RESUMEN
Housing temperature has been shown to influence thermoregulation and behavior of preclinical cancer models; and anti-cancer drugs typically reduce peripheral blood flow and body temperature. In the present study, the effects of paclitaxel (PTX)-induced reduction of body temperature and peripheral blood flow on metastatic 4T1 breast cancer was investigated in a mouse model and the modification of these effects by thermoneutral temperature was also assessed. A single dose of PTX decreased the body temperature and peripheral blood flow in mice housed at a standard temperature (23°C). Furthermore, although lung metastasis and angiogenesis of inoculated 4T1 cells increased in mice pretreated with PTX, mice housed at a thermoneutral temperature (30°C) could compensate their body temperature and peripheral blood flow compared with control mice, and also suppressed 4T1 angiogenesis and metastasis to lung. The present results imply that maintenance of body temperature or efficient energy supply for thermogenesis may prevent tumor relapse or metastasis after chemotherapy.
RESUMEN
Pain caused by subcutaneous injections is unpleasant, which may limit patient compliance. The objective of this study was to use spinal reflexes to quantify subcutaneous injection pain. Spinal reflexes were measured using an electromyogram (EMG) test. The effects of injection volume, pH and osmotic pressure were investigated. The EMG responses increased with injection volume and the acidity of the solution but did not depend on the osmotic pressure of the solution. The EMG responses differed for subcutaneously injected sodium chloride and glucose over the same range of osmotic pressures. Pain caused by the subcutaneous injections was unrelated to the osmotic ratio up to approximately 5. The injection pain caused by therapeutic protein solutions was also evaluated. We compared the EMG responses of the adalimumab and etanercept, as the injection of adalimumab is more painful than that of etanercept in humans. The EMG magnitude for adalimumab was twice that induced by etanercept as observed for the EMG tests performed in rats. Therapeutic proteins account for an increasingly large proportion of pharmaceutical drugs. When a high dose of therapeutic proteins is required, the protein solution must often be highly concentrated to reduce the injection volume. For patient comfort, it is critical to reduce injection pain. The EMG test reported here allows subcutaneous injection pain to be quantified and may be useful for optimizing drug formulations.
Asunto(s)
Adalimumab/efectos adversos , Antirreumáticos/efectos adversos , Modelos Animales de Enfermedad , Etanercept/efectos adversos , Dolor/inducido químicamente , Nervios Espinales/efectos de los fármacos , Tejido Subcutáneo/efectos de los fármacos , Adalimumab/administración & dosificación , Animales , Antirreumáticos/administración & dosificación , Electrodos Implantados , Electromiografía , Etanercept/administración & dosificación , Pie , Humanos , Concentración de Iones de Hidrógeno , Inyecciones Subcutáneas , Masculino , Presión Osmótica , Dimensión del Dolor , Ratas Sprague-Dawley , Reflejo/efectos de los fármacos , Tejido Subcutáneo/inervación , MusloRESUMEN
Peripheral neuropathies are common side effects of chemotherapeutic drugs, including taxanes, platinum-based drugs, vinca alkaloids, and thalidomide. The most common symptoms are numbness, tingling and/or burning pain in a stocking-glove distribution. Severe peripheral neuropathies result in dose reductions, a change in chemotherapy regimen, or early cessation of chemotherapy. There are no proven interventions to prevent or treat chemotherapy-induced peripheral neuropathy. We designed and built a unique magnetic stimulator to clarify the effects of magnetic stimulation in the mouse paclitaxel-induced peripheral neuropathic pain model. Magnetic stimulation significantly reversed paclitaxel-induced mechanical hyperalgesia. The analgesic efficacy of magnetic stimulation was inhibited by naloxone, a µ opioid receptor antagonist. These findings indicate that the analgesic effect of magnetic stimulation is likely to be mediated by the endogenous opioid system. Furthermore, a combination of magnetic stimulation and pregabalin, a Ca(2+) channel blocker, induced a potent combinational analgesic effect, suggesting that analgesic drug dose reduction might be possible. These findings indicate that there is a potential therapeutic utility for magnetic stimulation in pain relief.
Asunto(s)
Analgesia/métodos , Magnetoterapia/métodos , Neuralgia/inducido químicamente , Neuralgia/terapia , Paclitaxel/toxicidad , Analgésicos/uso terapéutico , Animales , Hiperalgesia/inducido químicamente , Hiperalgesia/terapia , Masculino , Ratones , Ratones Endogámicos ICR , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/fisiopatologíaRESUMEN
In small cell lung carcinoma (SCLC), acetylcholine (ACh) is synthesized and secreted, and it acts as an autocrine growth factor through activation of its receptors, muscarinic receptor (mAChR) and nicotinic receptor (nAChR). Alteration of tumor growth by blockade of M(3) mAChR in a human SCLC cell line, NCI-H82, was investigated in the present study. We used a highly selective M(3) muscarinic antagonist, N-(2-[3-([3R]-1-(cyclohexylmethyl)-3-piperidinyl]methylamino)-3-oxopropyl]amino-2-oxoethyl)-3,3,3-triphenyl-propioamide (J-115311). Our results show that J-115311 inhibited the increased intracellular calcium elicited by carbachol, a muscarinic agonist, in SCLC cells. J-115311 also inhibited SCLC cell growth in vitro. In a mouse orthotopic xenograft model, J-115311 dose-dependently reduced tumor growth when NCI-H82 cells were inoculated into the upper left lobe of the lung. These findings indicate that blockade of M(3) mAChR can suppress tumor growth in SCLC, suggesting the potential therapeutic utility of M(3) muscarinic antagonists as anti-cancer agents.