Results from two-year rodent oral carcinogenicity studies of cizolirtine, a substance-P and calcitonin gene-related peptide release modulator.

Cizolirtine is a substance-P and calcitonin gene-related peptide release modulator developed for the treatment of pain and urinary incontinence. To assess its carcinogenic potential, cizolirtine was administered by oral route once daily for up to 104 weeks to CD-1 mice at doses of 40, 90, or 200 mg/kg/day, and to Han Wistar rats at doses of 40, 90 or 200 mg/kg/day to males and 40, 110 or 160 mg/kg/day to females. There were treatment-related neoplastic findings both in mice and rats.

Evaluation of the Genotoxic Potential of the Selective COX-2 Inhibitor Enflicoxib in a Battery of in vitro and in vivo Genotoxicity Assays.

Aim: Enflicoxib, a selective COX-2 inhibitor approved for the treatment of pain and inflammation associated with osteoarthritis in dogs (Daxocox [Ecuphar/Animalcare Group]) was assessed for its genotoxic potential in a battery of and genotoxicity assays. These comprised a bacterial reverse mutation assay (Ames test), an human lymphocyte chromosome aberration assay and an mouse bone marrow micronucleus assay.

Methods: Relevant vehicle and positive control cultures and animals were included in all assays.

Long-term safety evaluation of Daxocox tablets (enflicoxib) in dogs after weekly oral administrations for seven months.

Background: Daxocox® [Ecuphar/Animalcare Group] contains the selective COX-2 inhibitor enflicoxib, approved in the EU for the treatment of pain and inflammation associated with osteoarthritis in dogs. The safety of Daxocox was evaluated in a target animal safety study: Groups of 4 dogs per sex each were treated once weekly with placebo or Daxocox tablets at 1-, 3- and 5-times (1X, 3X and 5X) the maximum recommended therapeutic dose of enflicoxib (0, 4, 12 or 20 mg/kg, respectively). After an initial loading dose, dogs in the placebo control, 1X and 3X groups were administered for 32 weeks, and those in the 5X group were administered for 13 weeks.

Twenty six-week repeat dose oral rat toxicity study of cizolirtine, a substance-P and calcitonin gene-related peptide release modulator.

Cizolirtine, a substance-P and calcitonin gene-related peptide release modulator developed for the treatment of pain and urinary incontinence, was orally administered for 26-weeks to rats at dosages of 20, 60 and 200 mg/kg/day. Clinical signs were limited to post-dosing salivation and brown staining on head and muzzle. There were slight decreases in bodyweight gain and slight increases in water consumption among cizolirtine-treated animals.

A Case of Rare Subtype of Multiple Myeloma: Secondary Plasma Cell Leukemia.

Description Plasma cell leukemia is a rare, aggressive form of multiple myeloma with the presence of circulating plasma cells in the peripheral blood. There are two types of plasma cell leukemia, primary and secondary, depending on if there was previous evidence of multiple myeloma. The diagnostic criterion of plasma cell leukemia is based on a percentage (>20%) or an absolute number of (≥2 × 10/L) plasma cells in the peripheral circulation.

Assessment of the Genotoxic Potential of Cizolirtine a Substance-P and Calcitonin Gene-Related Peptide Release Modulator.

The analysis of the genotoxic potential of cizolirtine, a compound being developed as a drug for analgesia and for urinary incontinence, was carried out using a battery of and assays as recommended in the guidelines for medicinal products. Negative results were obtained in an Ames test (up to 5000 µg/plate), in a Mouse Lymphoma assay (up to 2000 µg/ml) and in a single dose mouse bone marrow micronucleus assay (up to 300 mg/kg). In a human lymphocyte chromosome aberration assay, a slight statistical increase in the frequency of cells with chromosome aberrations including gaps was reported for the concentrations of 200 and 1600 μg/ml at the 24-h sampling time.

Towards the elimination of hepatitis C: implementation of reflex testing in Andalusia.

Background And Aim: undiagnosed hepatitis C virus (HCV) infection and/or inadequate access to care are barriers to the elimination of HCV. Reflex testing has proven to facilitate referral to care, treatment and viral elimination. In this study, a reflex testing program was implemented in Andalusia and its impact on access to care was evaluated.

Antituberculosis drug resistance in isolates of Mycobacterium tuberculosis complex in southeast Spain.

Objectives: The aim of this study was to determine resistance to antituberculosis (anti-TB) drugs in Mycobacterium tuberculosis complex isolates from patients diagnosed with Tuberculosis (TB) in southeast Spain and to study related epidemiological factors.

Methods: This retrospective study analysed 5-year data (2012-2016) obtained in southeast Spain for a total equivalent population of 1 735 608 inhabitants. Clinical samples were examined from 557 patients with suspected pulmonary TB (n=470; 84.

Adoption and adherence to chronic obstructive pulmonary disease GOLD guidelines in a primary care setting.

Objectives: Over 380 million people in the world live with chronic obstructive pulmonary disease, and it is the third leading cause of death in the United States. Despite updated guidelines, there may be significant variations in diagnosis and management of chronic obstructive pulmonary disease at a primary care level. The aim of the study was to examine primary care physician management of chronic obstructive pulmonary disease in two community clinics.

Legacy data sharing to improve drug safety assessment: the eTOX project.

The sharing of legacy preclinical safety data among pharmaceutical companies and its integration with other information sources offers unprecedented opportunities to improve the early assessment of drug safety. Here, we discuss the experience of the eTOX project, which was established through the Innovative Medicines Initiative to explore this possibility.

Correction: A new parrot taxon from the Yucatán Peninsula, Mexico-its position within genus based on morphology and molecular phylogeny.

[This corrects the article DOI: 10.7717/peerj.3475.

A new parrot taxon from the Yucatán Peninsula, Mexico-its position within genus based on morphology and molecular phylogeny.

Parrots (Psittaciformes) are a diverse group of birds which need urgent protection. However, many taxa from this order have an unresolved status, which makes their conservation difficult. One species-rich parrot genus is , which is widely distributed in the New World.

The influence of the carrier molecule on amoxicillin recognition by specific IgE in patients with immediate hypersensitivity reactions to betalactams.

The optimal recognition of penicillin determinants, including amoxicillin (AX), by specific IgE antibodies is widely believed to require covalent binding to a carrier molecule. The nature of the carrier and its contribution to the antigenic determinant is not well known. Here we aimed to evaluate the specific-IgE recognition of different AX-derived structures.

Is forest cover conserved and restored by protected areas?: The case of two wild protected areas inthe Central Pacific of Costa Rica.

Changes in land use are mainly a consequence of anthropogenic actions. The current agricultural and urban transformations in Costa Rica have raised questions about the effectiveness of conservation and restoration within protected areas. Herein we analyzed the patterns of land use change between three periods: 1997, 2005 and 2010 in terms of magnitude, direction, and pace through categorical maps generated by the photointerpretation for La Cangreja National Park (LCNP), Rancho Mastatal Wildlife Refuge (RMWR), and their surrounding areas (SA), this last compound of one kilometer radius outside the protected areas' boundaries.

Growth and photosynthetic performance of five tree seedlings species in response to natural light regimes from the Central Pacific of Costa Rica.

Environmental heterogeneity mostly dominated by differing light regimes affects the expression of phenotypic plasticity, which is important for plant growth and survival, especially in the forest understory. The knowledge about these responses to this heterogeneity is a key factor for forest restoration initiatives. In this study, we determine several phenotypic responses to contrasting light conditions in five native tree seedling species of La Cangreja National Park, Central Pacific of Costa Rica, four of them with threatened or relict populations.

[Visfatin in obese patients, relation with cardiovascular risk factors, a cross sectional study].

Background And Objective: Obesity and insulin resistance are associated with cardiovascular risk factors. The aim of the present study was to explore the relation of visfatin with insulin resistance, cardiovascular risk factors and anthropometry in obese patients without comorbidities.

Patients And Method: A population of 270 obese patients was analyzed in a prospective way.

Induction of hypothermic conditions associated with increased micronuclei formation in sigma-1 receptor knockout mice after administration of the antipsychotic compound E-5842.

The antipsychotic sigma-1 (sigma(1)) receptor ligand E-5842 has been shown to increase micronucleated polychromatic erythrocyte (MNPCE) frequency in mouse bone marrow secondary to compound-induced hypothermia. Interaction with sigma(1) receptor has been considered a plausible contributing factor for E-5842-induced hypothermia, raising concern for a possible class effect of sigma receptor ligands in the mouse micronucleus (MN) test. We assessed the potential of E-5842 (200 mg/kg, oral) to produce hypothermic conditions associated with increased micronuclei formation in sigma(1) receptor knockout (sigma(1)R-KO) and wild type (WT) mice.

Formation of micronucleated erythrocytes in mouse bone-marrow under conditions of hypothermia is not associated with stimulation of erythropoiesis.

Conditions of marked and long-lasting hypothermia have been shown to increase the formation of micronucleated polychromatic erythrocyte (MNPCE) in mouse bone-marrow. Stimulation of erythropoiesis as a consequence of anoxic conditions associated with decreased body temperature has been suggested as a possible mechanism for hypothermia-induced micronucleus formation. We examined whether chemically induced hypothermic conditions that produced increased MNPCE formation were associated with stimulation of erythropoiesis by measuring erythropoietin (EPO) concentrations in blood.

Evaluation of the genotoxic potential of three phenyltetrahydropyridinyl butylazole-derived sigma-receptor ligand drug candidates.

Three structurally related phenyltetrahydropyridinyl butylazole (PTHPB)-derived drug candidates with sigma receptor-binding properties were evaluated for genotoxic potential in the ICH standard battery of genetic toxicology assays. These comprised an Ames test, a mouse-lymphoma assay, and a mouse bone-marrow micronucleus test. The maximum test concentrations in the in vitro assays were determined by the solubility and/or the cytotoxicity of the compounds.

Sleep-stabilizing effects of E-6199, compared to zopiclone, zolpidem and THIP in mice.

Unlabelled: Gamma aminobutyric acid (GABA)A receptor modulators constitute the majority of clinically used sedative-hypnotics. These compounds have the capacity to initiate and maintain sleep, but decrease REM sleep and delta activity within NREM sleep. In order to avoid such sleep adverse effects, the development of novel compounds remains of interest.

Evaluation of the genotoxic potential of the natural neurotoxin Tetrodotoxin (TTX) in a battery of in vitro and in vivo genotoxicity assays.

The genotoxic potential of the natural neurotoxin Tetrodotoxin (TTX) was evaluated in a battery of in vitro and in vivo genotoxicity assays. These comprised a bacterial reverse-mutation assay (Ames test), an in vitro human lymphocyte chromosome-aberration assay, an in vivo mouse bone-marrow micronucleus assay and an in vivo rat-liver UDS assay. Maximum test concentrations in in vitro assays were determined by the TTX limit of solubility in the formulation vehicle (0.

Disease progression in vascular cognitive impairment: cognitive, functional and behavioural outcomes in the Consortium to Investigate Vascular Impairment of Cognition (CIVIC) cohort study.

Background And Purpose: Empirical studies to clarify the outcomes in Vascular Cognitive Impairment (VCI) are needed. We compared cognitive, functional, and behavioural outcomes in patients with VCI to patients with no cognitive impairment (NCI), and Alzheimer's disease (AD).

Methods: Secondary analysis of the Consortium to Investigate Vascular Impairment of Cognition (CIVIC), a multi-centre Canadian memory clinic 30-month cohort study.

Assessment of the genotoxic potential of the antipsychotic sigma receptor ligand E-5842.

The genotoxic potential of E-5842, a sigma ligand compound being developed as an antipsychotic drug, was evaluated by means of an extensive battery of in vitro and in vivo assays. Negative results were obtained in an Ames test (up to 5000 μg/plate), a mouse lymphoma assay (up to 535.1 μg/ml (-S9) and 891.

Clinical and radiographic subtypes of vascular cognitive impairment in a clinic-based cohort study.

Background And Purpose: There is a need for empirical studies to define criteria for vascular cognitive impairment (VCI) subtypes. In this paper, we report the predictive validity of a subtype classification scheme based on clinical and radiographic features.

Methods: Nine Canadian memory clinics participated in the Consortium to Investigate Vascular Impairment of Cognition.

Induction of micronuclei in mouse bone-marrow erythrocytes in association with hypothermia after administration of the sigma receptor ligand E-5842.

Oral administration of E-5842, a new sigma1 receptor ligand being developed as an antipsychotic drug, to male mice at single doses of 50, 100, 200 and 400 mg/kg produced marked and sustained decreases in rectal temperature. Both the intensity and the duration of the hypothermic effect increased with dose. Maximum decreases from the mean pre-administration temperature (36.