Safety evaluation of a novel topical combination of esafoxolaner, eprinomectin and praziquantel, in reproducing female cats

NexGard® Combo, a novel topical endectoparasiticide product for cats, is a combination of esafoxolaner, eprinomectin and praziquantel. The safety of this novel combination administered to females during reproduction and lactation was evaluated per analysis of breeding parameters and adverse reactions observed on females and offspring. Females with successful breeding history were randomized to three groups, a placebo group and groups treated with the novel formulation at 1× or 3× multiples of the maximum exposure dose. Females were dosed at 28-day intervals, at least twice before mating, then during a period including mating, pregnancy, whelping and 56 days of lactation. In the placebo, 1× and 3× groups, 10, 9 and 10 females, respectively completed the study (nine, seven and nine females achieved pregnancy), and were dosed 7.1 times on average. Breeding parameters included success of mating, success of gestation, length of gestation, abortion rate, number of live, dead and stillborn kittens at birth, number of kittens with abnormalities, weight of kittens after birth and at weaning, growth of kittens, proportion of male and female kittens, and proportion of kittens born alive and weaned. No significant adverse reactions related to the novel combination were observed on females and on kittens; no significant and adverse effects on breeding parameters were observed.

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Sex Differences in Drug-Induced Arrhythmogenesis

Frontiers in Physiology ◽

10.3389/fphys.2021.708435 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mathias Peirlinck ◽

Francisco Sahli Costabal ◽

Ellen Kuhl

Keyword(s):

Sex Differences ◽

Safety Evaluation ◽

New Drugs ◽

Specific Response ◽

Drug Induced ◽

Tissue Conductivity ◽

Male And Female ◽

Drug Safety Evaluation ◽

Qt Intervals ◽

Drug Concentrations

The electrical activity in the heart varies significantly between men and women and results in a sex-specific response to drugs. Recent evidence suggests that women are more than twice as likely as men to develop drug-induced arrhythmia with potentially fatal consequences. Yet, the sex-specific differences in drug-induced arrhythmogenesis remain poorly understood. Here we integrate multiscale modeling and machine learning to gain mechanistic insight into the sex-specific origin of drug-induced cardiac arrhythmia at differing drug concentrations. To quantify critical drug concentrations in male and female hearts, we identify the most important ion channels that trigger male and female arrhythmogenesis, and create and train a sex-specific multi-fidelity arrhythmogenic risk classifier. Our study reveals that sex differences in ion channel activity, tissue conductivity, and heart dimensions trigger longer QT-intervals in women than in men. We quantify the critical drug concentration for dofetilide, a high risk drug, to be seven times lower for women than for men. Our results emphasize the importance of including sex as an independent biological variable in risk assessment during drug development. Acknowledging and understanding sex differences in drug safety evaluation is critical when developing novel therapeutic treatments on a personalized basis. The general trends of this study have significant implications on the development of safe and efficacious new drugs and the prescription of existing drugs in combination with other drugs.

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Social Factors Influence Behavior in the Novel Object Recognition Task in a Mouse Model of Down Syndrome

Frontiers in Behavioral Neuroscience ◽

10.3389/fnbeh.2021.772734 ◽

2021 ◽

Vol 15 ◽

Author(s):

Cesar Sierra ◽

Ilario De Toma ◽

Lorenzo Lo Cascio ◽

Esteban Vegas ◽

Mara Dierssen

Keyword(s):

Down Syndrome ◽

Object Recognition ◽

Environmental Factors ◽

Mouse Models ◽

Recognition Task ◽

Novel Object Recognition ◽

The Novel ◽

Wild Type ◽

Male And Female ◽

Novel Object

The use of mouse models has revolutionized the field of Down syndrome (DS), increasing our knowledge about neuropathology and helping to propose new therapies for cognitive impairment. However, concerns about the reproducibility of results in mice and their translatability to humans have become a major issue, and controlling for moderators of behavior is essential. Social and environmental factors, the experience of the researcher, and the sex and strain of the animals can all have effects on behavior, and their impact on DS mouse models has not been explored. Here we analyzed the influence of a number of social and environmental factors, usually not taken into consideration, on the behavior of male and female wild-type and trisomic mice (the Ts65Dn model) in one of the most used tests for proving drug effects on memory, the novel object recognition (NOR) test. Using principal component analysis and correlation matrices, we show that the ratio of trisomic mice in the cage, the experience of the experimenter, and the timing of the test have a differential impact on male and female and on wild-type and trisomic behavior. We conclude that although the NOR test is quite robust and less susceptible to environmental influences than expected, to obtain useful results, the phenotype expression must be contrasted against the influences of social and environmental factors.

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Oestrous cycle and gestation length in the musky rat-kangaroo, Hypsiprymnodon moschatus (Potoroidae : Marsupialia)

Australian Journal of Zoology ◽

10.1071/zo00010 ◽

2001 ◽

Vol 49 (1) ◽

pp. 37 ◽

Cited By ~ 1

Author(s):

Shan Lloyd

Keyword(s):

Epithelial Cells ◽

Captive Breeding ◽

Common Ancestor ◽

Post Partum ◽

Reproductive Physiology ◽

Oestrous Cycle ◽

Gestation Length ◽

Vaginal Smears ◽

Breeding Colony ◽

Male And Female

Wild-caught male and female H. moschatus were maintained in a captive breeding colony. Vaginal smears were taken three times a week until oestrous cycles were detected and gestation lengths approximated. Thereafter, smears were usually taken daily when oestrus was expected. The gestation period (considered to be the number of days from the detection of sperm in the smear until the day young were found in the pouch) was found to last 19 days. Sperm were usually detected in the smear two days before the influx of semi-cornified and cornified epithelial cells, which occurred 17 days before parturition. A pre- or post-partum oestrus was not detected and females did not return to oestrus until at least 6 days after the removal of the last pouch young. H. moschatus has the shortest recorded gestation for any macropod, and gestation occupies approximately 75% of the oestrous cycle. The reproductive physiology of H. moschatus is similar to that of most phalangerids, which may be indicative of a common ancestor.

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Safety evaluation of SPF66 malaria vaccine in Brazil

Revista da Sociedade Brasileira de Medicina Tropical ◽

10.1590/s0037-86821996000500014 ◽

1996 ◽

Vol 29 (5) ◽

pp. 497-501 ◽

Cited By ~ 6

Author(s):

LM. Urdaneta ◽

A. Prata ◽

C.J. Struchiner ◽

C.E. Tosta ◽

P. Tauil ◽

...

Keyword(s):

Placebo Group ◽

Side Effects ◽

Malaria Vaccine ◽

Adverse Reactions ◽

Safety Evaluation ◽

Efficacy Trial ◽

Systemic Side Effects ◽

Local Reactions ◽

Severe Adverse Reactions ◽

Local Side

The frequency and description of side effects secondaiy to the subcutaneous application of SPf66 malaria vaccine and placebo are reported for each dose of application in the participants of the vaccine efficacy trial in Brazil. Side effects evaluated two hours after each application were detected in 8.0%, 30.2% and 8.8%, for the Is', and 3"' dose, respectively, in the SPf66group, and in 7.0%, 8.5% and 2.9% in the placebo group. Local reactions such as mild inflammation, nodule and pain or erythema frequently accompanied by pruritus were the most common reactions detected in both groups (3-8%, 29.1% and 8.5% in the SPf66 group and 4.0%, 7.6% and 2.5% in the placebo group). Among vaccinees, local side effects after the 2nd dose were more frequent in females. Systemic side effects were expressed mainly through general symptoms referred by the participants and were most frequent after the 1st dose in both groups (4.3% in the SPf66 group and 3-0% in the placebo group). Muscle aches and fever were refewred by few participants. No severe adverse reactions were detected for either dose of application or group.

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An Observational Study Evaluating the Introduction of a Prolonged-Release Protein Substitute to the Dietary Management of Children with Phenylketonuria

Nutrients ◽

10.3390/nu12092686 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2686

Author(s):

Anita MacDonald ◽

Catherine Ashmore ◽

Anne Daly ◽

Alex Pinto ◽

Sharon Evans

Keyword(s):

Adverse Reactions ◽

Fruit Juice ◽

Gastrointestinal Symptoms ◽

Previous Treatment ◽

Prolonged Release ◽

The Novel ◽

Protein Substitute ◽

Blood Phenylalanine ◽

Study Product ◽

Test Protein

Dietary restriction of phenylalanine combined with a protein substitute prevents intellectual disability in patients with phenylketonuria (PKU). However, current protein substitutes are associated with low adherence owing to unpalatability and burdensome administration regimens. This prospective, observational acceptability study in children with PKU assessed the use of a prolonged-release protein substitute designed with an ethyl cellulose and arginate coating masking the bitter taste, smell and reducing the osmolarity of free amino acids. The study product was mixed with the subject’s food or drink and replaced ≥1 dose per day of the subject’s usual protein substitute for 7 days. Seven of 13 subjects were able to take their prescribed dose over the 7 day period. Most subjects mixed the test protein substitute with food or fruit juice. Reduced blood phenylalanine levels (n = 5) and improved phenylalanine/tyrosine ratio (n = 4) were recorded from baseline to Day 7, respectively. Four subjects reported fewer gastrointestinal symptoms compared to baseline. There were no cases of diarrhoea, constipation, bloating, nausea or vomiting. No adverse reactions were reported. In conclusion, the novel prolonged-release protein substitute was taken in a different way to a typical protein substitute and enabled satisfactory blood phenylalanine control. The study product was well tolerated; subjects experienced fewer gastrointestinal symptoms than with their previous treatment. Although the results of this pilot study provide reassuring data, longer-term studies evaluating adherence and blood phenylalanine control are necessary.

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Abstract 674: Clinical testing of the novel predictive biomarker for monitoring adverse reactions to radiation therapy

10.1158/1538-7445.am2018-674 ◽

2018 ◽

Author(s):

Paul Okunieff ◽

Elena Peletskaya ◽

Steven Swarts ◽

Jinwei Du ◽

Larry Pastor ◽

...

Keyword(s):

Radiation Therapy ◽

Adverse Reactions ◽

Predictive Biomarker ◽

The Novel ◽

Clinical Testing

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The Anatomy of Eroticism: Reimagining Sex and Sexuality in the Late Ming Novel Xiuta Yeshi

NAN Nü ◽

10.1163/138768007x244361 ◽

2007 ◽

Vol 9 (2) ◽

pp. 284-329

Author(s):

Ka Wong

Keyword(s):

Sixteenth Century ◽

Human Body ◽

The Novel ◽

Sexual Content ◽

Material World ◽

Male And Female ◽

Female Relationships ◽

Late Ming ◽

Sex And Sexuality ◽

New Interpretation

AbstractDue to its explicit and outrageous sexual content, Xiuta yeshi is often deemed an "obscene book" that lacks literary sophistication. Precisely because of its obscenity, however, the novel provides a unique perspective from which to study the discourse of sex and sexuality in the late Ming period. By examining Xiuta yeshi on its own terms as pornography, one can explore more fully the dynamics of gender, desire, and male-female relationships in this supposedly decadent era. In its construct of eroticism, the novel hinges as much on the detailed recounting of the material world and, in particular, a new interpretation of the human body, as on sex itself. Using foul language to exploit most of the modern pornographic tropes—from rape to orgy to both male and female homosexual acts—this late sixteenth-century work not only redefines a popular genre but also reveals the exhilarating, extravagant, and even grotesque aspects of a libertine culture captivated by and capitalizing on sex.

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Safety evaluation of Aloe vera soft capsule in acute, subacute toxicity and genotoxicity study

PLoS ONE ◽

10.1371/journal.pone.0249356 ◽

2021 ◽

Vol 16 (3) ◽

pp. e0249356

Author(s):

Jun Wu ◽

Ying Zhang ◽

Zhongming Lv ◽

Ping Yu ◽

Weiqing Shi

Keyword(s):

Acute Toxicity ◽

Toxicity Test ◽

Mutagenic Activity ◽

Aloe Vera ◽

Safety Evaluation ◽

Health Food ◽

Male And Female ◽

Subacute Toxicity ◽

Icr Mice ◽

Toxicological Profile

Aloe vera has been widely used in health and nutritional supplements in Chinese herbal medicine. Furthermore, Aloe vera production has been an emerging industry for making cosmetics and functional food. However, the reported adverse effects raised questions as to whether Aloe vera and its products were safe enough to be used in medicine and health care. In view of this, the safety evaluation of Aloe vera products before marketing is very important. The present study aimed to assess the toxicological profile of Aloe vera soft capsule (ASC), through acute, subacute toxicity and genotoxicity tests. Male and female ICR mice were received by oral gavage 15000 mg/kg bodyweight of ASC in the acute toxicity test. Male and female SD rats were fed on diet blended with different doses of ASC (equivalent to 832.5, 1665 and 3330 mg/kg bodyweight of ASC) for the subacute toxicity test. In the acute toxicity study, no mortality or behavioral changes were observed, indicating the LD50 was higher than 15000 mg/kg bodyweight. In the subacute toxicity test, no significant changes were observed in bodyweight, food consumption, hematological, biochemical or histopathological parameters in the rats exposed. These data suggested that ASC used in this study did not produce any marked subacute toxic effects up to a maximum concentration of 3330 mg/kg bodyweight. In the genotoxicity study, ASC showed no mutagenic activity in the Ames test and no evidence of potential to induce bone marrow micronucleus or testicular chromosome aberrations in ICR mice exposed to 10000 mg/kg bodyweight. Collectively, ASC could be considered safe before it was marketed as a laxative and moistening health food.

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SEXUAL ABUSE IN LAURIE HALSE ANDERSON’S NOVEL SPEAK

JOURNAL OF LANGUAGE ◽

10.30743/jol.v3i1.3712 ◽

2021 ◽

Vol 3 (1) ◽

pp. 28-34

Author(s):

Dwi Anggriani ◽

M. Amrin Siregar

Keyword(s):

Sexual Abuse ◽

Sexual Assault ◽

Sexual Harassment ◽

Qualitative Method ◽

Female Sexuality ◽

Strong Impact ◽

The Novel ◽

Male And Female ◽

Descriptive Qualitative

This paper discusses the impacts of sexual abuse found in the novel Speak which has been selected as the source of data because this novel has a strong impact on sexual abuse victim. The story is about a female teenager who becomes a victim of abuse and it gives her many impacts. The aims of this study are to find out and analyze the impacts of sexual abuse and is conducted based on the concept of sexual abuse, a crime related to sexuality and more specifically related to male and female sexuality. Sexual abuse can include sexual harassment and sexual assault. Sexual abuse is an act that can harm and damage the victims with physical, psychological, sexual and even emotional impacts. This study applies descriptive qualitative method which collects the data taken from the novel that has been read. The result of the study shows that there are three forms of sexual abuse impacts: physical, psychological and behavioral.

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Efficacy of a novel topical combination of esafoxolaner, eprinomectin and praziquantel for the prevention of heartworm disease in cats

Parasite ◽

10.1051/parasite/2021026 ◽

2021 ◽

Vol 28 ◽

pp. 30

Author(s):

Christine Baker ◽

John McCall ◽

Abdelmoneim Mansour ◽

Scott McCall ◽

Tayna Shaffer ◽

...

Keyword(s):

Adverse Reactions ◽

Experimental Studies ◽

Controlled Study ◽

Infection Model ◽

The Novel ◽

Geometric Means ◽

Treatment Groups ◽

Heartworm Disease ◽

Third Stage ◽

Label Dose

NexGard® Combo is a novel topical endectoparasiticide formulation for cats combining the insecticide/acaricide esafoxolaner, the nematodicide eprinomectin and the cestodicide praziquantel. The efficacy of this novel formulation for the prevention of heartworm disease in cats was tested in two experimental studies using an induced infection model and a randomized, blinded, placebo-controlled study design, and two USA isolates of Dirofilaria immitis. In each study, 20 naïve cats were each inoculated sub-cutaneously with 100 third-stage larvae of D. immitis 30 days before treatment. Following randomization to two treatment groups of ten cats, each cat was treated topically once, either with the minimum recommended dose of the novel formulation, or with an identical volume of placebo. Five months after treatment (6 months after infections), the cats were humanely euthanized for parasite recovery and count. Efficacy was calculated by comparison of the numbers of adult D. immitis recovered in the control and in the novel formulation groups. In the control groups of each study, D. immitis were recovered in seven and nine cats (respective worm counts ranges 1–7 and 1–16, respective geometric means 1.6 and 5.1). In both studies, none of the treated cats harbored any D. immitis at necropsy and the calculated efficacy of the novel formulation was 100%. There were no adverse reactions related to treatment with the novel formulation. The results of these two studies demonstrate that a topical NexGard® Combo application at the minimum label dose is well-tolerated and efficacious in preventing heartworm disease in cats.

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