with the highest dose reducing nicotine distribution to brain by 78%.

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The effects of passive immunization on fetal nicotine distribution were dose-related (ANOVA p p p p
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immunogenicity of the vaccine and effects of nicotine distribution to brain.

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  • Dose-response relationship for nicotine distribution after treatment with NICmAb311 compared with control-mAb. Data points for each of two rats at each dose are shown. Increasing NICmAb311 dose was associated with increasing serum nicotine concentration measured 3 min after a nicotine dose (r = 0.99; p r = 0.99; p , are shown for comparison.

    Effects of NICmAb311 Dose on Nicotine Distribution. There was a strong correlation between the log NICmAb311 dose and nicotine retention in serum (r = 0.99; p r = 0.99; p ). The highest NICmAb dose of 160 mg/kg reduced brain nicotine concentration by 78% compared with control-IgG. The reduction in brain nicotine concentration produced by the 80 mg/kg NICmAb311 dose (71%) was similar to that of 10 mg/kg Nic-IgG determined in the previous experiment (69%). Serum protein binding of nicotine increased, and the unbound nicotine concentration decreased, with increasing NICmAb311 dose (; p r = 0.99; p , bottom). Serum NICmAb311 concentrations (mean of two values) measured 30 min after the antibody dose were dose-related; 0.22, 0.37, 0.93, 1.57, and 4.23 mg/ml with increasing NICmAb311 dose.

  • In the range of Kd values evaluated, lower Kd was associated with greater efficacy for retaining nicotine in serum, increasing protein binding of nicotine in serum, reducing unbound nicotine concentration in serum, and reducing nicotine distribution to brain. These data suggest that a monoclonal antibody with a lower Kd than that of NICmAb311 would be even more effective than this monoclonal antibody. Nevertheless, several considerations suggest that NICmAb311 is sufficiently effective to be of interest as a means of reducing nicotine effects. First, the Kd of 60 nM is only slightly higher than that of antibodies elicited by vaccination of rats (range 19–40 nM) with this same immunogen (; ; ), and vaccination has been shown to attenuate many nicotine-related effects in rats that are relevant to nicotine addiction (; ). In addition, the monoclonal nicotine-specific antibody studied by Carrera et al. (), with an even higher Kd of 200 nM, produced a substantial reduction of the locomotor activating effect of a single nicotine dose (). Second, the magnitude of NICmAb311 effect is a function of dose. The 40 mg/kg dose of NICmAb311, which is within the range of antibody content of a vaccinated rat, produced a 20-fold increase in serum nicotine concentration and a 60% decrease in brain concentration compared with controls, values essentially identical to those reported after vaccination using the same protocol (). Higher NICmAb311 doses produced greater effects, and at the 80 mg/kg dose these effects were comparable with those of 3 mg of Nic-IgG. Thus, the lesser efficacy of NICmAb311 compared with Nic-IgG could be compensated with a suitable increase in NICmAb311 dose.

    Dose-Response for Effects of NICmAb311 on Nicotine Distribution. The purpose of this experiment was to study the relationship between NICmAb dose and nicotine distribution. NICmAb311 was chosen to study because it had the lowest Kd and the largest pharmacokinetic effect of the NICmAbs evaluated previously. Because the availability of NICmAb311 was limited, antibody administration was restricted to two rats per dose. Rats in this experiment were prepared and studied as described immediately above, receiving NICmAb311 at doses of 10 to 160 mg/kg, i.v., followed in 30 min by 0.03 mg/kg nicotine and decapitation and sampling 3 min after the nicotine dose.

  • The binding data confirm that NICmAb effects and mechanism of action are similar to those of vaccination against nicotine (). Antibodies are largely excluded from the brain by the blood-brain barrier owing to their large size, so that only unbound nicotine can distribute to brain (). The highly significant correlations between unbound nicotine concentration in serum and brain nicotine concentration found in this study strongly support the hypothesis that immunization reduces nicotine distribution to brain by reducing the concentration of the unbound nicotine in serum.

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The similar serum nicotine concentrations in control groups, immunized with the unconjugated carrier protein, after 10 min NSE or 10 min i.v. infusion confirms that the nicotine dose delivered by 10 min NSE was in the target range of 0.015 mg/kg, similar to mg/kg estimates of nicotine uptake from a single cigarette by a smoker []. Vaccination substantially reduced nicotine distribution to brain whether nicotine was administered via smoke or by itself as an i.v. infusion, showing that the effects of vaccination on nicotine distribution are quite robust despite marked differences in route and manner of nicotine administration. These findings support the validity of the i.v. dosing paradigm in rats as a model of vaccine effects on cigarette smoking in humans. Several comparisons suggested that vaccination might be minimally more effective in the setting of NSE exposure than IV infusion exposure, but these were probably incidental because brain nicotine concentrations, the most important measure of efficacy, were comparable after these exposures.