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1.
Br J Clin Pharmacol ; 84(1): 179-188, 2018 Jan.
Article in English | MEDLINE | ID: mdl-28865237

ABSTRACT

AIMS: LY3031207, a novel microsomal prostaglandin E synthase 1 inhibitor, was evaluated in a multiple ascending dose study after nonclinical toxicology studies and a single ascending dose study demonstrated an acceptable toxicity, safety and tolerability profile. METHODS: Healthy subjects were randomized to receive LY3031207 (25, 75 and 275 mg), placebo or celecoxib (400 mg) once daily for 28 days. The safety, tolerability and pharmacokinetic and pharmacodynamic profiles of LY3031207 were evaluated. RESULTS: The study was terminated when two subjects experienced drug-induced liver injury (DILI) after they had received 225 mg LY3031207 for 19 days. Liver biopsy from these subjects revealed acute liver injury with eosinophilic infiltration. Four additional DILI cases were identified after LY3031207 dosing had been stopped. All six DILI cases shared unique presentations of hepatocellular injury with hypersensitivity features and demonstrated a steep dose-dependent trend. Prompt discontinuation of the study drug and supportive medical care resulted in full recovery. Metabolites from metabolic activation of the imidazole ring were observed in plasma and urine samples from all subjects randomized to LY3031207 dosing. CONCLUSIONS: This study emphasized the importance of careful safety monitoring and serious adverse events management in phase I trials. Metabolic activation of the imidazole ring may be involved in the development of hepatotoxicity of LY3031207.


Subject(s)
Chemical and Drug Induced Liver Injury/etiology , Drug Hypersensitivity/etiology , Enzyme Inhibitors/adverse effects , Imidazoles/adverse effects , Prostaglandin-E Synthases/antagonists & inhibitors , Administration, Oral , Adult , Area Under Curve , Celecoxib/adverse effects , Chemical and Drug Induced Liver Injury/pathology , Cyclooxygenase 2 Inhibitors/adverse effects , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Drug Hypersensitivity/pathology , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Female , Half-Life , Healthy Volunteers , Humans , Imidazoles/administration & dosage , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Liver/drug effects , Liver/immunology , Liver/pathology , Male , Middle Aged , Pain/drug therapy , Withholding Treatment
2.
Int J Toxicol ; 35(5): 499-520, 2016 09.
Article in English | MEDLINE | ID: mdl-27381384

ABSTRACT

The study of developmental neurotoxicity (DNT) continues to be an important component of safety evaluation of candidate therapeutic agents and of industrial and environmental chemicals. Developmental neurotoxicity is considered to be an adverse change in the central and/or peripheral nervous system during development of an organism and has been primarily evaluated by studying functional outcomes, such as changes in behavior, neuropathology, neurochemistry, and/or neurophysiology. Neurobehavioral evaluations are a component of a wide range of toxicology studies in laboratory animal models, whereas neurochemistry and neurophysiology are less commonly employed. Although the primary focus of this article is on neurobehavioral evaluation in pre- and postnatal development and juvenile toxicology studies used in pharmaceutical development, concepts may also apply to adult nonclinical safety studies and Environmental Protection Agency/chemical assessments. This article summarizes the proceedings of a symposium held during the 2015 American College of Toxicology annual meeting and includes a discussion of the current status of DNT testing as well as potential issues and recommendations. Topics include the regulatory context for DNT testing; study design and interpretation; behavioral test selection, including a comparison of core learning and memory systems; age of testing; repeated testing of the same animals; use of alternative animal models; impact of findings; and extrapolation of animal results to humans. Integration of the regulatory experience and scientific concepts presented during this symposium, as well as from subsequent discussion and input, provides a synopsis of the current state of DNT testing in safety assessment, as well as a potential roadmap for future advancement.


Subject(s)
Behavior, Animal/drug effects , Neurotoxins/analysis , Postnatal Care , Toxicity Tests , Animals , Congresses as Topic , Disease Models, Animal , United States , United States Environmental Protection Agency
3.
Birth Defects Res B Dev Reprod Toxicol ; 107(2): 94-107, 2016 Apr.
Article in English | MEDLINE | ID: mdl-27074409

ABSTRACT

Pregabalin was administered to pregnant Wistar rats during organogenesis to evaluate potential developmental toxicity. In an embryo-fetal development study, compared with controls, fetuses from pregabalin-treated rats exhibited increased incidence of jugal fused to maxilla (pregabalin 1250 and 2500 mg/kg) and fusion of the nasal sutures (pregabalin 2500 mg/kg). The alterations in skull development occurred in the presence of maternal toxicity (reduced body weight gain) and developmental toxicity (reduced fetal body weight and increased skeletal variations), and were initially classified as malformations. Subsequent investigative studies in pregnant rats treated with pregabalin during organogenesis confirmed the advanced jugal fused to maxilla, and fusion of the nasal sutures at cesarean section (gestation day/postmating day [PMD] 21) in pregabalin-treated groups. In a study designed to evaluate progression of skull development, advanced jugal fused to maxilla and fusion of the nasal sutures was observed on PMD 20-25 and PMD 21-23, respectively (birth occurs approximately on PMD 22). On postnatal day (PND) 21, complete jugal fused to maxilla was observed in the majority of control and 2500 mg/kg offspring. No treatment-related differences in the incidence of skull bone fusions occurred on PND 21, indicating no permanent adverse outcome. Based on the results of the investigative studies, and a review of historical data and scientific literature, the advanced skull bone fusions were reclassified as anatomic variations. Pregabalin was not teratogenic in rats under the conditions of these studies.


Subject(s)
Organogenesis/drug effects , Pregabalin/toxicity , Skull/drug effects , Skull/embryology , Animals , Cesarean Section , Dose-Response Relationship, Drug , Embryo, Mammalian/drug effects , Embryonic Development/drug effects , Female , Fetal Development/drug effects , Fetal Weight/drug effects , Fetus/drug effects , Maternal Exposure , No-Observed-Adverse-Effect Level , Pregabalin/administration & dosage , Pregnancy , Rats , Rats, Wistar , Teratogens/toxicity , Toxicity Tests
4.
J Med Chem ; 59(2): 750-5, 2016 Jan 28.
Article in English | MEDLINE | ID: mdl-26683992

ABSTRACT

A transdermal SARM has a potential to have therapeutic benefit through anabolic activity in muscle while sparing undesired effects of benign prostate hyperplasia (BPH) and liver-mediated decrease in HDL-C. 2-Chloro-4-[(2-hydroxy-2-methyl-cyclopentyl)amino]-3-methyl-benzonitrile 6 showed the desired muscle and prostate effects in a preclinical ORX rat model. Compound 6 had minimal effect on HDL-C levels in cynomolgus monkeys and showed human cadaver skin permeability, thus making it an effective tool for proof-of-concept studies in a clinical setting.


Subject(s)
Anabolic Agents/therapeutic use , Androgen Antagonists/therapeutic use , Aniline Compounds/therapeutic use , Muscular Atrophy/drug therapy , Nitriles/therapeutic use , Administration, Cutaneous , Anabolic Agents/administration & dosage , Anabolic Agents/chemical synthesis , Androgen Antagonists/administration & dosage , Androgen Antagonists/chemical synthesis , Aniline Compounds/administration & dosage , Aniline Compounds/chemical synthesis , Animals , Cholesterol, HDL/metabolism , Humans , Hypercholesterolemia/chemically induced , In Vitro Techniques , Liver/drug effects , Liver/metabolism , Macaca fascicularis , Male , Models, Molecular , Nitriles/administration & dosage , Nitriles/chemical synthesis , Orchiectomy , Prostatic Hyperplasia/chemically induced , Rats , Skin Absorption , Structure-Activity Relationship
5.
Ther Innov Regul Sci ; 50(2): 174-187, 2016 Mar.
Article in English | MEDLINE | ID: mdl-30227010

ABSTRACT

BACKGROUND: Access and use of historical control data was identified as a top stakeholder concern across organizations according to results of a survey of needs and challenges related to nonclinical data conducted by the FDA/PhUSE Nonclinical Working Group in 2011. There is a perception there may be additional ways to capitalize on historical control data to enhance studies or submissions across industry, academia, and government. During the working sessions of the FDA/PhUSE Computational Sciences Symposium in March 2012, a Historical Control subgroup of the FDA/PhUSE Nonclinical Working Group was formed to investigate how the industry might more effectively harness the vast amount of data from untreated/vehicle control animals. The subgroup includes broad representation of stakeholders with interest in nonclinical data. METHODS: This paper describes progress to date and includes results of a second survey to determine how organizations use and would like to use historical control data. RESULTS: Respondents to the survey strongly support that historical control data are useful and should be in an accessible format. Four potential project options were posed in the survey, with an overall positive response; also, several write-in options were suggested by respondents. CONCLUSIONS: Community-supported projects to increase the availability of well-annotated and scientifically curated collections of historical control data appear to be of most interest.

6.
Toxicol Sci ; 128(1): 9-21, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22539615

ABSTRACT

Pregabalin, (S)-3-(aminomethyl)-5-methylhexanoic acid, binds with high affinity to the α(2)δ subunit of voltage-gated calcium channels and exerts analgesic, anxiolytic, and antiseizure activities. Two-year carcinogenicity studies were completed in B6C3F1 and CD-1 mice and two separate studies in Wistar rats. Doses in mice were 200, 1000, and 5000 mg/kg/day, with systemic exposures (AUC(0-24 h)) up to 31 times the mean exposure in humans, given the maximum recommended clinical dose. In rats, doses were 50, 150, and 450 mg/kg/day in males and 100, 300, and 900 mg/kg/day in females; systemic exposures up to 24 times were achieved in clinical trials. In both strains of mice, pregabalin treatment was associated with an increased incidence of hemangiosarcoma primarily in liver, spleen, and bone marrow. The incidence of hemangiosarcoma was higher in B6C3F1 mice than in CD-1 mice, consistent with its spontaneous incidence. Pregabalin did not increase the incidence of any other tumor type in rats and was not genotoxic, based on an extensive battery of in vivo and in vitro tests in bacterial and mammalian systems. Thus, pregabalin is a single-species, single tumor-type, nongenotoxic mouse carcinogen. Hemangiosarcomas occurring in mice treated with pregabalin were genotypically distinct from hemangiosarcomas induced by genotoxic carcinogens in humans with respect to ras and p53 mutation patterns and were similar to spontaneous tumors. Furthermore, there was a strong association between pregabalin treatment and bone marrow changes in these studies in mice, suggesting a possible link between the effects observed in bone marrow and the increase in tumor incidence in pregabalin-treated mice.


Subject(s)
Hemangiosarcoma/chemically induced , Mutagens/toxicity , gamma-Aminobutyric Acid/analogs & derivatives , Animals , Carcinogenicity Tests , Dose-Response Relationship, Drug , Genes, p53 , Genes, ras , Hemangiosarcoma/genetics , Incidence , Mice , Mice, Inbred ICR , Mutagenicity Tests , Pregabalin , Rats , Rats, Wistar , gamma-Aminobutyric Acid/toxicity
7.
Curr Drug Saf ; 3(2): 132-42, 2008 May.
Article in English | MEDLINE | ID: mdl-18690991

ABSTRACT

OBJECTIVE: Review nonclinical and clinical trial data for hepatic effects of duloxetine. METHODS: Review studies of toxicology, metabolism, mitochondrial effects, and clinical trials. RESULTS: Nonclinical studies revealed no treatment-related transaminase elevations and no effects of duloxetine on mitochondrial beta-oxidation in rat hepatocytes. In patients with a normal baseline alanine transaminase (ALT), duloxetine was associated with elevated transaminases >3X ULN in about 1% of patients. ALT and aspartate transaminase values peaked at 8 weeks, alkaline phosphatase steadily increased to maximum value at Week 52 and mean total bilirubin values were not increased. Hepatic-related treatment-emergent adverse events were uncommon. Seven of 23,000 duloxetine- and 2/6000 placebo-treated patients met criteria for modified Hy's rule (significant elevation of both ALT and total bilirubin) but were complicated by contributing factors such as excessive alcohol consumption (n=3), gall stones, common bile duct calculus, hepatitis C, and liver adenocarcinoma (n=1 each). CONCLUSIONS: Duloxetine has an effect on the liver, manifested by transient, self-limiting transaminase elevations. Rare events characterized as hepatocellular injury, cholestatic injury, or mixed type of hepatic injury have been reported. The pattern of liver effects was different from that in laboratory animals.


Subject(s)
Adrenergic Uptake Inhibitors/adverse effects , Chemical and Drug Induced Liver Injury , Liver/drug effects , Selective Serotonin Reuptake Inhibitors/adverse effects , Thiophenes/adverse effects , Adrenergic Uptake Inhibitors/toxicity , Alanine Transaminase/blood , Alkaline Phosphatase/blood , Animals , Aspartate Aminotransferases/blood , Bilirubin/blood , Biomarkers/blood , Clinical Trials as Topic , Consumer Product Safety , Drug Evaluation, Preclinical , Duloxetine Hydrochloride , Humans , Liver/enzymology , Liver Diseases/enzymology , Risk Assessment , Risk Factors , Selective Serotonin Reuptake Inhibitors/toxicity , Species Specificity , Thiophenes/toxicity
8.
Bioorg Med Chem Lett ; 17(13): 3544-9, 2007 Jul 01.
Article in English | MEDLINE | ID: mdl-17482463

ABSTRACT

Structure-activity relationship studies are described, which led to the discovery of novel selective estrogen receptor modulators (SERMs) for the potential treatment of uterine fibroids. The SAR studies focused on limiting brain exposure and were guided by computational properties. Compounds with limited impact on the HPO axis were selected using serum estrogen levels as a biomarker for ovarian stimulation.


Subject(s)
Leiomyoma/drug therapy , Ovary/drug effects , Selective Estrogen Receptor Modulators/pharmacology , Animals , Brain/metabolism , Dose-Response Relationship, Drug , Drug Design , Estrogens/blood , Female , Humans , Models, Chemical , Ovary/metabolism , Rats , Rats, Sprague-Dawley , Selective Estrogen Receptor Modulators/chemistry , Software , Structure-Activity Relationship
9.
Toxicol Pathol ; 33(6): 711-9, 2005.
Article in English | MEDLINE | ID: mdl-16263696

ABSTRACT

A selective estrogen receptor modulator (SERM) is a nonsteroidal compound with tissue specific estrogen receptor (ER) agonist or antagonist activities. In animals, SERMs may produce morphologic changes in hormonally-sensitive tissues like the mammary gland. Mammary glands from female rats given the SERM LY2066948 hydrochloride (LY2066948) for 1 month at >or= 175 mg/kg had intralobular ducts and alveoli lined by multiple layers of vacuolated, hypertrophied epithelial cells, resembling in part the morphology of the normal male rat mammary gland. We hypothesized that these SERM-mediated changes represented an androgen-dependent virilism of the female rat mammary gland. To test this hypothesis, the androgen receptor antagonist flutamide was co-administered with LY2066948 (175 mg/kg) to female rats for 1 month. Female rats given SERM alone had hyperandrogenemia and the duct and alveolar changes described here. Flutamide cotreatment did not affect serum androgen levels but completely blocked the SERM-mediated mammary gland change. In the mouse, a species that does not have the sex-specific differences in the mammary gland observed in the rat, SERM treatment resulted in hyperandrogenemia but did not alter mammary gland morphology. These studies demonstrate that LY2066948 produces species-specific, androgen-dependent mammary gland virilism in the female rat.


Subject(s)
Mammary Glands, Animal/drug effects , Naphthalenes/pharmacology , Piperidines/pharmacology , Selective Estrogen Receptor Modulators/pharmacology , Androgen Antagonists/pharmacology , Androgens/blood , Androgens/physiology , Animals , Drug Combinations , Estradiol/blood , Female , Flutamide/administration & dosage , Flutamide/pharmacology , Luteinizing Hormone/blood , Male , Mammary Glands, Animal/pathology , Mice , Naphthalenes/administration & dosage , Naphthalenes/pharmacokinetics , Piperidines/administration & dosage , Piperidines/pharmacokinetics , Rats , Rats, Inbred F344 , Selective Estrogen Receptor Modulators/administration & dosage , Selective Estrogen Receptor Modulators/pharmacokinetics , Sex Factors , Species Specificity , Virilism/etiology , Virilism/pathology
10.
Endocrinology ; 146(10): 4524-35, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16002528

ABSTRACT

The use of selective estrogen receptor modulators for the treatment of estrogen-dependent diseases in premenopausal women has been hindered by undesirable ovarian stimulation and associated risks of ovarian cysts. We have identified a selective estrogen receptor modulator compound (LY2066948) that is a strong estrogen antagonist in the uterus yet has minimal effects on the ovaries of rats. LY2066948 binds with high affinity to both estrogen receptors and has potent estrogen antagonist activity in human uterine and breast cancer cells. Oral administration of LY2066948 to immature rats blocked uterine weight gain induced by ethynyl estradiol with an ED50 of 0.07 mg/kg. Studies in mature rats demonstrated that LY2066948 decreases uterine weight by 51% after 35 d treatment, confirming potent uterine antagonist activity over several estrous cycles. This strong uterine response contrasted with the minimal effects on the ovaries: serum estradiol levels remained within the normal range, whereas histologic evaluation showed granulosa cell hyperplasia in few of the rats. Bone studies demonstrated that LY2066948 prevented ovariectomy-induced bone loss and treatment of ovary-intact rats caused no bone loss, confirming estrogen receptor agonist skeletal effects. Collectively, these data show that LY2066948 exhibits a tissue-specific profile consistent with strong antagonist activity in the uterus, agonist activity in bone, and minimal effects in the ovaries.


Subject(s)
Bone and Bones/physiology , Naphthalenes/pharmacology , Ovulation Induction , Piperidines/pharmacology , Receptors, Estrogen/physiology , Uterus/physiology , Animals , Bone and Bones/drug effects , Cell Line, Tumor , Ethinyl Estradiol/pharmacology , Female , Humans , Kinetics , Ovariectomy , Rats , Receptors, Estrogen/agonists , Receptors, Estrogen/antagonists & inhibitors , Receptors, Estrogen/drug effects , Sexual Maturation , Uterus/drug effects
11.
Environ Health Perspect ; 112(2): 266-71, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14754582

ABSTRACT

Children differ from adults both physiologically and behaviorally. These differences can affect how and when exposures to xenobiotics occur and the resulting responses. Testing using animal models may be used to predict whether children display novel toxicities not observed in adults or whether children are more or less sensitive to known toxicities. Historically, evaluation of developmental toxicity has focused on gestational exposures and morphological changes resulting from this exposure. Functional consequences of gestational exposure and postnatal exposure have not been as well studied. Difficulties with postnatal toxicity evaluations include divergent differentiation of structure, function and physiology across species, lack of understanding of species differences in functional ontogeny, and lack of common end points and milestones across species.


Subject(s)
Child Welfare , Environmental Pollutants/poisoning , Models, Animal , Animals , Child , Child Development , Child, Preschool , Humans , Infant , Infant, Newborn , Predictive Value of Tests , Reproducibility of Results , Risk Assessment
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