Early phase pharmacokinetics but not pharmacodynamics are influenced by propofol infusion rate

Background: Conventional compartmental pharmacokinetic models wrongly assume instantaneous drug mixing in the central compartment, resulting in a flawed prediction of drug disposition for the first minutes, and the flaw affects pharmacodynamic modeling. This study examined the influence of the administration rate and other covariates on early phase kinetics and dynamics of propofol by using the enlarged structural pharmacokinetic model. Methods: Fifty patients were randomly assigned to one of five groups to receive 1.2 mg/kg propofol given with the rate of 10 to 160 mg . kg(-1) . h(-1). Arterial blood samples were taken frequently, especially during the first minute. The authors compared four basic pharmacokinetic models by using presystemic compartments and the time shift of dosing, LAG time. They also examined a sigmoidal maximum possible drug effect pharmacodynamic model. Patient characteristics and dose rate were obtained to test the model structure. Results: Our final pharmacokinetic model includes two conventional compartments enlarged with a LAG time and six presystemic compartments and includes following covariates: dose rate for transit rate constant, age for LAG time, and weight for central distribution volume. However, the equilibration rate constant between central and effect compartments was not influenced by infusion rate. Conclusions: This study found that a combined pharmacokinetic-dynamic model consisting of a two-compartmental model with a LAG time and presystemic compartments and a sigmoidal maximum possible drug effect model accurately described the early phase pharmacology of propofol during infusion rate between 10 and 160 mg . kg(-1) . h(-1). The infusion rate has an influence on kinetics, but not dynamics. Age was a covariate for LAG time

Molecular hydrogen attenuates neuropathic pain in mice.

Neuropathic pain remains intractable and the development of new therapeutic strategies are urgently required. Accumulating evidence indicates that overproduction of oxidative stress is a key event in the pathogenesis of neuropathic pain. However, repeated intra-peritoneal or intrathecal injections of antioxidants are unsuitable for continuous use in therapy. Here we show a novel therapeutic method against neuropathic pain: drinking water containing molecular hydrogen (H2) as antioxidant. The effect of hydrogen on neuropathic pain was investigated using a partial sciatic nerve ligation model in mice. As indicators of neuropathic pain, temporal aspects of mechanical allodynia and thermal hyperalgesia were analysed for 3 weeks after ligation. Mechanical allodynia and thermal hyperalgesia were measured using the von Frey test and the plantar test, respectively. When mice were allowed to drink water containing hydrogen at a saturated level ad libitum after ligation, both allodynia and hyperalgesia were alleviated. These symptoms were also alleviated when hydrogen was administered only for the induction phase (from day 0 to 4 after ligation). When hydrogen was administered only for the maintenance phase (from day 4 to 21 after ligation), hyperalgesia but not allodynia was alleviated. Immunohistochemical staining for the oxidative stress marker, 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine, showed that hydrogen administration suppressed oxidative stress induced by ligation in the spinal cord and the dorsal root ganglion. In conclusion, oral administration of hydrogen water may be useful for alleviating neuropathic pain in a clinical setting

Hydrogen suppressed the development of oxidative stress in the DRG.

<p>(A–C) Representative images of immunohistochemical staining for oxidative stress markers 4-HNE in the DRG at the level of L5. Weak staining for 4-HNE (arrows) was observed in the DRG from mice without hydrogen at the end of 4 days period after PSNL (A), whereas staining for 4-HNE was not observed in sham operation mice (C). (B) Staining for 4-HNE was reduced in mice with hydrogen at the end of 4 days period after PSNL. (D) The proportion of 4-HNE positive cells was significantly decreased when compared with the H₂ (–) group (A). Results are expressed as percent of total neurons. *<i>P</i><0.05 compared with control (<i>t</i> test, n = 6 mice for each). Scale bar: 20 µm.</p

4-HNE were mainly produced on oligodendrocyte in the spinal cord 4 days after PSNL.

<p>(A–E) Double immunostaining of 4-HNE with cellular markers for neurons (A), astrocyte (B), oligodendrocyte (C, D), and microglia (E). 4-HNE signals were mainly colocalized with the oligodendrocyte marker NG2 and olig2, but not with NeuN, GFAP, and Iba1 in the spinal cord at the end of 4 days period after PSNL. Scale bar: 20 µm.</p

Hydrogen treatment suppressed thermal hyperalgesia in the PSNL model.

<p>Thermal hyperalgesia was analysed by the plantar test. The same sets of mice used for the von Frey test were used in the plantar test. (A) The reduction of paw withdrawal latency was attenuated in mice with hydrogen compared with those without hydrogen (n = 12 mice for each group). (B) Sham operation did not cause hyperalgesia regardless of hydrogen treatment (n = 12 mice for each group). We used a two-way RM ANOVA with a Bonferroni post-hoc test; *<i>P</i><0.05 vs. contralateral side of control mice,^#<i>P</i><0.05 vs. ipsilateral side of control mice.</p