxidant defense system and prevented an increase in lipid peroxidation, platinum content and plasma creatinine concentrations in a dose-dependent manner.