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Invertebrate animal studies of methamphetamine (METH) could allow for high throughput, inexpensive, and high-animal number pharmacology and toxicology studies. We hypothesized that in Periplaneta americana cockroaches, METH would increase locomotion compared to saline and produce lethality. Lethal dose, 50% (LD50) was determined with 0–1,780 µg/g (mg/kg) METH (n = 15–16/group) using logit analysis. Locomotor activity after METH (0–560 mg/kg, intra-abdominal, n = 8 per group) administration and spontaneous locomotor activity in surviving cockroaches in an open field 24 h after LD50 study doses was measured with Noldus Ethovision. The LD50 of METH was 823.1 mg/kg (more than 10-fold greater than the value in rats). There were significant decreases in spontaneous locomotor activity in surviving cockroaches after administration of 650 and 750 mg/kg METH (P < 0.05). While 100 mg/kg METH did not significantly increase METH locomotor activity relative to saline, 300 mg/kg METH significantly increased locomotor activity compared to saline (P < 0.05), and 560 mg/kg METH resulted in most of the cockroaches slowly moving around the open field in the supine position for most of the trial. In conclusion, METH produces pharmacological and toxicological effects in P. americana. The high availability, low cost, and relative ease of use of these animals makes them a potential, very accessible option for studying METH use disorder. [ABSTRACT FROM AUTHOR]

The standard circulating biomarker of liver injury in both clinical settings and drug safety testing is alanine aminotransferase (ALT). However, ALT elevations sometimes lack specificity for tissue damage. To identify novel serum biomarkers with greater specificity for injury, we combined unique animal models with untargeted proteomics, followed by confirmation with immunoblotting. Using proteomics, we identified 109 proteins in serum from mice with acetaminophen (APAP)-induced liver injury that were not detectable in serum from mice with benign ALT elevations due to high-dose dexamethasone (Dex). We selected 4 (alcohol dehydrogenase 1A1 [Aldh1a1], aldehyde dehydrogenase 1 [Adh1], argininosuccinate synthetase 1 [Ass1], and adenosylhomocysteinase [Ahcy]) with high levels for further evaluation. Importantly, all 4 were specific for injury when using immunoblots to compare serum from Dex-treated mice and mice with similar lower ALT elevations due to milder models of APAP or bromobenzene-induced liver injury. Immunoblotting for ALDH1A1, ADH1, and ASS1 in serum from APAP overdose patients without liver injury and APAP overdose patients with mild liver injury revealed that these candidate biomarkers can be detected in humans with moderate liver injury as well. Interestingly, further experiments with serum from rats with bile duct ligation-induced liver disease indicated that Aldh1a1 and Adh1 are not detectable in serum in cholestasis and may therefore be specific for hepatocellular injury and possibly even drug-induced liver injury, in particular. Overall, our results strongly indicate that ALDH1A1, ADH1, and ASS1 are promising specific biomarkers for liver injury. Adoption of these biomarkers could improve preapproval drug safety assessment. [ABSTRACT FROM AUTHOR]

Invertebrate animal studies of methamphetamine (METH) could allow for high throughput, inexpensive, and high-animal number pharmacology and toxicology studies. We hypothesized that in Periplaneta americana cockroaches, METH would increase locomotion compared to saline and produce lethality. Lethal dose, 50% (LD50) was determined with 0-1,780 µg/g (mg/kg) METH (n = 15-16/group) using logit analysis. Locomotor activity after METH (0-560 mg/kg, intra-abdominal, n = 8 per group) administration and spontaneous locomotor activity in surviving cockroaches in an open field 24 h after LD50 study doses was measured with Noldus Ethovision. The LD50 of METH was 823.1 mg/kg (more than 10-fold greater than the value in rats). There were significant decreases in spontaneous locomotor activity in surviving cockroaches after administration of 650 and 750 mg/kg METH (P < 0.05). While 100 mg/kg METH did not significantly increase METH locomotor activity relative to saline, 300 mg/kg METH significantly increased locomotor activity compared to saline (P < 0.05), and 560 mg/kg METH resulted in most of the cockroaches slowly moving around the open field in the supine position for most of the trial. In conclusion, METH produces pharmacological and toxicological effects in P. americana. The high availability, low cost, and relative ease of use of these animals makes them a potential, very accessible option for studying METH use disorder., (© The Author(s) 2020. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Developing specific medications to treat (+)-methamphetamine (METH) addiction is a difficult challenge because METH has multiple sites of action that are intertwined with normal neurological function. As a result, no small molecule medication for the treatment of METH addiction has made it through the FDA clinical trials process. With the invention of a new generation of proteinbased therapies, it is now possible to consider treating drug addiction by an entirely different approach. This new approach is based on the discovery of very high affinity anti-METH monoclonal antibodies (mAbs), which are non-addictive and antagonize METH effects from the blood stream without entering the brain. Due to a very long biological half-life, anti-METH mAbs would only need to be administered once every 2-4 weeks, aiding in patient compliance. As a relapse prevention medication, anti-METH mAbs could reduce or prevent the rewarding effects of a relapse to METH use and thereby improve a patient's probability of remaining in therapy and recovering from their addiction. In this review, we discuss the discovery process of anti-METH mAbs, with a focus on the preclinical development leading to high affinity anti-METH mAb antagonists.