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1.
Mol Pharm ; 13(8): 2677-82, 2016 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-27299507

RESUMEN

Cisplatin is widely used to treat a variety of cancers. However, ototoxicity and nephrotoxicity remain serious side effects of cisplatin-based chemotherapy. In order to inform the study of cisplatin's off-target effects, a new drug-fluorophore conjugate was synthesized that exhibited utility as a tracer to determine the cellular uptake and in vivo distribution of cisplatin. This probe will serve as a useful tool to facilitate investigations into the kinetics and biodistribution of cisplatin and its associated side effects in preclinical models after systemic administration.


Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Cisplatino/administración & dosificación , Cisplatino/uso terapéutico , Animales , Relación Dosis-Respuesta a Droga , Humanos , Neoplasias/tratamiento farmacológico
2.
Cancer Chemother Pharmacol ; 62(2): 235-41, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17909806

RESUMEN

Dosing and route of administration of N-acetylcysteine (NAC) for protection against cisplatin (CDDP) nephrotoxicity was investigated in rats. Two models of toxicity were tested: a single high dose of CDDP (10 mg/kg intraperitoneally (IP)), and multiple low dose treatments (1 mg/kg IP twice a day for 4 days, 10 days rest, then repeated). NAC (50-1,200 mg/kg) was given to the rats by IP, oral (PO), intravenous (IV) and intra-arterial (IA) routes. Renal toxicity was determined by blood urea nitrogen (BUN) and creatinine (CR) levels 3 days after treatment. Blood collected 15 min after NAC was analyzed for total NAC. Both models of CDDP administration produced renal toxicity. In the single dose CDDP model, NAC 400 mg/kg given IP and PO produced no renal protection as measured by BUN (131.8 +/- 8.2 and 123.3 +/- 8.2, respectively) or CR (2.3 +/- 0.38 and 1.77 +/- 0.21, respectively). IV NAC reduced nephrotoxicity, (BUN 26.3 +/- 6.8, CR 0.47 +/- 0.15). NAC 50 mg/kg IA gave better protection than IV. In the repeated-dose CDDP model, nephrotoxicity was blocked by 800 mg/kg NAC given IV but not IP. Blood concentrations of total NAC showed a dose response after IV NAC, but high dose NAC (1,200 mg/kg) by the PO route gave very low levels of NAC. Thus the protective properties of NAC are affected by the dose and route of administration.


Asunto(s)
Acetilcisteína , Antineoplásicos/toxicidad , Cisplatino/toxicidad , Depuradores de Radicales Libres , Enfermedades Renales/prevención & control , Acetilcisteína/administración & dosificación , Acetilcisteína/farmacología , Acetilcisteína/uso terapéutico , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Depuradores de Radicales Libres/administración & dosificación , Depuradores de Radicales Libres/farmacología , Depuradores de Radicales Libres/uso terapéutico , Inyecciones Intraarteriales , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Enfermedades Renales/inducido químicamente , Pruebas de Función Renal , Ratas , Ratas Long-Evans
3.
J Neurooncol ; 81(1): 81-91, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-16858513

RESUMEN

Although knowledge of molecular biology and cellular physiology has advanced at a rapid pace, much remains to be learned about delivering chemotherapy and antibodies across the blood-brain barrier (BBB) for the diagnosis and treatment of central nervous system (CNS) disease. A meeting, partially funded by an NIH R13 grant, was convened to discuss the state of the science, current knowledge gaps, and future directions in the delivery of drugs and proteins to the CNS, for the treatment of primary and metastatic brain tumors. Meeting topics included CNS metastases and the BBB, and chemoprotection and chemoenhancement in CNS disorders. The discussions regarding CNS metastases generated possibilities of chemoprotection as a means not only to decrease treatment-related toxicity but also to increase chemotherapy dose intensity. The increasing incidence of sanctuary brain metastasis from breast cancer, in part due to the difficulty of monoclonal antibodies (mAbs) such as herceptin to cross the BBB, was one of the most salient "take home" messages of the meeting.


Asunto(s)
Antineoplásicos/administración & dosificación , Barrera Hematoencefálica/fisiología , Neoplasias Encefálicas/terapia , Sistemas de Liberación de Medicamentos/métodos , Inmunoterapia/métodos , Metástasis de la Neoplasia/terapia , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Transporte Biológico , Barrera Hematoencefálica/efectos de los fármacos , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/secundario , Niño , Preescolar , Humanos , Lactante , Metástasis de la Neoplasia/diagnóstico , Metástasis de la Neoplasia/inmunología , Síndromes de Neurotoxicidad/prevención & control
4.
J Pharmacol Exp Ther ; 314(3): 1052-8, 2005 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-15951398

RESUMEN

Cisplatin (CDDP) is a common, highly toxic chemotherapeutic agent. This study investigates chemoprotective effects of N-acetylcysteine (NAC) and sodium thiosulfate (STS) on in vitro and in vivo CDDP toxicities. For ototoxicity studies, CDDP (6 mg/kg) was administered to rats via a retrograde carotid artery infusion. Auditory brainstem response thresholds at 4 to 20 kHz were tested before and 7 days post-treatment. STS (8 g/m(2) i.v.) was administered at 4, 8, or 12 h after CDDP. For nephrotoxicity studies, rats were treated with CDDP intraperitoneally (10 mg/kg) before or after NAC (400 mg/kg) or STS (8 g/m(2)), and blood urea nitrogen (BUN) and creatinine concentrations were measured after 3 days. In vitro cytotoxicity and chemoprotection in human tumor cell lines were assessed by cell viability and immunoblotting assays. Rats treated with STS 4 h after CDDP exhibited no hearing change. The STS 8-h group had less otoprotection, whereas 12-h rats had ototoxicity. CDDP induced high BUN and creatinine, corresponding to renal tubule toxicities. All NAC-treated animals showed normal BUN and reduced creatinine levels compared with CDDP alone and no histopathological evidence of nephrotoxicity. Delayed STS treatment was not consistently protective against nephrotoxicity. STS administration fully protected against the in vitro cytotoxic and apoptotic effects of CDDP if added within 2 h of CDDP, but chemoprotection decreased if STS administration was 4 h, and was minimal by 6 h, after CDDP. Thus, the chemoprotection route and timing of administration can be manipulated to maintain CDDP antitumor efficacy while protecting against toxicities.


Asunto(s)
Acetilcisteína/farmacología , Antineoplásicos/toxicidad , Cisplatino/toxicidad , Tiosulfatos/farmacología , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Supervivencia Celular/efectos de los fármacos , Femenino , Audición/efectos de los fármacos , Riñón/efectos de los fármacos , Ratas , Ratas Long-Evans , Transducción de Señal/efectos de los fármacos
5.
Laryngoscope ; 112(11): 1997-2001, 2002 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-12439169

RESUMEN

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.


Asunto(s)
Antineoplásicos/efectos adversos , Antioxidantes/farmacología , Carboplatino/efectos adversos , Cisplatino/efectos adversos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/prevención & control , Compuestos de Platino/efectos adversos , Animales , Barrera Hematoencefálica , Humanos , Metionina/farmacología , Tiosulfatos/farmacología
6.
Am J Primatol ; 2(2): 159-166, 1982.
Artículo en Inglés | MEDLINE | ID: mdl-31995903

RESUMEN

The purpose of this study was to describe the autonomic innervation of the carotid sinus and heart in the rhesus monkey. Nine male rhesus monkeys (Macaca mulatta) and one male crab-eating macaque (M. fascicularis) were carefully dissected from the origin of the vagus nerves and superior cervical ganglia to the level of the fourth thoracic ganglion. The specimens were either freshly killed or obtained no later than 24 hours post mortem. The macaque monkeys were found to possess an innervation pattern that displayed features common to dog (connections between the vagus nerves and middle cervical ganglia), baboon (distinct cervical sympathetic and cervical vagal nerve trunks), and man (nerves projecting from the middle cervical and stellate ganglia to the heart). Distinct inferior cervical and first thoracic ganglia were never seen, but rather, large and well defined stellate ganglia were found. The macaque innervation pattern, when considered as a whole, most closely resembled the baboon.

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