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The growth in our knowledge of the diversity of the herpetofauna of Mexico has occurred over the period of approximately 445 years from the work of Francisco Hernández to that of a broad multinational array of present-day herpetologists. The work of this huge group of people has established Mexico as one of the most significant centers of herpetofaunal biodiversity in the world. This status is the result of a complex orography, in addition to diverse habitats and environments and the biogeographic history of Mexico. The current herpetofauna consists of 1,421 native and introduced species, allocated to 220 genera, and 61 families. This figure is comprised of 1,405 native species and 16 non-native species (as of April 2023). The non-native species include two anurans, 13 squamates, and one turtle. The level of endemism is very high, presently lying at 63%, with this level expected to increase with time. Species richness varies among the 32 federal entities in the country, from a low of 50 in Tlaxcala to a high of 492 in Oaxaca. Amphibian species richness by state-level can be envisioned as comprising three levels of low, medium, and high, with the lowest levels occurring in the Peninsula of Baja California, a group of seven states in north-central and central Mexico, and a group of three states in the Yucatan Peninsula, with the highest levels occupying the southern states of Guerrero, Puebla, Veracruz, Oaxaca, and Chiapas, and the medium level in the remaining states of the country. Reptile species richness also can be allocated to three categories, with the lowest level occupying Baja California Sur, a group of central states, and the states of the Yucatan Peninsula, and the highest level found in a cluster of the states of Veracruz, Guerrero, Oaxaca, and Chiapas. Knowledge of the Mexican herpetofauna will continue to grow with additional studies on systematics, conservation, and the construction of checklists at various levels.
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INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic impacted the ski industry worldwide by closing or limiting access to ski resorts. Subsequently, anecdotal reports of increased backcountry use emerged in the press, with concerns of inexperienced skiers causing or having problems in the backcountry. This study attempted to quantify this and identify motivations for new backcountry skiers. METHODS: Self-identified backcountry skiers and snowboarders (aged ≥18 y) in the United States and Canada completed an anonymous 29-question online survey distributed by regional avalanche centers, education providers, and skiing organizations (n=4792). Respondents were stratified by backcountry experience, defining "newcomers" who began backcountry skiing from 2019 to 2021, coincident with the COVID-19 pandemic. Percentages of ski days spent in the backcountry were compared before and during the COVID-19 pandemic using paired t-tests and across cohorts using repeated-measures analysis of variance. Avalanche education was compared using unpaired χ2 tests. RESULTS: Of established skiers, 81% noticed more people in the backcountry and 27% reported increasing their own use. Participants reported spending 17% (95% CI, 15.8-17.9) more of their days in the backcountry during the COVID-19 pandemic, with newcomers increasing their time spent by 36% and established skiers increasing their time spent by 13% (P<0.0001). Of newcomers, 27% cited the COVID-19 pandemic as motivation to enter the backcountry and 24% lacked formal avalanche education, which is significantly higher than the 14% of established skiers (P<0.0001). CONCLUSIONS: Influenced by factors related to COVID-19, reported backcountry use increased during the pandemic. Newcomers had a lower level of avalanche education and less confidence in evaluating terrain. Because 80% of participants were recruited from avalanche safety or education websites, this likely underestimates skiers lacking avalanche awareness or education and is further limited by the nature of online surveys.
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Traumatismos en Atletas , Avalanchas , COVID-19 , Esquí , Humanos , COVID-19/epidemiología , Pandemias , HábitosRESUMEN
Sex-determination systems are highly variable amongst vertebrate groups, and the prevalence of genomic data has greatly expanded our knowledge of how diverse some groups truly are. Gecko lizards are known to possess a variety of sex-determination systems, and each new study increases our knowledge of this diversity. Here, we used RADseq to identify male-specific markers in the banded gecko Coleonyx brevis, indicating this species has a XX/XY sex-determination system. Furthermore, we show that these sex-linked regions are not homologous to the XX/XY sex chromosomes of two related Coleonyx species, C. elegans and C. mitratus, suggesting that a cis-sex chromosome turnover-a change in sex chromosomes without a concomitant change in heterogamety-has occurred within the genus. These findings demonstrate the utility of genome-scale data to uncover novel sex chromosomes and further highlight the diversity of gecko sex chromosomes.
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Caenorhabditis elegans , Lagartos , Animales , Masculino , Caenorhabditis elegans/genética , Cromosomas Sexuales/genética , Lagartos/genética , Genoma , Genómica , Procesos de Determinación del SexoRESUMEN
A substantial number of changes to the composition of the herpetofauna of the Mexican state of Oaxaca, including taxonomic additions and deletions, have occurred in the five years since our original assessment of this region. These changes now establish a herpetofauna of 480 species for the state. A number of taxonomic and nomenclatural changes involving the Oaxacan herpetofauna also are discussed. Updated patterns of physiographic distribution, endemism, and conservation status of the members of the state herpetofauna are examined.
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Filogenia , Anfibios/clasificación , Animales , México , Reptiles/clasificaciónRESUMEN
Among the principal causes producing detrimental effects on global biodiversity are introductions of alien species. Very few attempts to control introduced amphibians and reptiles in Middle America (Mexico and Central America) can be identified, so listings are provided for 24 exotic species, 16 translocated species, and 11 species that were removed from the introduced species listing because of lack of substantiating evidence that they are from established populations. Biosecurity methods are also identified that can be applied for preventing, controlling, and managing introduced and especially invasive species.
ResumenEntre las principales causas que producen efectos perjudiciales sobre la biodiversidad mundial se encuentran la introducción de especies exóticas. Se pueden identificar muy pocos intentos de controlar anfibios y reptiles introducidos en América Central (México y América Central), por lo que proporcionamos listas de 24 especies exóticas, 16 especies translocadas y 11 especies que eliminamos de la lista de especies introducidas debido a la falta de evidencia que corrobore que provienen de poblaciones establecidas. También identificamos métodos de bioseguridad que se pueden aplicar para prevenir, controlar y gestionar especies introducidas y especialmente invasoras.
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Habitat heterogeneity and local resource distribution play key roles in animal search patterns. Optimal strategies are often considered for foraging organisms, but many of the same predictions are applicable to mate searching. We quantified movement and space use by a pitviper to test whether Native Habitats (NH) and human-made Resource Hotspots (RH) facilitate alternative seasonal spatial strategies as a result of critical resources, including potential mating partners, being widely dispersed in NH and clustered in RH. Independent of habitat category, seasonal patterns resembled an intermediate mating system with elements of prolonged male mate-searching and female-defense. However, individuals using primarily NH or RH exhibited alternative strategies. NH rattlesnakes displayed greater movement and larger home ranges than RH rattlesnakes across behavioral seasons. NH males increased movement distances and home ranges during the mating season, while RH males displayed minimal or no seasonal shifts. NH females also elevated movement distances during the mating season, while RH females showed no significant seasonal differences. Despite contrasting spatial patterns, mating success and female-defense effort were not significantly affected by habitat category. This unique study system highlights the potential for interactions among sexual selection, habitat heterogeneity, and behavioral plasticity to facilitate divergent search tactics within populations.
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Migración Animal , Ecosistema , Ambiente , Preferencia en el Apareamiento Animal , Reproducción , Estaciones del Año , Viperidae/fisiología , Distribución Animal , Animales , Femenino , Geografía , Humanos , Masculino , Análisis EspacialRESUMEN
Male Hartley guinea pigs and male rhesus macaques were used to determine an efficacious dose of 1,1'-methylenebis{4-[(hydroxyimino)methyl] pyridinium} dimethanesulfonate (MMB4 DMS) that would result in 80% survival, 24 hours following a single exposure to cyclosarin (GF). The pharmacokinetic/pharmacodynamic relationship between acetylcholinesterase activity and MMB4 plasma concentrations relative to survival was evaluated. Guinea pigs and non-human primates (NHPs) were concurrently administered MMB4 DMS (guinea pigs: 0, 10, 30, or 40 mg/kg, intramuscular [IM] and NHPs: 0.1, 1, 5, 10, or 20 mg/kg, IM), atropine, and diazepam following a 3 × median lethal dose (LD50) GF challenge. Clinical observations were evaluated using a quality-of-life (QOL) scoring system. All GF-exposed animals exhibited typical signs of nerve agent poisoning immediately following challenge. In guinea pigs, 24-hour survival was 0%, 50%, 90%, and 90% for 0, 10, 30, and 40 mg/kg MMB4 DMS groups, respectively. In addition, nearly all animals surviving to 24 hours were clinically normal, with many in the 30 and 40 mg/kg MMB4 DMS dose group observed as normal by 4 hours post-challenge. In NHPs, survival was 100% for all treatment groups, with all animals noted as clinically normal by 48 hours. Following treatment with atropine/MMB4 DMS/diazepam, NHPs exhibited dose- and temporal-related decreases in incidence and duration of the clinical signs of toxicity. The QOL scores improved with increasing MMB4 DMS dose in both species. The estimated ED80s were 25.5 mg/kg MMB4 DMS (human equivalent dose [HED] of 5.5 mg/kg) and ≤ 0.1 mg/kg (HED of 0.03 mg/kg) in guinea pigs and NHPs, respectively.
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Antídotos/farmacocinética , Antídotos/uso terapéutico , Compuestos Organofosforados/toxicidad , Oximas/farmacocinética , Oximas/uso terapéutico , Animales , Antídotos/administración & dosificación , Atropina/uso terapéutico , Inhibidores de la Colinesterasa/toxicidad , Diazepam/uso terapéutico , Relación Dosis-Respuesta a Droga , Cobayas , Macaca mulatta , Masculino , Oximas/administración & dosificaciónRESUMEN
Organophosphorus (OP) nerve agents pose tremendous threats to both military and civilian populations. The substance 1,1'-methylenebis[4-[(hydroxyimino)methyl]-pyridinium] (MMB4) is being developed as a replacement for the currently fielded 2-pyridine aldoxime, or pralidoxime (2-PAM) as a treatment for OP nerve agent-induced toxicity. The present study characterized pharmacokinetic (PK) profiles of MMB4 in male and female Sprague-Dawley rats, New Zealand White rabbits, and beagle dogs given a single intravenous (IV) administration of MMB4 dimethanesulfonate (DMS) at 55, 25, and 15 mg/kg dose, respectively. The plasma MMB4 concentration versus time profiles were biphasic for all species tested and fit a 2-compartment model with first-order elimination. There were no overt sex-related differences in the calculated PK parameters. For the rat, rabbit, and dog, the average systemic exposure parameters predicted Cmax (µg/mL) and AUC∞ (µg·h/mL) were 273 and 71.0, 115 and 48.1, and 87.4 and 39.6; the average volume of distribution (mL/kg) values to the central and peripheral compartments were 207 and 143, 242 and 172, and 198 and 213; and the average elimination half-life (hour) and clearance (mL/h/kg) values were 0.18 and 778, 0.29 and 577, and 0.32 and 430, respectively, when the PK parameters for males and females were combined. The current study revealed a similarity in the volume of distribution to the central compartment for MMB4 among the 3 species tested while demonstrating species-related differences in the elimination half-life and clearance of MMB4.
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Antídotos/administración & dosificación , Antídotos/farmacocinética , Oximas/administración & dosificación , Oximas/farmacocinética , Animales , Área Bajo la Curva , Perros , Femenino , Semivida , Inyecciones Intravenosas , Masculino , Estructura Molecular , Conejos , Ratas , Ratas Sprague-DawleyRESUMEN
1,1'-Methylenebis[4-[(hydroxyimino)methyl]-pyridinium] (MMB4) dimethanesulfonate (DMS) is a bisquaternary pyridinium aldoxime that reactivates acetylcholinesterase inhibited by organophosphorus nerve agent. Time courses of MMB4 concentrations in plasma were characterized following 7-day repeated intramuscular (IM) administrations of MMB4 DMS to male and female Sprague-Dawley rats, New Zealand White rabbits, beagle dogs (single dose only), and rhesus monkeys at drug dose levels used in earlier toxicology studies. In general, there were no significant differences in MMB4 toxicokinetic (TK) parameters between males and females for all the species tested in these studies. After a single IM administration to rats, rabbits, dogs, and monkeys, MMB4 DMS was rapidly absorbed, resulting in average T max values ranging from 5 to 30 minutes. Although C max values did not increase dose proportionally, the overall exposure to MMB4 in these preclinical species, as indicated by area under the curve (AUC) extrapolated to the infinity (AUC∞) values, increased in an approximately dose-proportional manner. The MMB4 DMS was extensively absorbed into the systemic circulation after IM administration as demonstrated by greater than 80% absolute bioavailability values for rats, rabbits, and dogs. Repeated administrations of MMB4 DMS for 7 days did not overtly alter TK parameters for MMB4 in rats, rabbits, and monkeys (150 and 300 mg/kg/d dose groups only). However, C max and AUC values decreased in monkeys given 450 and 600 mg/kg IM doses of MMB4 DMS following repeated administrations for 7 days. Based on the TK results obtained from the current study and published investigations, it was found that the apparent volume of distribution and clearance values were similar among various preclinical species, except for the rat.
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Antídotos/farmacocinética , Antídotos/toxicidad , Oximas/farmacocinética , Oximas/toxicidad , Animales , Antídotos/administración & dosificación , Perros , Esquema de Medicación , Femenino , Inyecciones Intramusculares , Macaca mulatta , Masculino , Oximas/administración & dosificación , Oximas/sangre , Conejos , Ratas , Ratas Sprague-DawleyAsunto(s)
Antídotos/farmacología , Intoxicación por Organofosfatos/tratamiento farmacológico , Oximas/farmacología , Animales , Antídotos/metabolismo , Antídotos/farmacocinética , Sustancias para la Guerra Química/toxicidad , Aprobación de Drogas , Humanos , Oximas/metabolismo , Oximas/farmacocinética , Estados UnidosRESUMEN
Studies were conducted in Sprague-Dawley rats, New Zealand White (NZW) rabbits, and rhesus monkeys to characterize the toxicity of 1,1'-methylenebis[4-[(hydroxyimino)methyl]-pyridinium] dimethanesulfonate (MMB4 DMS) following intramuscular administration. Rats received MMB4 DMS once daily for 7 days at 100, 200, 400, and 800 mg/kg/d; rabbits received a range of dose levels in 3 separate 7-day studies from 3 to 800 mg/kg/d and in a single-dose study from 50 to 200 mg/kg; and monkeys received MMB4 DMS at 150 to 600 mg/kg/d. Mortality was noted in rats and rabbits administered ≥ 200 mg/kg. All monkeys survived until scheduled termination. Adverse clinical observations were noted in the rats at ≥ 400 mg/kg/d and in rabbits administered ≥ 200 mg/kg; no adverse findings were noted in the monkeys. Clinical pathology changes were noted in the rabbit related to cardiac and renal function. In the rabbit and monkey, elevations in myoglobin, alanine aminotransferase/aspartate aminotransferase, platelets, creatine kinase, and coagulation factors were related to local inflammation at the intramuscular administration site. Light microscopic examination at the injection sites revealed acute skeletal muscle necrosis in vehicle control and treated groups. Target tissues in the rabbit studies were identified as kidney, heart, and lungs at ≥ 100 mg/kg/d. All changes noted in all the species demonstrated partial to complete recovery comparable to control values or to a clinically irrelevant level of effect. The NZW rabbit was the most sensitive species, and the no observed adverse effect level (NOAEL) was determined as 50 mg/kg/d; the NOAEL in the rat was 100 mg/kg/d; and the NOAEL in rhesus monkeys was >600 mg/kg/d.
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Antídotos/toxicidad , Oximas/toxicidad , Acetilglucosaminidasa/genética , Acetilglucosaminidasa/metabolismo , Animales , Antídotos/administración & dosificación , Peso Corporal/efectos de los fármacos , Creatina Quinasa/genética , Creatina Quinasa/metabolismo , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Macaca mulatta , Masculino , Mioglobina/genética , Mioglobina/metabolismo , Oximas/administración & dosificación , Conejos , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Troponina I/genética , Troponina I/metabolismoRESUMEN
1,1'-Methylenebis[4-[(hydroxyimino)methyl]-pyridinium] (MMB4) dimethanesulfonate (DMS) is a bisquaternary pyridinium aldoxime that reactivates acetylcholinesterase inhibited by organophosphorus nerve agent. Drug metabolism and plasma protein binding for MMB4 DMS were examined using various techniques and a wide range of species. When (14)C-MMB4 DMS was incubated in liver microsomes, 4-pyridine aldoxime (4-PA) and an additional metabolite were detected in all species tested. Identity of the additional metabolite was postulated to be isonicotinic acid (INA) based on liquid chromatography with a tandem mass spectrometry analysis, which was confirmed by comparison with authentic INA. Formation of INA was dependent on species, with the highest level found in monkey liver microsomes. The MMB4 DMS exhibited reversible inhibition in a concentration-dependent manner toward cytochrome P450 1A2 (CYP1A2), CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in human liver microsomes showing the highest inhibition for CYP2D6. Human recombinant CYPs were used to evaluate inhibitory curves more adequately and determine detailed kinetic constants for reversible inhibition and potential time-dependent inhibition (TDI). The MMB4 DMS exhibited reversible inhibition toward human-recombinant CYP2D6 with an inhibition constant (K i) value of 66.6 µmol/L. Based on the k inact/K I values, MMB4 DMS was found to exhibit the most potent TDI toward CYP2D6. The MMB4 DMS at 5 different concentrations was incubated in plasma for 5 hours using an equilibrium dialysis device. For all species tested, there were no concentration-dependent changes in plasma protein binding, ranging from 10% to 17%. These results suggest that MMB4 was not extensively bound to plasma protein, and there were no overt species-related differences in the extent of MMB4 bound to plasma protein.
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Antídotos/farmacología , Proteínas Sanguíneas/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Oximas/farmacología , Unión Proteica/fisiología , Animales , Proteínas Sanguíneas/química , Interacciones Farmacológicas , Haplorrinos , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Conejos , Ratas , Especificidad de la Especie , Factores de TiempoRESUMEN
1,1'-Methylenebis[4-[(hydroxyimino)methyl]-pyridinium] dimethanesulfonate (MMB4 DMS) is currently under development for the treatment of chemical warfare organophosphorus nerve agent poisoning. The present study evaluates the absorption, distribution, metabolism, and excretion of (14)C-MMB4 DMS administered intramuscularly to rats and rabbits. The formulated mixture of radiolabeled and nonradiolabeled MMB4 DMS was administered as a single or 7-day repeated dose. Rat doses were 55 or 220 mg/kg (100 µCi/kg), and rabbit doses were 25 or 100 mg/kg (31.25 and 62.5 µCi/kg, respectively). Urine, bile (rats only), feces, blood, and tissues were collected for up to 72 hours. Metabolic profiling using high-performance liquid chromatography with radiodetection was performed on selected urine samples. For both animal species, the majority of the total radioactivity was excreted in the urine (74%-94%) by 72 hours after dosing with greater than 90% of the radioactivity measured in the urine within 8 to 12 hours after dosing. There were no apparent species or dose differences in the urine excretion pattern. The distribution of (14)C-MMB4 DMS-derived radioactivity was rapid and generally reached the highest concentration by the first collection time point (0.25 hours). The tissue-blood concentration ratios were highest at the injection sites and in the kidneys and gastrointestinal tract contents for both the species. Two metabolites of MMB4 DMS were detected in rat and rabbit urine; their structure was confirmed by liquid chromatography with tandem mass spectrometry as 4-pyridine aldoxime and isonicotinic acid (pyridine-4-carboxylic acid).
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Antídotos/farmacocinética , Oximas/farmacocinética , Animales , Antídotos/administración & dosificación , Antídotos/química , Radioisótopos de Carbono , Heces/química , Femenino , Inyecciones Intramusculares , Masculino , Estructura Molecular , Oximas/administración & dosificación , Oximas/química , Proyectos Piloto , Conejos , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Distribución TisularRESUMEN
Acetylcholinesterase (AChE) reactivation studies were conducted in guinea pigs (GPs) and nonhuman primates (NHPs) to determine the 1,1'-methylenebis{4-[(hydroxyimino)methyl] pyridinium} dimethanesulfonate (MMB4 DMS) dose that reactivated at least 20% of blood AChE within 15 minutes following cyclosarin (GF) dosing (used as the criterion for efficacy). Male GPs and male rhesus macaques (NHPs) were pretreated with atropine 15 minutes prior to GF administration (1 × median lethal dose [LD50]) and MMB4 DMS 15 minutes following GF administration. The GP survival was 5 of 8, 8 of 8, 8 of 8, and 6 of 8 for the 0.75, 3.0, 6.0, or 12.0 mg/kg MMB4 DMS treatment groups, respectively. In NHPs, survival was 6 of 6 at 0.5, 1.2, 3.0, or 9.3 mg/kg MMB4 DMS, respectively, 24 hours post-challenge, with the majority of animals noted as clinically normal by 24 hours. Pharmacokinetic/pharmacodynamic modeling revealed that 1.8 mg/kg in GPs or 0.013 mg/kg in NHPs would result in an average 20% reactivation; human equivalent doses were calculated as 0.39 mg/kg (based on GP data) and 0.004 mg/kg (based on NHP data). The model suggested that MMB4 plasma concentrations of 1000 ng/mL and AChE reactivation of 80% would be most effective. Although a 0.5 mg/kg MMB4 DMS dose in NHPs resulted in 100% survival and an average of 78% AChE reactivation, adverse effects associated with GF administration were still observed 24 hours post-challenge (tremors, mydriasis, and weakness were observed in 3 of 6 animals). In comparison, 6 of 6 animals treated with 1.2 mg/kg MMB4 DMS were observed as clinically normal 24 hours post-challenge.
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Acetilcolinesterasa/metabolismo , Antídotos/uso terapéutico , Inhibidores de la Colinesterasa/toxicidad , Compuestos Organofosforados/toxicidad , Oximas/uso terapéutico , Animales , Antídotos/administración & dosificación , Cobayas , Dosificación Letal Mediana , Macaca mulatta , Masculino , Oximas/administración & dosificación , Oximas/sangreRESUMEN
Plants containing thujone have widespread use and hence have significant human exposure. α-Thujone caused seizures in rodents following gavage administration. We investigated the toxicokinetics of α-thujone in male and female F344/N rats and B6C3F1 mice following intravenous and gavage administration of α-thujone or a mixture of α- and ß-thujone (which will be referred to as α,ß-thujone). Absorption of α-thujone following gavage administration was rapid without any dose-, species-, sex- or test article-related effect. Absolute bioavailability of α-thujone following administration of α-thujone or α,ß-thujone was generally higher in rats than in mice. In rats, females had higher bioavailability than males following administration of either test article although a sex difference was not observed in mice. Cmax and AUC∞ increased greater than proportional to the dose in female rats following administration of α-thujone and in male and female mice following administration of α,ß-thujone suggesting possible saturation of elimination kinetics with increasing dose. Dose-adjusted AUC∞ for male and female rats was 5- to 15-fold and 3- to 24-fold higher than mice counterparts following administration of α-thujone and α,ß-thujone, respectively (p-value<0.0001 for all comparisons). Following both intravenous and gavage administration, α-thujone was distributed to the brains of rats and mice with females, in general, having higher brain:plasma ratios than males. These data are in support of the observed toxicity of α-thujone and α,ß-thujone where females were more sensitive than males of both species to α-thujone-induced neurotoxicity. In general there was no difference in toxicokinetics between test articles when normalized to α-thujone concentration.
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Monoterpenos/toxicidad , Algoritmos , Animales , Área Bajo la Curva , Monoterpenos Bicíclicos , Disponibilidad Biológica , Química Encefálica/efectos de los fármacos , Química Farmacéutica , Interpretación Estadística de Datos , Femenino , Cromatografía de Gases y Espectrometría de Masas , Semivida , Inyecciones Intravenosas , Intubación Gastrointestinal , Isomerismo , Masculino , Ratones , Ratones Endogámicos , Monoterpenos/administración & dosificación , Monoterpenos/farmacocinética , Farmacocinética , Ratas , Ratas Endogámicas F344RESUMEN
1. Isoeugenol (IEG) has been tested for toxicity and carcinogenicity due to high potential for human exposure and the structural resemblance to known carcinogenic allylbenzenes. In order to support the interpretation of toxicity and carcinogenecity study outcomes, a toxicokinetic study was performed in which both sexes of F344 rats and B6C3F1 mice were given IEG as a single intravenous (IV) or gavage administration. 2. Following IV administration, IEG was rapidly eliminated from systemic circulation in both species and sexes. Gavage administration revealed a rapid absorption of IEG with tmax values ≤20 min for both species and sexes. In rats, AUC increased in a greater than dose-proportional manner and Clapp values decreased with increasing dose in both sexes suggesting saturation of IEG metabolism. On the other hand, Clapp values in male mice increased with increasing dose suggesting induction of IEG metabolism although this was not evident in the females. 3. Absolute bioavailability was greater in female rats (19%) than male rats (10%) (p < 0.0001), but was not different between the sexes for mice (28% males; 31% females) (p = 0.2437). The collective toxicokinetic data supported that low bioavailability following administration of IEG was the result of extensive first-pass metabolism.
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Eugenol/análogos & derivados , Administración Intravenosa , Animales , Disponibilidad Biológica , Aductos de ADN/metabolismo , Eugenol/administración & dosificación , Eugenol/sangre , Eugenol/metabolismo , Eugenol/farmacocinética , Eugenol/toxicidad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos , Ratas , Ratas Endogámicas F344 , Factores de TiempoRESUMEN
1. Methyleugenol (MEG) has been used as a flavouring agent in food, as a fragrance in cosmetic products, and as an insect attractant. MEG was carcinogenic in both rats and mice following gavage administration. In this study we investigated plasma toxicokinetics of MEG in F344 rats and B6C3F1 mice of both sexes following single gavage (37, 75, or 150 mg/kg) and intravenous (IV) (37 mg/kg) administration. 2. Following IV administration, MEG was rapidly distributed and cleared from the systemic circulation in both species and sexes. Absorption of MEG was rapid following gavage administration with secondary peaks in the plasma MEG concentration-versus-time profiles. C(max) and AUC(T) increased and the clearance decreased greater than proportional to the dose in rats and mice of both sexes. In general, rats had higher internal exposure to MEG than mice. 3. The results for AUC(T) and clearance suggest that perhaps the metabolism of MEG is saturated at higher doses tested in this study. Absolute bioavailability following gavage administration of 37 mg/kg was low in both rats (~4%) and mice (7-9%) of both sexes indicating extensive first-pass metabolism. There was no sex difference in plasma toxicokinetics of MEG following gavage administration both in rats and mice.
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Eugenol/análogos & derivados , Administración Intravenosa , Animales , Área Bajo la Curva , Disponibilidad Biológica , Eugenol/administración & dosificación , Eugenol/sangre , Eugenol/química , Eugenol/farmacocinética , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Farmacocinética , Ratas , Ratas Endogámicas F344 , Factores de TiempoRESUMEN
ST-20 (sodium 2,2-dimethylbutyrate) is a potential therapeutic agent for treatment of ß-thalassemia and sickle cell disease. A subchronic oral toxicity study was conducted in Sprague-Dawley rats (10/sex/dose) at gavage dosages of 0 (vehicle control), 200, 600, or 1,000 mg/kg, once daily for up to 15 days followed by a 14-day recovery. Ataxia (females), rough coat/thin appearance (males), and decreased body weights were observed at 1,000 mg/kg. Functional observational battery (FOB) deficits were observed more frequently in females and included decreased body tone, rectal temperature, emotional reactivity, neuromotor-neuromuscular activity (as exhibited by a deficit in visual/tactile placing accuracy, ataxia, hind limb dragging, and decreased grip strength), and rearing. ST-20 caused a decrease in WBC/RBC counts and RBC parameters; increase in reticulocytes and red cell inclusion bodies; decrease in total protein, globulin, and glucose; and increase in AG ratio. Micronucleated polychromatic erythrocytes of the bone marrow increased significantly in males at 1,000 mg/kg. Mean liver and kidney weights increased, and hepatocellular hypertrophy was observed in males at 1,000 mg/kg. Toxicologic findings were fully recovered during the 14-day recovery period. In conclusion, the no-observed adverse effect level for FOB and general toxicity was 200 mg/kg following gavage administration of ST-20 for up to 15 consecutive days.
Asunto(s)
Butiratos/toxicidad , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Reticulocitos/efectos de los fármacos , Pruebas de Toxicidad Aguda/métodos , Administración Oral , Animales , Peso Corporal , Butiratos/farmacología , Relación Dosis-Respuesta a Droga , Recuento de Eritrocitos , Femenino , Recuento de Leucocitos , Modelos Lineales , Masculino , Pruebas de Micronúcleos , Nivel sin Efectos Adversos Observados , Ratas , Ratas Sprague-DawleyRESUMEN
Midazolam in an autoinjector was evaluated in an open-label dose escalation study involving 39 healthy participants. Safety and pharmacokinetic parameters were determined for doses ranging from 5 to 30 mg. No serious adverse events were noted during the study. Two participants (30 mg) experienced changes in their electrocardiogram (trigeminy and prolongation of QRS complex) that met the criteria for dose-limiting adverse events. No significant respiratory depression was noted during the study. The midazolam doses studied exhibited a median t(max) of 0.5 hours with a geometric mean terminal elimination half-life value of 4.1 hours (range, 2.9-4.5 hours). The extent of systemic exposure, assessed by area under the curve (AUC) and maximum concentration (C(max)), tended to increase proportionally with increasing doses from 5 to 30 mg; however, for the male 30-mg group, there was evidence of a larger than proportional increase in AUC.
Asunto(s)
Hipnóticos y Sedantes/administración & dosificación , Hipnóticos y Sedantes/farmacocinética , Midazolam/administración & dosificación , Midazolam/farmacocinética , Adulto , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Hipnóticos y Sedantes/efectos adversos , Inyecciones Intramusculares , Masculino , Midazolam/efectos adversos , Factores SexualesRESUMEN
BACKGROUND: STAT3 overexpression has been detected in several cancers including head and neck squamous cell carcinoma (HNSCC). Previous studies using intratumoral administration of a STAT3 decoy oligonucleotide that abrogates STAT3-mediated gene transcription in preclinical cancer models have demonstrated antitumor efficacy. This study was conducted to observe the toxicity and biologic effects of the STAT3 decoy in a non-human primate model, in anticipation of initiating a clinical trial in HNSCC patients. METHODS: Three study groups (two monkeys/sex/group) were administered a single intramuscular injection of low dose of STAT3 decoy (0.8 mg total dose/monkey), high dose of STAT3 decoy (3.2 mg total dose/monkey) or vehicle control (PBS alone) on day 1 and necropsies were performed on days 2 and 15 (one monkey/sex/group/day). Low and high doses of the decoy were administered in the muscle in a volume of 0.9 ml. Tissue and blood were harvested for toxicology and biologic analyses. RESULTS: Upon observation, the STAT3 decoy-treated animals exhibited behavior that was similar to the vehicle control group. Individual animal body weights remained within 1% of pretreatment weights throughout the study. Hematological parameters were not significantly different between the control and the treatment groups. Clinical chemistry fluctuations were considered within normal limits and were not attributed to the STAT3 decoy. Assessment of complement activation breakdown product (Bb) levels demonstrated no activation of the alternative pathway of complement in any animal at any dose level. At necropsy, there were no gross or microscopic findings attributed to STAT3 decoy in any organ examined. STAT3 target gene expression at the injection site revealed decreased Bcl-X(L) and cyclin D1 expression levels in the animals treated with high dose of STAT3 decoy compared to the animals injected with low dose of STAT3 decoy or the vehicle as control. CONCLUSION: Based on these findings, the no-observable-adverse-effect-level (NOAEL) was greater than 3.2 mg/kg when administered as a single dose to male and female Cynomolgus monkeys. Plans are underway to test the safety and biologic effects of intratumoral administration of the STAT3 decoy in HNSCC patients.