RESUMEN
GDF15 and its receptor GFRAL/RET form a non-homeostatic system that regulates food intake and body weight in preclinical species. Here, we describe a GDF15 analog, LY3463251, a potent agonist at the GFRAL/RET receptor with prolonged pharmacokinetics. In rodents and obese non-human primates, LY3463251 decreased food intake and body weight with no signs of malaise or emesis. In a first-in-human study in healthy participants, single subcutaneous LY3463251 injections showed a safety and pharmacokinetic profile supporting further clinical development with dose-dependent nausea and emesis in a subset of individuals. A subsequent 12-week multiple ascending dose study in overweight and obese participants showed that LY3463251 induced significant decreases in food intake and appetite scores associated with modest body weight reduction independent of nausea and emesis (clinicaltrials.gov: NCT03764774). These observations demonstrate that agonism of the GFRAL/RET system can modulate energy balance in humans, though the decrease in body weight is surprisingly modest, suggesting challenges in leveraging the GDF15 system for clinical weight-loss applications.
Asunto(s)
Obesidad , Pérdida de Peso , Animales , Humanos , Peso Corporal , Obesidad/tratamiento farmacológico , Vómitos , Factor 15 de Diferenciación de CrecimientoRESUMEN
Pharmaceutic products designed to perturb the function of epigenetic modulators have been approved by regulatory authorities for treatment of advanced cancer. While the predominant effort in epigenetic drug development continues to be in oncology, non-oncology indications are also garnering interest. A survey of pharmaceutical companies was conducted to assess the interest and concerns for developing small molecule direct epigenetic effectors (EEs) as medicines. Survey themes addressed (1) general levels of interest and activity with EEs as therapeutic agents, (2) potential safety concerns, and (3) possible future efforts to develop targeted strategies for nonclinical safety assessment of EEs. Thirteen companies contributed data to the survey. Overall, the survey data indicate the consensus opinion that existing ICH guidelines are effective and appropriate for nonclinical safety assessment activities with EEs. Attention in the framework of study design should, on a case by case basis, be considered for delayed or latent toxicities, carcinogenicity, reproductive toxicity, and the theoretical potential for transgenerational effects. While current guidelines have been appropriate for the nonclinical safety assessments of epigenetic targets, broader experience with a wide range of epigenetic targets will provide information to assess the potential need for new or revised risk assessment strategies for EE drugs.
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Industria Farmacéutica/normas , Control de Medicamentos y Narcóticos , Epigénesis Genética/efectos de los fármacos , Preparaciones Farmacéuticas/normas , Encuestas y Cuestionarios , Animales , Evaluación Preclínica de Medicamentos/normas , Evaluación Preclínica de Medicamentos/tendencias , Industria Farmacéutica/tendencias , Control de Medicamentos y Narcóticos/tendencias , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Epigénesis Genética/genética , Humanos , Preparaciones Farmacéuticas/administración & dosificación , Medición de Riesgo/normas , Medición de Riesgo/tendenciasRESUMEN
To develop novel treatments for type 2 diabetes and dyslipidemia, we pursued inhibitors of serine palmitoyl transferase (SPT). To this end compounds 1 and 2 were developed as potent SPT inhibitors in vitro. 1 and 2 reduce plasma ceramides in rodents, have a slight trend toward enhanced insulin sensitization in DIO mice, and reduce triglycerides and raise HDL in cholesterol/cholic acid fed rats. Unfortunately these molecules cause a gastric enteropathy after chronic dosing in rats.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Imidazoles/farmacología , Piperidinas/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Serina C-Palmitoiltransferasa/antagonistas & inhibidores , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Humanos , Imidazoles/administración & dosificación , Imidazoles/química , Células MCF-7 , Masculino , Ratones , Ratones Obesos , Estructura Molecular , Piperidinas/administración & dosificación , Piperidinas/química , Pirazoles/administración & dosificación , Pirazoles/química , Piridinas/administración & dosificación , Piridinas/química , Ratas , Ratas Sprague-Dawley , Serina C-Palmitoiltransferasa/metabolismo , Relación Estructura-ActividadRESUMEN
Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator that represents a promising target for the treatment of several metabolic diseases. Administration of recombinant wild type FGF21 to diabetic animals leads to a dramatic improvement in glycaemia and ameliorates other systemic measures of metabolic health. Here we report the pharmacologic outcomes observed in non-human primates upon administration of a recently described FGF21 analogue, LY2405319 (LY). Diabetic rhesus monkeys were treated subcutaneously with LY once daily for a period of seven weeks. The doses of LY used were 3, 9 and 50 mg/kg each delivered in an escalating fashion with washout measurements taken at 2, 4, 6 and 8 weeks following the final LY dose. LY therapy led to a dramatic and rapid lowering of several important metabolic parameters including glucose, body weight, insulin, cholesterol and triglyceride levels at all doses tested. In addition, we observed favorable changes in circulating profiles of adipokines, with increased adiponectin and reduced leptin indicative of direct FGF21 action on adipose tissue. Importantly, and for the first time we show that FGF21 based therapy has metabolic efficacy in an animal with late stage diabetes. While the glycemic efficacy of LY in this animal was partially attenuated its lipid lowering effect was fully preserved suggesting that FGF21 may be a viable treatment option even in patients with advanced disease progression. These findings support continued exploration of the FGF21 pathway for the treatment of metabolic disease.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Factores de Crecimiento de Fibroblastos/farmacología , Adipoquinas/sangre , Animales , Glucemia/análisis , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Ingestión de Energía/efectos de los fármacos , Factores de Crecimiento de Fibroblastos/farmacocinética , Insulina/sangre , Macaca mulatta , Pérdida de Peso/efectos de los fármacosRESUMEN
Spontaneous ejaculation has been reported in a variety of mammalian species and may occur either as a result of pharmacological treatment or as a component of the daily behavior of normal, untreated animals. Infrequently, increased numbers of spontaneous ejaculatory plugs have been reported among the clinical signs in rat toxicology studies. This mini-review presents an overview on the presence of ejaculatory plugs in rodents and provides recommendations to consider when attempting to understand the toxicological significance of increased numbers of ejaculatory plugs in rat toxicology studies.
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Eyaculación/fisiología , Fenómenos Fisiológicos , Animales , Masculino , Observación , RatasRESUMEN
The carcinogenic potential of naveglitazar, a gamma-dominant peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual agonist, was evaluated in a two-year study in F344 rats (0, 0.3, 1.0, or 3.0 mg/kg, males; 0, 0.1, 0.3, or 1.0 mg/kg, females). Increased mortality in male rats of the high-dose group was related to cardiac-associated lesions, neoplasms, and undetermined causes. Degeneration and hypertrophy of the myocardium occurred with dose-responsive increased incidence and severity. Neoplasms with increased incidence included sarcomas in male rats and urinary bladder neoplasms in female rats. Most sarcomas in male rats occurred in the adipose tissue of the subcutis and were diagnosed as fibrosarcomas, with fewer liposarcomas and other histologic types. Non-neoplastic changes in adipose tissue included expansion of adipose tissue in multiple sites, alterations in cytoplasmic vesicular pattern in brown and white fat, increases in stroma and mesenchymal cells, and fibrosis. The severity of chronic progressive nephropathy was decreased in a dose-responsive manner in males, and hyperplasia and neoplasia of the mammary gland were decreased in incidence in females. The adverse effects of cardiotoxicity and increased incidence of neoplasms occurred with dose-responsive incidence and/or severity, and a no-effect level for these effects was not achieved in this study.
Asunto(s)
Pruebas de Carcinogenicidad/métodos , Neoplasias Experimentales/inducido químicamente , Fenilpropionatos/toxicidad , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/patología , Análisis de Varianza , Animales , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Genitales/patología , Histocitoquímica , Hiperplasia/inducido químicamente , Masculino , Neoplasias Experimentales/patología , PPAR alfa/agonistas , PPAR gamma/agonistas , Ratas , Ratas Endogámicas F344 , Sarcoma/inducido químicamente , Sarcoma/patología , Urotelio/patologíaRESUMEN
Naveglitazar, a gamma-dominant peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual agonist, was tested for carcinogenicity in F344 rats in a 2-year study. Changes in urine composition and urothelial morphology were characterized in a companion 18-month investigative study. A significant increase in neoplasms of the bladder occurred only in females of the high-dose group (14/60) in the carcinogenicity study. Trends toward increased cell proliferation in the urothelium were noted in both sexes at all time points evaluated in the 18-month study. Group means for urothelial mitogenesis were increased statistically significantly only in high-dose females at 12 and 18 months. Urothelial hyperplasia occurred in high-dose females at 18 months. Morphologic changes in the urothelium at earlier time points were limited to hypertrophy and decreased immunolabeling of the superficial cells for cytokeratin 20 (a marker of terminal differentiation in urothelial cells) in both males and females. No treatment-related changes in urinary parameters, including urinary sediments, were associated with the occurrence of urothelial proliferation. Urinary pH was unaffected by treatment in both males and females, but expected diurnal changes were demonstrated. Collectively, these data indicate that naveglitazar was associated with hypertrophic and proliferative effects on the urothelium, but a link with changes in urinary parameters was not demonstrated.
Asunto(s)
PPAR gamma/agonistas , Fenilpropionatos/toxicidad , Neoplasias de la Vejiga Urinaria/inducido químicamente , Vejiga Urinaria/efectos de los fármacos , Urolitiasis/inducido químicamente , Urotelio/efectos de los fármacos , Animales , Calcio/orina , Pruebas de Carcinogenicidad , Proliferación Celular/efectos de los fármacos , Cristalización , Relación Dosis-Respuesta a Droga , Femenino , Hiperplasia/inducido químicamente , Hiperplasia/patología , Longevidad/efectos de los fármacos , Masculino , Ratas , Ratas Endogámicas F344 , Urinálisis , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/patología , Urolitiasis/patología , Urotelio/patología , Urotelio/ultraestructuraRESUMEN
Octamethylcyclotetrasiloxane (D(4)) has been shown to have effects on the female rat reproductive cycle. This study evaluated the phase of the female rat reproductive cycle affected by D(4) using a study design that allowed the complete female reproductive cycle, as well as phases of the cycle, from pre-mating through gestation, to be evaluated. Rats were exposed via whole body vapor inhalation up to 700 ppm D(4) during the overall phase (28 days prior to mating through gestation day (GD) 19), the ovarian phase (31-3 days prior to mating), the fertilization phase (3 days prior to the start of mating through gestation day 3), and the implantation phase (GD 2-GD 5) of the reproductive cycle. D(4) was associated with decreases in implantation sites and litter size in the overall and fertilization phases, but not in the ovarian or implantation phases. In order to further define the sensitive period for D(4) exposure, additional groups of rats were exposed on single days. A single 6h exposure to D(4) on the day prior to mating resulted in a significant reduction in fertility. These data indicate that there is a very narrow window, around the time of ovulation and fertilization, for D(4) to exert effects on the reproductive cycle of the female rat. Subsequent research, reported elsewhere, has elucidated the mode of action and assessed its potential relevance to humans.
Asunto(s)
Adyuvantes Inmunológicos/toxicidad , Reproducción/efectos de los fármacos , Siloxanos/toxicidad , Administración por Inhalación , Animales , Implantación Tardía del Embrión/efectos de los fármacos , Femenino , Fertilidad/efectos de los fármacos , Exposición por Inhalación , Tamaño de la Camada/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
This two-generation reproduction study assessed the reproductive hazard potential of decamethylcyclopentasiloxane (D(5)). Sprague-Dawley rats (30/sex/group) were exposed by whole-body vapor inhalation to a target concentration of 30, 70, or 160 ppm D(5) or filtered air for 6h/day. Exposures for the F(0) and F(1) generations started at least 70 days prior to mating and lasted through weaning of the respective pups on postnatal day (PND) 21. Female exposures were interrupted from gestation day (GD) 21 through PND 4 to allow for parturition and to permit continuous maternal care for the early neonates. F(2) pups were not directly exposed to D(5). There were no exposure-related mortalities, clinical signs of toxicity, or effects on body weight or food consumption. There were no treatment-related gross findings or organ weight effects at the F(0) and F(1) necropsies. Other than minimal alveolar histiocytosis in all exposed groups, there were no noteworthy microscopic findings. Reproductive parameters (number of days between pairing and mating, mating and fertility indices, gestation length, and parturition), spermatogenic parameters and ovarian primordial follicle counts and numbers of corpora lutea in the F(0) and F(1) parental animals were not significantly changed between treated and control groups. Mean live litter sizes, number of pups born, sex ratios, pup body weights, postnatal pup survival and general physical condition of offspring in each generation were not affected. The slight, but statistically significant, increase in the mean F(1) male pup AGD in the 160 ppm group was not considered to be related to treatment. Vaginal patency and balanopreputial separation were unchanged compared to controls. Thus, the No-Observed-Adverse-Effect-Level (NOAEL) for parental and reproductive toxicity was determined to be 160 ppm D(5).
Asunto(s)
Reproducción/efectos de los fármacos , Siloxanos/toxicidad , Administración por Inhalación , Animales , Animales Recién Nacidos/crecimiento & desarrollo , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Fertilidad/efectos de los fármacos , Exposición por Inhalación , Tamaño de la Camada/efectos de los fármacos , Longevidad/efectos de los fármacos , Masculino , Nivel sin Efectos Adversos Observados , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Maduración Sexual/efectos de los fármacos , Maduración Sexual/fisiología , Espermatogénesis/efectos de los fármacosRESUMEN
Standardized protocols for repeat-dose toxicity studies have many advantages, including experimental redundancy (i.e., the use of more than a single experimental approach in the assessment of a given organ or tissue) and evaluation of numerous tissues to ensure detection of adverse effects, as well as the ability to develop robust historical control databases. However, traditional toxicology study designs may not adequately address questions of a mechanistic nature that might provide insights on whether particular toxicology findings in animals are relevant to humans. Such questions may be more readily answered using mechanism-based technologies such as toxicogenomics, proteomics, or metabonomics. Such newer approaches may permit, for example, the detailed assessment of the transcriptional profile differences that distinguish a normal healthy tissue from a diseased or damaged tissue. The resultant information can be used to elucidate the mechanism and accompanying biomarkers for toxicity, as well as to identify potential molecular targets for therapeutic intervention by drugs. Despite their conceptual appeal, the use of emerging technologies in toxicology is accompanied by significant challenges. For example, toxicogenomic assessments entail the generation of large amounts of bioinformatic data that must be interpretable for their full value to be realized. Also, none of these newer approaches have established uniformly acceptable quality standards (e.g., such as may be defined in interlaboratory validation studies) or a track record of achievement in guiding regulatory decisions. As a result, newer techniques, at least for the present, are more likely to be focused on mechanistic questions with compounds of known toxicity (either positive indicator compounds or "failed" pharmaceutical candidates). If the use of a nascent or emerging technology is contemplated for mechanistic studies of pharmaceutical compounds later in preregistration development, it will be crucial for toxicologists to engage their regulatory colleagues in discussions at an early stage to ensure closer alignment in thought. The successful use of emerging technologies to address toxicology issues will require a close partnership between industry and regulatory agencies.