RESUMEN
The persisting need for effective clinical treatment of chemotherapy-induced neurotoxicity (CIN) motivates critical evaluation of preclinical models of CIN for their translational relevance. The present study aimed to provide the first quantitative evaluation of neural tissue exposed in vivo to a platinum-based anticancer compound, oxaliplatin (OX) during and after two commonly used dosing regimens: slow IV infusion used clinically and bolus IP injection used preclinically. Inductively-coupled plasma mass spectrometry analysis of dorsal root ganglia indicated that while differences in the temporal dynamics of platinum distribution exist, key drivers of neurotoxicity, e.g. peak concentrations and exposure, were not different across the two routes of administration. We conclude that the IP route of OX administration achieves clinically relevant pharmacokinetic exposure of neural tissues in a rodent model of CIN.
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Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Oxaliplatino/administración & dosificación , Oxaliplatino/farmacocinética , Administración Intravenosa , Animales , Vías de Administración de Medicamentos , Infusiones Parenterales , Compuestos de Platino/administración & dosificación , Compuestos de Platino/farmacocinética , Ratas , Ratas Endogámicas F344RESUMEN
Introduction: Paclitaxel is a microtubule stabilizer that is currently one of the most utilized chemotherapeutic agents. Its efficacy in breast, uterine, lung and other neoplasms made its safety profile enhancement a subject of great interest. Neurotoxicity is the most common paclitaxel-associated toxicities. In addition, hypersensitivity reactions, hematological, gastrointestinal, and cardiac toxicities are all encountered.Areas covered: The current review explores paclitaxel-induced toxicities mechanisms and risk factors. Studies investigating these toxicities pharmacogenomic biomarkers are reviewed and summarized. There is a limited margin of consistency between the retrieved associations. Variants in genes related to neuro-sensitivity are the most promising candidates for future studies.Expert opinion: Genome-wide association studies highlighted multiple-candidate biomarkers relevant to neuro-sensitivity. Most of the identified paclitaxel-neurotoxicity candidate genes are derived from congenital neuropathy and diabetic-induced neurotoxicity pathways. Future studies should explore these sets of genes while considering the multifactorial nature of paclitaxel-induced neurotoxicity. In the absence of certain paclitaxel-toxicity biomarkers, future research should avoid earlier studies' caveats. Genes in paclitaxel's pharmacokinetic pathways could not provide consistent results in any of its associated toxicities. There is a need to dig deeper into toxicity-development mechanisms and personal vulnerability factors, rather than targeting only the genes suspected to affect drug exposure.
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Antineoplásicos Fitogénicos/efectos adversos , Paclitaxel/efectos adversos , Farmacogenética , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/farmacocinética , Biomarcadores/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , Neoplasias/tratamiento farmacológico , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/genética , Paclitaxel/administración & dosificación , Paclitaxel/farmacocinéticaRESUMEN
BACKGROUND/AIM: Oxaliplatin-induced neurotoxicity (OIN) can be severe and dose-limiting with clinically significant symptoms that persist for years. Few published reports have described postoperative exacerbation of OIN and more longitudinal data are needed to better characterize the phenomenon. PATIENTS AND METHODS: We identified 13 patients diagnosed with colon (n=7), rectal (n=4) or pancreatic (n=2) cancer who experienced postoperative OIN exacerbation at our medical center. Charts were reviewed for demographic and clinical data regarding OIN. RESULTS: OIN exacerbation was documented 0.5-7.0 months after the first surgery following oxaliplatin exposure, with a median duration of 10.6 months (range=1.4-86.1 months). OIN exacerbation persisted in 3/13 patients at last follow-up, and improved to pre-operative levels in 6/13 patients (with complete resolution in 4/13) within a median of 3.6 months from initial exacerbation. CONCLUSION: Given the widespread use of oxaliplatin in neoadjuvant and first-line treatment for gastrointestinal cancers, further study is warranted to prospectively and systematically define risks for postoperative OIN exacerbation.
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Neoplasias Gastrointestinales/complicaciones , Neoplasias Gastrointestinales/tratamiento farmacológico , Síndromes de Neurotoxicidad/etiología , Oxaliplatino/uso terapéutico , Adulto , Femenino , Neoplasias Gastrointestinales/patología , Humanos , Masculino , Persona de Mediana Edad , Oxaliplatino/farmacología , Periodo PosoperatorioRESUMEN
Chemotherapy-Induced Peripheral Neurotoxicity (CIPN) is often dose-limiting and impacts life quality and survival of cancer patients. Ghrelin agonists have neuroprotectant effects and may have a role in treating or preventing CIPN. We evaluated the CNS-penetrant ghrelin agonist HM01 in three experimental models of CIPN at doses of 3-30â¯mg/kg p.o. daily monitoring orexigenic properties, nerve conduction, mechanical allodynia, and intra-epidermal nerve fiber density (IENFD). In a cisplatin-based study, rats were dosed daily for 3 days (0.5â¯mg/kg i.p.) + HM01. Cisplatin treatment induced mechanical hypersensitivity which was significantly reduced by HM01. In a second study, oxaliplatin was administered to mice (6â¯mg/kg i.p. 3 times/week for 4 weeks) resulting in significant digital nerve conduction velocity (NCV) deficits and reduction of IENFD. Concurrent HM01 dose dependently prevented the decline in NCV and attenuated the reduction in IENFD. Pharmacokinetic studies showed HM01 accumulation in the dorsal root ganglia and sciatic nerves which reached concentrations >â¯10 fold that of plasma. In a third model, HM01 was tested in preventive and therapeutic paradigms in a bortezomib-based rat model (0.2â¯mg/kg i.v., 3 times/week for 8 weeks). In the preventive setting, HM01 blocked bortezomib-induced hyperalgesia and IENFD reduction at all doses tested. In the therapeutic setting, significant effect was observed, but only at the highest dose. Altogether, the robust peripheral nervous system penetration of HM01 and its ability to improve multiple oxaliplatin-, cisplatin-, and bortezomib-induced neurotoxicities suggest that HM01 may be a useful neuroprotective adjuvant for CIPN.
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Antineoplásicos/efectos adversos , Derivados del Benceno/farmacología , Ghrelina/agonistas , Sistema Nervioso/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Peso Corporal/efectos de los fármacos , Cisplatino/efectos adversos , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Femenino , Masculino , Ratones , Conducción Nerviosa/efectos de los fármacos , Piperidinas , RatasRESUMEN
Besides their deleterious action on cardiac muscle, anthracycline-type cytostatic agents exert significant neurotoxic effects on primary sensory neurons. Since cardiac sensory nerves confer protective effects on heart muscle and share common traits with cutaneous chemosensitive nerves, this study examined the effects of cardiotoxic doses of adriamycin on the function and morphology of epidermal nerves. Sensory neurogenic vasodilatation, plasma extravasation, and the neural CGRP release evoked by TRPV1 and TRPA1 agonists in vitro were examined by using laser Doppler flowmetry, the Evans blue technique, and ELISA, respectively. Carrageenan-induced hyperalgesia was assessed with the Hargreaves method. Immunohistochemistry was utilized to study cutaneous innervation. Adriamycin treatment resulted in profound reductions in the cutaneous neurogenic sensory vasodilatation and plasma extravasation evoked by the TRPV1 and TRPA1 agonists capsaicin and mustard oil, respectively. The in vitro capsaicin-, but not high potassium-evoked neural release of the major sensory neuropeptide, CGRP, was markedly attenuated after adriamycin treatment. Carrageenan-induced inflammatory hyperalgesia was largely abolished following the administration of adriamycin. Immunohistochemistry revealed a substantial loss of epidermal TRPV1-expressing nociceptive nerves and a marked thinning of the epidermis. These findings indicate impairments in the functions of TRPV1 and TRPA1 receptors expressed on cutaneous chemosensitive nociceptive nerves and the loss of epidermal axons following the administration of cardiotoxic doses of adriamycin. Monitoring of the cutaneous nociceptor function in the course of adriamycin therapy may well be of predictive value for early detection of the deterioration of cardiac nerves which confer protection against the deleterious effects of the drug.