Changes in cardiovascular parameters and plasma norepinephrine level in rats after chronic constriction injury on the sciatic nerve

To evaluate whether neuropathic pain affects autonomic nervous activities, we investigated daily change in cardiovascular parameters and plasma norepinephrine (NE) in free-moving rats after chronic constriction injury (CCI) on the sciatic nerve. Arterial blood pressure (BP), heart rate (HR), and the power spectrum of pulse interval variability were analyzed. Daily change in motor activity and nociceptive behavior was also measured from some CCI rats. In others, NE from daily blood samples was quantified and spontaneous pain was evaluated by daily monitoring of foot guarding behavior. We identified three stages in the daily change of cardiovascular parameters and plasma NE level over 3 weeks following CCI. The first stage (up to 3 days after the surgery) was characterized by increased MAP and HR, especially in the daytime, even though plasma NE was unchanged and motor activity decreased. The second stage (mid first to mid second postoperative weeks) was characterized by increased daytime MAP and HR, and the animals developed punctate hyperalgesia in the affected hindpaw. An NE surge that may have been related to spontaneous pain was present 3-5 days after CCI. The third stage, which appeared after the second postoperative week, was characterized by normalized MAP and decreased HR, and increased high-frequency (0.8-3.0Hz) power in pulse interval variability, which is an index of cardiac parasympathetic tone. These results demonstrated that cardiovascular function was kept high through sympathetic and non-sympathetic activity for 2 weeks after CCI, followed by a predominance of parasympathetic tone.     

Weighted target interval stochastic control methods with global optimization and their applications in individualizing therapy

Several improvements on the target interval stochastic control (TISC) method are addressed for individualizing therapy. In particular, a global optimization control strategy is implemented to obtain the optimal dosage regimen, and weighting functions are introduced to balance the drug efficacy and the risk of toxicity. Since general guidance is often lacking in the determination of a weighting function, we introduce a systematic approach, i.e., the standard reference gamble method of medical decision theory, for the determination of the weighting function. The population model for the individualization of theophylline therapy reported by D’Argenio and Katz is applied in this research. The present method of the integration of weighting functions and global optimal strategy offer an effective and safe means to balance the drug efficacy and risk of toxicity. In addition, it also achieves better accuracy than the existing TISC method which uses a local optimal strategy.     

Tolerance of low‐frequency ultrasound sonophoresis: a double‐blind randomized study on humans

Background: Sonophoresis [low‐frequency ultrasound (US)] has been used in animals and in vitro to investigate enhanced percutaneous absorption of drugs. No study focused on its clinical human tolerance has been published as yet. Methods: We aimed to assess the bioeffects of low‐frequency US in vivo on human skin in a double‐blind randomized‐controlled study. We applied pulse‐mode US at 36 kHz for 5 min in a step procedure of increasing dosage, from 1.57 to 3.50 W/cm², and placebo. The primary outcome was toxic effects of the procedure, defined as a pain score >40 on a 0–100 mm visual analogue scale or necrosis. Erythema (scored from 0 to 3 in severity) was also evaluated. The secondary outcomes were measurements of skin thickness by high‐resolution skin imaging, of skin capacitance and temperature. Results: We included 34 healthy volunteers. We found no pain score >38 and no skin necrosis with either US or placebo. Erythema was systematically observed immediately after US application, but after 1 day, we observed three cases in the knee group. The most frequent adverse effect was tinnitus. We observed no marked increase in temperature or cutaneous thickness after US or placebo. Cutaneous capacitance increased immediately after both applications. Conclusion: Such data demonstrating good tolerance of sonophoresis can be useful before the initiation of a clinical trial of the therapeutic use of low‐frequency sonophoresis in humans.