Biology subjects

Javors, M. A.

Publications and source records attributed to Javors, M. A..

4 recordsLinked to original sources

bioRxiv2024

Cardiovascular and Locomotor Effects of Binary Mixtures of Common Bath Salts Constituents: Studies with Methylone, MDPV, and Caffeine in Rats

Background and PurposeThe use of "Bath Salts" drug preparations has been associated with high rates of toxicity and death. Preparations often contain mixtures of drugs including multiple synthetic cathinones or synthetic cathinones and caffeine; however, little is known about whether interactions among "Bath Salts" constituents contribute to the adverse effects often reported in users. Experimental ApproachThis study used adult male Sprague-Dawley rats to characterize the cardiovascular effects, locomotor effects, and pharmacokinetics of methylone, MDPV, and caffeine, administered alone and as binary mixtures. Dose-addition analyses were used to determine the effect levels predicted for a strictly additive interaction for each dose pair. Key ResultsMethylone, MDPV, and caffeine increased heart rate and locomotion, with methylone producing the largest increase in heart rate, MDPV producing the largest increase in locomotor activity, and caffeine being the least effective in stimulating heart rate and locomotor activity. MDPV and caffeine increased mean arterial pressure, with caffeine being more effective than MDPV. The nature of the interactions between methylone and MDPV tended toward sub-additivity for all endpoints, whereas interactions between MDPV or methylone and caffeine tended to be additive or sub-additive for cardiovascular endpoints, and additive or supra-additive for increases in locomotion. No pharmacokinetic interactions were observed between individual constituents, but methylone displayed non-linear pharmacokinetics at the largest dose evaluated. Conclusion and ImplicationsThese findings demonstrate that the composition of "Bath Salts" preparations can impact both cardiovascular and locomotor effects and suggest that such interactions among constituent drugs could contribute to the "Bath Salts" toxidrome reported by human users. What is already known"Bath Salts" preparations are associated with a sympathomimetic toxidrome in human users. What this study addsCharacterization of both pharmacokinetic and pharmacodynamic interactions between common "Bath Salts" constituents with regard to cardiovascular and locomotor effects. Clinical SignificanceThe vast majority of drug overdose deaths involve more than one substance. Though these studies focused on combinations of stimulant drugs, they provide direct evidence that the toxidrome resulting from multi-drug overdoses can be significantly different than would be expected for a single drug.

pharmacology and toxicology↗

bioRxiv2021

Phytochemical Nrf2 activator attenuates skeletal muscle mitochondrial dysfunction and impaired proteostasis in a preclinical model of musculoskeletal aging

Musculoskeletal dysfunction is an age-related syndrome associated with impaired mitochondrial function and proteostasis. However, few interventions have tested targeting two drivers of musculoskeletal decline. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that stimulates transcription of cytoprotective genes and improves mitochondrial function. We hypothesized daily treatment with a Nrf2 activator in Hartley guinea pigs, a model of age-related musculoskeletal dysfunction, attenuates the progression of skeletal muscle mitochondrial dysfunction and impaired proteostasis, preserving musculoskeletal function. We treated 2-month- and 5-month-old male and female Hartley guinea pigs for 3 and 10 months, respectively, with the phytochemical Nrf2 activator PB125 (Nrf2a). Longitudinal assessments of voluntary mobility were measured using Any-Maze open-field enclosure monitoring. Cumulative skeletal muscle protein synthesis rates were measured using deuterium oxide over the final 30 days of treatment. Mitochondrial oxygen consumption in permeabilized soleus muscles was measured using ex vivo high resolution respirometry. In both sexes, Nrf2a 1) increased electron transfer system capacity; 2) attenuated the disease/age-related decline in coupled and uncoupled mitochondrial respiration; and 3) attenuated declines in protein synthesis in the myofibrillar, mitochondrial, and cytosolic subfractions of the soleus. These improvements were not associated with statistically significant prolonged maintenance of voluntary mobility in guinea pigs. Collectively, these results demonstrate that treatment with an oral Nrf2 activator contributes to maintenance of skeletal muscle mitochondrial function and proteostasis in a pre-clinical model of musculoskeletal decline. Further investigation is necessary to determine if these improvements are also accompanied by slowed progression of other aspects of musculoskeletal decline.

physiology↗

bioRxiv2021

Pharmacokinetics of long-term low-dose oral rapamycin in four healthy middle-aged companion dogs

ObjectiveTo determine the blood concentration and pharmacokinetic parameters of rapamycin in companion dogs following long-term, low-dose oral administration of rapamycin. AnimalsFour healthy, middle-aged, medium-to-large breed privately owned dogs participated. ProceduresAll dogs had been receiving oral rapamycin at a dose of 0.025 mg/kg on Monday, Wednesday, and Friday mornings for at least one month. An initial blood sample was collected prior to morning rapamycin administration, and samples were collected at 1, 2, 6, and 24 hours after rapamycin was given. Blood samples were transferred to blood spot collection cards, air-dried and stored at -80{degrees}C. Rapamycin concentrations were determined via HPLC/MS. All blood collections occurred on Wednesdays, so that the previous dose of rapamycin had taken place 48 hours prior to blood collection. ResultsFor all dogs, rapamycin Tmax was 2 hours. Median Cmax was 1.47 ng/ml (0.912 - 2.13), and the median AUC0-last was 15.7 ng*hr/mL (1.30 - 36.3). Due to sample size and timing, the only estimates related to elimination rate reported are for mean residence time with a median of 4.70 hrs (0.90 - 7.30). Conclusions and Clinical RelevanceA 0.025 mg/kg oral dose of rapamycin, administered three times a week, resulted in concentrations of rapamycin in the blood capable of being measured in ng/ml.

pharmacology and toxicology↗

bioRxiv2020

Canagliflozin Extends Lifespan in Genetically Heterogeneous Male But Not Female Mice

Canagliflozin (Cana) is an inhibitor of the sodium glucose transporter 2 (SGLT2), and is thought to act by blocking renal reuptake and intestinal absorption of glucose. Cana is FDA-approved for treatment of diabetes, and affords protection from cardiovascular and kidney diseases. In the context of the mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing 180 ppm Cana at 7 months of age until their death. Cana extended median survival of male mice by 14%, with p < 0.001 by log-rank test. Cana also increased by 9% the age for 90th percentile survival (p < 0.001 by Wang/Allison test), with parallel effects seen at each of three test sites. Cana did not alter the distribution of inferred cause of death, nor of incidental pathology findings at end-of-life necropsies. No benefits were seen in female mice. The lifespan benefit of Cana is likely to reflect blunting of peak glucose levels, because similar longevity effects are seen in mice given acarbose, a diabetes drug that blocks glucose surges through a distinct mechanism, i.e. slowing breakdown of carbohydrate in the intestine. Interventions that control daily peak glucose levels deserve attention as possible preventive medicines to protect from a wide range of late-life neoplastic and degenerative diseases.Competing Interest StatementThe authors have declared no competing interest.View Full Text

pathology↗