Sandbox Reserved 1474: Difference between revisions
No edit summary |
No edit summary |
||
| Line 67: | Line 67: | ||
Screening for anti(+)METH IgG response was conducted by radioimmunoassay (RIA)<ref name="Using hapten design to discover therapeutic monoclonal antibodies for treating methamphetamine abuse"/> in which radio labelled [(+)-3H] METH is competing with unlabelled (+)-METH and (+)-AMP for the binding site of Abs in a manner similar to what has been previously described<ref name ="Antibodies against arylcyclohexylamines and their similarities in binding specificity with the phencyclidine receptor"/>. An IC50 value was determined for each compound after fitting a sigmoidal curve to the data points<ref name="Pharmacodynamic mechanisms of monoclonal antibody-based antagonism of (+)-methamphetamine in rats"/><ref name="Using hapten design to discover therapeutic monoclonal antibodies for treating methamphetamine abuse"/>. | Screening for anti(+)METH IgG response was conducted by radioimmunoassay (RIA)<ref name="Using hapten design to discover therapeutic monoclonal antibodies for treating methamphetamine abuse"/> in which radio labelled [(+)-3H] METH is competing with unlabelled (+)-METH and (+)-AMP for the binding site of Abs in a manner similar to what has been previously described<ref name ="Antibodies against arylcyclohexylamines and their similarities in binding specificity with the phencyclidine receptor"/>. An IC50 value was determined for each compound after fitting a sigmoidal curve to the data points<ref name="Pharmacodynamic mechanisms of monoclonal antibody-based antagonism of (+)-methamphetamine in rats"/><ref name="Using hapten design to discover therapeutic monoclonal antibodies for treating methamphetamine abuse"/>. | ||
Anti-(+)METH mAb6H4 was reported with Kd = 11 | Anti-(+)METH mAb6H4 was reported with Kd = 11 NM <ref name="Pharmacodynamic mechanisms of monoclonal antibody-based antagonism of (+)-methamphetamine in rats"/>, having <.01% cross-reactivity with almost all compounds tested except for (+)-methylenedioxymethamphetamine (MDMA) which has just slightly higher relative affinity than METH (9 nM to 11nM)<ref name="Pharmacodynamic mechanisms of monoclonal antibody-based antagonism of (+)-methamphetamine in rats"/>. Besides (+)METH and (+)MDMA, the tested chemicals also include: (-)-METH, (+/-)-AMP,(-)-MDMA,4-OH METH, Pseudoephedrine, Ephedrine, Dopamine, Norepinephrine, Serotonin, Epinephrine.<ref name="Pharmacodynamic mechanisms of monoclonal antibody-based antagonism of (+)-methamphetamine in rats"/>It was also reported stereospecific<ref name="Pharmacodynamic mechanisms of monoclonal antibody-based antagonism of (+)-methamphetamine in rats"/>, having an approximately 100 times higher relative affinity for the plus form than the minus forms of these substances<ref name="Pharmacodynamic mechanisms of monoclonal antibody-based antagonism of (+)-methamphetamine in rats"/>. No significant cross activity has been observed in the test for other compounds<ref name="Pharmacodynamic mechanisms of monoclonal antibody-based antagonism of (+)-methamphetamine in rats"/> including methylenedioxyamphetamine, (+)-norpseudoephedrine, L-phenylephrine, (+)-phenylpropanolamine, beta-phenylethylamine, and tyramine<ref name="Pharmacodynamic mechanisms of monoclonal antibody-based antagonism of (+)-methamphetamine in rats"/>. | ||
====Effect of mAb6H4 on METH and AMP pharmacokinetics==== | |||
the t1/2lamdaZ of mAb6H4 is reported to be 8 days<>, and the METH induced behavior effects on locomotor effects is within 400 min after METH administration for the maximum dosage (3.0mg/kg) reported<>. Thus to compare the disposition of drugs with or without mAb6H4, AUC4.5h 38min was used because it was not possible to conduct complete pharmacokinetic profile for 8 days. | |||
For METH doses of 0.3mg/kg and 1 mg/kg in rats, administration of mAb6H4 has led to significantly higher serum concentrations corresponding to significantly lower brain concentration of METH<> during the time frame with the drug dose was less than the mAb6H4 binding capacity. It was obvious that mAb6H4 administration initially caused a rapid efflux of METH from the brain due to its high affinity, however, compared to METH concentration in the brain without mAb6H4, after 4.5 hours, there seems to be a very slight rebound of the concentration in the brain. The reason is unknown, and could be explained as slower redistribution of the drug from other tissues. Yet, however, at this point, even with the rebound, both the METH concentration in control and in the animals administered with mAb6H4 are well below the threshold associated with increased locomotor activity. | |||
mAb6H4 also appeared to have more mild effect to AMP<> because it had little cross activity with AMP in vitro. It was explained possibility because increased the amounts of METH in the serum available for metabolism. | |||
However, for METH dose of 3.0mg/kg, which was greater than the mAb6H4 binding capacity, METH induced locomotor effects appeared to be increased<>. Although there are possible explanations, the reason remained to be understood<>. The idea that mAb may slow the input of METH while prolonging exposure is proposed. | |||
==Clinical development== | ==Clinical development== | ||