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Rationale Recent evidence suggests that imidazoline I2 receptor ligands are suitable for combination therapy with opioids. Quantitative analysis of I2 receptor ligands combined with non-opioid drugs is necessary for justification of alternative pain therapies. Objective This study systematically examined the anti-hyperalgesic and response rate-suppressing effects of selective I2 receptor ligands (2-BFI and phenyzoline) alone and in combination with acetaminophen. Methods Von Frey and Hargreaves tests were used to examine the anti-hyperalgesic effects of drugs in complete Freund’s adjuvant (CFA)-induced inflammatory pain in rats. Food-reinforced schedule-controlled responding was used to assess the rate-suppressing effects of study drugs. Dose-addition and isobolographic analyses were used to assess drug-drug interactions for all assays. Results 2-BFI (3.2–17.8 mg/kg, i.p.), phenyzoline (17.8–100 mg/kg, i.p.), and acetaminophen (56–178 mg/kg, i.p.) all dose-dependently produced significant antinociceptive effects. When studied as combinations, 2-BFI and acetaminophen produced infra-additive to additive interactions while phenyzoline and acetaminophen produced additive to supra-additive interactions. The same drug combinations suppressed response rate in a supra-additive manner. Conclusions Quantitative analysis of the anti-hyperalgesic and response rate-suppressing effects suggests that I2 receptor ligands are not well suited to combination therapy with acetaminophen.

IntroductionChemokine ligand 5, also known as CCL5 or regulated on activation normal T-cell expressed and secreted (RANTES), is a chemokine expressed in inflamed tissue and capable of inducing migration of immature dendritic cells (DCs) or Langerhans cells. In this study, we explored the effect of RANTES on EG7 cells.Material and methods In vivo, RANTES gene transfer reduced the tumourigenic capacity of EG7 and prolonged the survival of tumour-bearing mice. To reveal the underlying mechanism, we performed the following experiments and provided evidence to support our hypothesis of RANTES gene therapy for EG7. Higher natural killer (NK) cell and cytotoxic T lymphocyte (CTL) activity was induced after RANTES gene transfer, accompanied by higher levels of Th1 type cytokines (IL-2 and IFN-γ).ResultsTumour necrosis was also markedly observed in the tumour tissues after RANTES gene transfer, which was attributed to reduced expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP-2).ConclusionsWe draw the conclusion that reduced tumourigenicity of EG7 after RANTES gene transfer can be attributed to higher NK cell and CTL activity, anti-angiogenesis and higher levels of Th1 type cytokines induced by RANTES. These results support the notion that higher chemokine expression in tumour tissue elicits potent anti-tumour immunity.

Methamphetamine abuse remains an alarming public heath challenge with no approved pharmacotherapies available. Agmatine is a naturally-occurring cationic polyamine that has previously been shown to attenuate the rewarding and psychomotor-sensitizing effects of methamphetamine. This study examined the effects of agmatine on the discriminative stimulus and hyperthermic effects of methamphetamine. Adult male rats were trained to discriminate 0.32 mg/kg methamphetamine from saline. Methamphetamine dose-dependently increased drug-associated lever responding. The nonselective dopamine receptor antagonist haloperidol (0.1 mg/kg) significantly attenuated the discriminative stimulus effects of methamphetamine (5.9-fold rightward shift). Agmatine (10 –100 mg/kg) did not substitute for methamphetamine but significantly attenuated the stimulus effects of methamphetamine, leading to a maximum of 3.5-fold rightward shift. Acute 10 mg/kg methamphetamine increased the rectal temperature by a maximum of 1.96 ± 0.17 °C. Agmatine (10 – 32 mg/kg) pretreatment significantly attenuated the hyperthermic effect of methamphetamine. Agmatine (10 mg/kg) also significantly reversed methamphetamine-induced temperature increase. Together, these results support further exploration of the value that agmatine may have for treating methamphetamine abuse and overdose.

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