PubMed Health⌕ Search

Biomedical subjects

Brian W Blakley

Publications and source records attributed to Brian W Blakley.

8 recordsLinked to original sources
PubMed2006

Prevention of aminoglycoside-induced sensorineural hearing loss.

BACKGROUND: Aminoglycoside antibiotics are some of the most commonly used agents for treating gram-negative bacterial infections. They are extremely efficacious but can result in ototoxicity. It has been postulated that the mechanism inducing damage is the formation of oxygen free radicals. Many compounds have been employed in an attempt to reduce aminoglycoside-induced hearing loss. We endeavour to do likewise using sodium thiosulphate. This free radical scavenging agent has a proven ability to minimize cochlear damage owing to the chemotherapeutic agent cisplatin. OBJECTIVES: This study had two distinct objectives. The first was to determine if sodium thiosulphate can reduce hearing loss in C57 mice concurrently subjected to gentamicin. The second goal was to assess the value of this animal model. METHODS: This study was accomplished by creating four treatment arms. The animals were provided with daily intraperitoneal injections of gentamicin (120 mg/kg), sodium thiosulphate (1600 mg/kg), gentamicin plus sodium thiosulphate, or normal saline. Auditory brainstem response threshold changes were calculated comparing differences between baseline values and those observed at day 35. RESULTS: The results indicate a trend suggesting that sodium thiosulphate may afford some degree of otologic protection when provided in conjunction with gentamicin. However, a statistical significance could not be established. Our mice appear to be more resistant to gentamicin-induced ototoxicity than found in previously reported animal models. CONCLUSION: We were unable to demonstrate that sodium thiosulphate can attenuate gentamicin-induced ototoxicity. Furthermore, we observe that the susceptibility to hearing loss varies considerably between individual C57 mice. Consequently, we hold some degree of reservation with the use of this model to assess the benefit of prospective rescue agents.

Animals↗
PubMed2005

Effect of sodium thiosulphate and cis-diamminedichloroplatinum on FADU tumour cells in nude mice.

OBJECTIVES: To study the effect of cis-diamminedichloroplatinum (CDDP) on FADU squamous cell carcinoma cells in a nude mouse model and to determine the effect of sodium thiosulphate (STS) on CDDP activity. METHODS: CD1 nude mice were inoculated with FADU tumour cells to both flanks. They were then randomized to four treatment groups: control, CDDP only, STS only, or CDDP and STS. Tumour growth was measured using calipers and charted at 3-day intervals. RESULTS: Tumour volumes were calculated as an ellipsoid and charted against time. CONCLUSIONS: CDDP inhibited FADU tumour cell growth compared with saline controls (p < .005). The addition of STS did not inhibit the CDDP activity when compared with CDDP-alone activity (p = .989). Compared with saline control solution, STS alone also inhibited tumour growth significantly (p < .005).

Animals↗
PubMed2004

WR-2721 (Amifostine) ameliorates cisplatin-induced hearing loss but causes neurotoxicity in hamsters: dose-dependent effects.

Chemoprotective agents reduce the toxic side effects of chemotherapy agents such as cisplatin. The conventional belief is that the chemoprotective agent WR-2721 (Amifostine), while protecting against most cisplatin-induced side effects, does not protect against cisplatin-induced ototoxicity (i.e., hearing loss). There is no knowledge, however, about the efficacy of high doses of WR-2721 (WR) in possibly protecting against cisplatin-induced ototoxicity. Thus, the dose-dependent effects of WR in possibly ameliorating cisplatin-induced ototoxicity were investigated. Hamsters were given a series of 5 cisplatin injections (3 mg/kg/injection once every other day, i.p.) either alone or in combination with 18, 40, 80, or 400 mg/kg/injection of the rescue agent WR ( n = 5 or 10/group). Other groups received either 80 mg/kg/injection WR alone ( n = 5) or were untreated ( n = 14). Ototoxicity was assessed by auditory brain stem responses (ABR). WR provided dose-dependent rescue from cisplatin's ototoxicity with no protection at the low dose of 18 mg/kg, moderate protection at 40 mg/kg, and nearly complete protection at 80 and 400 mg/kg. However, WR doses of 40 mg/kg or higher caused neurotoxicity as evidenced by prolongations in the ABR's interpeak latencies. Thus, high doses of WR provided the beneficial effect of protecting against cisplatin-induced ototoxicity, but had the harmful side effect of neurotoxicity. Previous failures to find chemoprotection from cisplatin-induced ototoxicity were likely due to the use of WR doses that were too small. The clinical implications of the beneficial and harmful effects of high doses of WR are discussed.

Amifostine↗
PubMed2003

Assessment of the protective effects of amifostine against cisplatin-induced toxicity.

OBJECTIVE: The goals of this study were to determine whether the toxicity of cisplatin, a chemotherapeutic alkylating agent, could be reduced by the use of amifostine and to determine whether amifostine alone could cause ototoxicity. STUDY DESIGN: Prospective, animal study. METHODS: Auditory brainstem response click threshold, latencies, and blood work were used to measure ototoxicity, nephrotoxicity, and myelotoxicity before and 4 weeks after treatment. Groups of guinea pigs received either cisplatin alone (30 mg/kg), amifostine (1000 mg/kg), cisplatin plus amifostine (1000 mg/kg), or no agent. RESULTS: Amifostine reduced the hearing loss caused by cisplatin for many animals. Amifostine partially protected against cisplatin-induced ototoxicity and renal toxicity. We did not find evidence for myelotoxicity owing to cisplatin in this sample. CONCLUSION: Amifostine may have a role in reducing toxicity or permitting larger doses of cisplatin to be given, but toxicity can still be significant even with protection.

Amifostine↗
PubMed2003

Quantification of sodium thiosulphate protection on cisplatin-induced toxicities.

OBJECTIVE: To quantify the amount of protection from cisplatin (CDDP)-induced mortality and toxicity provided by sodium thiosulphate (STS). DESIGN: Prospective controlled animal study. SETTING: Animal research facility. METHOD: Nephrotoxicity, myelotoxicity, and auditory/neurotoxicity were studied in guinea pigs. Total CDDP doses of 15, 21, 25, 35, and 45 mg/kg were administered to animals in groups of five. In some groups, STS (8000 mg/kg) was given. Animals underwent bloodwork and auditory brainstem response (ABR) testing to estimate toxicity before and 1 month after treatment. MAIN OUTCOME MEASURES: Blood urea nitrogen, creatinine, and white blood cell count were used to assess renal and myelotoxicity. Hearing was assessed with ABR thresholds to click stimuli. Survival was an overall measure of toxicity. RESULTS: Forty guinea pigs in six treatment groups were studied. Animals given 21 mg/kg CDDP all died within 1 month and showed evidence of severe toxicity. Eighty percent of subjects treated with CDDP 15 mg/kg survived and showed evidence of nephrotoxicity and ototoxicity. Subjects treated with STS and CDDP showed survival comparable to the control group treated with CDDP 15 mg/kg. Under STS protection, CDDP was tolerated in doses three times the toxic dose without protection. Without STS, the maximum dose of CDDP tolerated for a month was 15 mg/kg. CONCLUSIONS: STS protects against mortality owing to CDDP by reducing toxicity. Under STS protection, the maximum tolerated dose of CDDP is greatly increased in guinea pigs.

Animals↗
PubMed2002

Strategies for prevention of toxicity caused by platinum-based chemotherapy: review and summary of the annual meeting of the Blood-Brain Barrier Disruption Program, Gleneden Beach, Oregon, March 10, 2001.

OBJECTIVES: To summarize the findings relevant to otolaryngology from the annual meeting of the Blood-Brain Barrier Disruption Consortium in Gleneden Beach, Oregon, March 10, 2001. STUDY DESIGN: Summaries are provided by the speakers, as well as related data from the published literature. Findings in otology and oncology regarding ototoxicity that were discussed at the meeting are included. RESULTS: Data considered included physiological research, animal studies, and clinical trials that relate to platinum-based chemotherapy and prevention of toxicity. CONCLUSIONS: The dose-limiting side effects of platinum-based chemotherapy are preventable, but questions about the effect of the protective agents on oncological efficacy remain. Strategies for prevention of chemotherapy-induced toxicity include temporal or anatomical separation of cisplatin or carboplatin from sodium thiosulfate, D-methionine, or N-acetyl-cysteine. Clinical application of these methods has begun. The mechanisms presumably involve free radicals or drug conjugation, or both. Understanding the role of free radicals in medicine is likely to become important in the future.

Animals↗