Search

This study assessed clinical scenarios of continuing monoclonal antibody (mAb) treatment for (+)-methamphetamine (METH) addiction, and the implications of missing or discontinuing this therapy. We hypothesized that chronic anti-METH mAb7F9 (METH KD=9 nM) treatment of rats could significantly decrease METH-induced behaviors; even with repeated METH challenges, use of METH doses in excess of mAb binding sites, and after discontinuing mAb treatment which results in a 10-fold reduction in mAb7F9 serum concentrations. Male Sprague Dawley rats (n=6/group) were treated with i.v. saline or a loading dose of mAb7F9 to achieve instant steady-state conditions followed by two weekly (141 mg/kg) doses ending on day 14. METH (0.56 mg/kg) was administered 4h and three days after each saline or mAb7F9 treatment, and on day 21. This produced locomotion and rearing behavior that lasted about 120 min in control rats. In mAb7F9 treated rats, METH-induced distance traveled was significantly reduced from 60 to 120 min (P<0.05) on days 0-21 and rearing was significantly reduced from 60 to 120 min on days 0-17. METH serum concentrations determined 5h after METH dosing was significantly increased in mAb7F9-treated rats after all METH challenges. On days 24 and 28 (the final day), the rats were administered a 3-fold higher METH dose (1.68 mg/kg). MAb7F9 treated rats showed a substantially earlier termination of the METH-induced locomotion on both days, even though the METH dose exceeded mAb7F9s binding capacity. METH brain concentrations determined 5h after METH on day 28 were also significantly decreased in mAb7F9-treated rats. In conclusion, over one month, mAb7F9 significantly and continuously bound METH and reduced METH-induced locomotor effects even after discontinuation of mAb treatment and challenge with higher METH doses., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: The diagnosis of pheochromocytoma relies on the measurement of plasma free metanephrines assay whose reliability has been considerably improved by ultra-high pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Here we report an analytical interference occurring between 4-hydroxy-3-methoxymethamphetamine (HMMA), a metabolite of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"), and normetanephrine (NMN) since they share a common pharmacophore resulting in the same product ion after fragmentation., Design and Methods: Synthetic HMMA was spiked into plasma samples containing various concentrations of NMN and the intensity of the interference was determined by UPLC-MS/MS before and after improvement of the analytical method., Results: Using a careful adjustment of chromatographic conditions including the change of the UPLC analytical column, we were able to distinguish both compounds. HMMA interference for NMN determination should be seriously considered since MDMA activates the sympathetic nervous system and if confounded with NMN may lead to false-positive tests when performing a differential diagnostic of pheochromocytoma., (Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

These studies examined the in vivo pharmacokinetics and efficacy of five anti-methamphetamine monoclonal antibodies (mAbs, K(D) values from 11 to 250 nM) in rats. While no substantive differences in mAb systemic clearance (t(1/2)=6.1-6.9 days) were found, in vivo function was significantly reduced within 1-3 days for four of the five mAbs. Only mAb4G9 was capable of prolonged efficacy, as judged by prolonged high methamphetamine serum concentrations. MAb4G9 also maintained high amphetamine serum concentrations, along with reductions in methamphetamine and amphetamine brain concentrations, indicating neuroprotection. The combination of broad specificity for methamphetamine-like drugs, high affinity, and prolonged action in vivo suggests mAb4G9 is a potentially efficacious medication for treating human methamphetamine-related medical diseases.

The purpose of these studies was to determine if a high-affinity, anti-(+)-methamphetamine (METH) monoclonal antibody (mAb6H4; KD=11 nM) protects against METH-induced central nervous and cardiovascular system effects in rats. Rats (n=5 per group) received one of three anti-METH mAb6H4 doses, equal to 0.32, 0.56 or 1 times the mole equivalent (mol-eq) amount of METH in the body following a 1 mg/kg i.v. METH dose. Each rat was challenged with METH (1 mg/kg, i.v.) 1 and 4 days after the anti-METH mAb dose. The 1 mol-eq anti-METH mAb dose significantly reduced the duration of METH-induced locomotor activity (horizontal locomotion and rearing events), heart rate and blood pressure effects from 2 to 3 h to about an hour. This resulted in a significant reduction in total locomotor activity and the area under the hemodynamic effect vs. time curve for heart rate and blood pressure. In addition, the time to peak locomotor activity was decreased after the 1 mol-eq mAb dose vs. the lower doses. These changes were limited to the first METH challenge. The responses to the second METH challenge were not different from baseline. The peak hemodynamic and locomotor activity values were unchanged after both challenges. These results indicate anti-METH mAb6H4 can safely reduce the hemodynamic and locomotor effects of METH given one day after anti-METH IgG, and that the mAb is safe when administered in the absence of METH. These results are important because they indicate these antibody medications have simultaneous beneficial effects in multiple organ systems.

Methamphetamine is a psychomotor stimulant, whereas first generation antihistamines cause sedation. Several studies have demonstrated that first generation antihistamines potentiate methamphetamine-induced psychomotor activation and two possible mechanisms have been postulated. One is blockage of the central histaminergic neuron system and the other is inhibition of dopamine reuptake. However, the exact mechanism is still controversial. In this study, we examined in behavioral tests the effects of selected antihistamines on methamphetamine-induced psychomotor activation in rats, and measured plasma and brain tissue concentrations of methamphetamine. We found that some antihistamines significantly potentiate methamphetamine-induced psychomotor activation in rats and that plasma and brain tissue concentrations of methamphetamine in rats treated with methamphetamine in combination with D-chlorpheniramine were markedly higher than those in rats treated with methamphetamine alone. These results suggest that the potentiating effects of antihistamines are due to not only central effects but also the alteration of the pharmacokinetics of methamphetamine.

Exposure to methamphetamine causes behavioral sensitization in experimental animals. However, the precise mechanism of this behavioral sensitization has not yet been fully elucidated. Accordingly, we evaluated the pharmacokinetic properties of methamphetamine in rats behaviorally sensitized to methamphetamine following its repeated administration (6 mg/kg, i.p., once a day for 5 days followed by a 21-day drug abstinence period). In the sensitized rats, methamphetamine (0.8 mg/kg)-induced locomotor activity was significantly enhanced, suggesting the successful establishment of behavioral sensitization to methamphetamine. Significant increases in the concentrations of methamphetamine in plasma and brain dialysate, as well as the delayed disappearance of methamphetamine from plasma, were observed in the sensitized rats after intravenous injection of methamphetamine (5 mg/kg). The tissue to plasma concentration ratio (Kp) of methamphetamine in lung and heart decreased in the sensitized rats. The renal excretion of methamphetamine, which is sensitive to several cations, was also decreased in the sensitized rats. Moreover, in the sensitized rats, the expression of organic cation transporter 3 (OCT3) mRNA was decreased in kidney, brain and heart as measured by reverse transcriptase-polymerase chain reaction (RT-PCR). Taken together, these results suggest that the behavioral outcome of sensitization to methamphetamine might, in part, be due to the increased levels of methamphetamine in plasma and brain extracellular areas, as well as an altered tissue distribution of methamphetamine associated with changes in the cation transport system.

A method capable of extracting and derivatizing methamphetamine (MA) and amphetamine (AM) in blood simultaneously was developed. In this method ethyl acetate, triethylamine and pentafluorobenzyl bromide were added to blood, the extraction and pentafluorobenzyl derivatization of MA and AM were performed simultaneously by heating and stirring on a hot place stirrer. Pentafluorobenzyl derivatives were determined by gas chromatography/chemical ionization-mass spectrometry (GC/CI-MS). Deuterium labeled MA and AM were used as internal standards. This method enabled an accurate and precise quantitative analysis from blood containing MA and AM. Excellent results were obtained for autopsy cases with possible MA.

The effects of nimodipine on the amphetamine- and methamphetamine-induced decrease in central tryptophan hydroxylase activity was examined. Rats were administered 4 or 5 injections of amphetamine or methamphetamine at 6-h intervals with or without nimodipine (1 mg/kg), and killed 1 or 18 h after the last drug administration. The decrease in hippocampal tryptophan hydroxylase activity induced by amphetamine and methamphetamine was potentiated by the administration of nimodipine. Moreover, while hippocampal tryptophan hydroxylase activity was not altered by 2.5 mg/kg methamphetamine alone, the coadministration of 1 mg/kg nimodipine decreased the enzymatic activity to 68% of control. The decrease in striatal tryptophan hydroxylase activity caused by these amphetamine analogues was not significantly altered by the coadministration of nimodipine. Interestingly, nimodipine increased hippocampal and striatal amphetamine concentrations to 187 and 162%, respectively, of the concentrations measured in animals treated with amphetamine alone. Nimodipine also increased by 2-fold the plasma concentration of methamphetamine and amphetamine measured 3 h after a single administration of methamphetamine, whereas the hippocampal concentrations of these compounds were raised to 354 and 516%, respectively, of that in animals treated with methamphetamine alone. These results suggest that nimodipine altered drug distribution and potentiated the methamphetamine-induced decrease in hippocampal tryptophan hydroxylase activity by increasing the cerebral methamphetamine concentration.