1343. Prophylactic Dosing of Baloxavir Acid Eliminates Mortality in Mice Lethal Influenza A Virus Infection Model

Abstract Background Baloxavir acid (BXA), an active form of orally available prodrug baloxavir marboxil (BXM, formerly S-033188), is a novel small molecule inhibitor of cap-dependent endonuclease (CEN) of influenza A and B virus, and was recently launched for the treatment of acute and uncomplicated influenza with single dosing of BXM (the trade name XOFLUZA™) in Japan in March 2018. Here, we evaluated the prophylactic efficacy of BXA in mice lethally infected with influenza A virus. Methods T1/2 of BXA in human is more than 10 times longer than that in mice. Therefore, suspension of BXA was subcutaneously administered at 0.8 or 1.6 mg/kg in mice to maintain the plasma concentration of BXA as seen in humans, and then mice were intranasally inoculated with a lethal dose of A/PR/8/34 strain at 48, 72, or 96 hours after the administration of BXA. Survival time and body weight change were then monitored through a 28-day period after virus infection. Mice were euthanized and regarded as dead if their body weights were lower than 70% of the initial body weights according to humane endpoints. Results Single dosing of BXA (1.6 mg/kg) completely eliminated mortality in mice, when the mice were administrated the drug at 48, 72, or 96 hours before virus infection (Figure 1). BXA treatment also significantly prevented body weight loss, consistent with the prolonged survival. Conclusion Prophylactic dosing of BXA exhibited significant protective efficacy against mortality and body weight loss in mice following a lethal infection with influenza A virus. The significant prophylactic efficacy observed in our mouse model suggests the potential utility of BXM for the prophylaxis of influenza in human. Disclosures S. Shano, Shionogi & Co., Ltd.: Employee, Salary. K. Fukao, Shionogi & Co., Ltd.: Employee, Salary. T. Noshi, Shionogi & Co., Ltd.: Employee, Salary. K. Sato, Shionogi & Co., Ltd.: Employee, Salary. M. Sakuramoto, Shionogi & Co., Ltd.: Employee, Salary. K. Baba, Shionogi TechnoAdvance Research & Co., Ltd.: Employee, Salary. T. Shishido, Shionogi & Co., Ltd.: Employee, Salary. A. Naito, Shionogi & Co., Ltd.: Employee, Salary.

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Efficacy of Repeated Intravenous Injection of Peramivir against Influenza A (H1N1) 2009 Virus Infection in Immunosuppressed Mice

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02324-12 ◽

2013 ◽

Vol 57 (5) ◽

pp. 2286-2294 ◽

Cited By ~ 11

Author(s):

Mitsutaka Kitano ◽

Makoto Kodama ◽

Yasushi Itoh ◽

Takushi Kanazu ◽

Masanori Kobayashi ◽

...

Keyword(s):

Weight Loss ◽

Body Weight ◽

Virus Infection ◽

Influenza A ◽

Body Weight Loss ◽

Repeated Administration ◽

Vehicle Group ◽

Influenza A H1n1 ◽

Immunosuppressed Mice ◽

Viral Titers

ABSTRACTThe efficacy of intravenous peramivir against influenza A (H1N1) 2009 virus infection was evaluated in mice in which the immune system was suppressed by cyclophosphamide (CP) treatment. The mortality rate of the vehicle control group was 100%, and the mice lost 20% of their body weight on average by day 13 postinfection (p.i.). Repeated administration of peramivir (40 mg/kg of body weight once a day, given intravenously for 20 days), starting at 1 h p.i., significantly reduced mortality, body weight loss, viral titers, and cytokine production in infected mice compared with results for administration of vehicle (P< 0.01). In addition, repeated administration of peramivir, starting at 24 h, 48 h, or 72 h p.i., also resulted in increases in survival rates and reduction of viral titers in the lungs (P< 0.01). The mean days to death (MDD) of the vehicle group was 14.5 days, while in the groups treated with peramivir starting at 24 h, 48 h, and 72 h p.i., the MDDs were >23.0, 20.9, and 21.8 days, respectively. In comparison, repeated administration of oseltamivir phosphate (5 mg/kg twice a day, given orally for 20 days), starting at 24 h, 48 h, and 72 h p.i., also significantly prevented body weight loss, whereas no significant differences in mortality rates and viral titers in the lungs were observed compared with results for the vehicle group. These data indicated that repeated administration of peramivir was effective in promoting the survival and reducing virus replication in immunosuppressed mice infected with influenza A (H1N1) 2009 virus.

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Some observations on high- and low-potassium Chokla sheep given water intermittently under semi-arid conditions

The Journal of Agricultural Science ◽

10.1017/s0021859600066247 ◽

1981 ◽

Vol 96 (2) ◽

pp. 463-469 ◽

Cited By ~ 1

Author(s):

T. More ◽

P. S. Rawat ◽

K. L. Sahni

Keyword(s):

Weight Loss ◽

Body Weight ◽

Water Intake ◽

Water Deprivation ◽

Body Weight Loss ◽

High Potassium ◽

Group I ◽

Body Weights ◽

Blood Potassium ◽

Breeding Groups

SUMMARYNon-breeding groups, I, II and III, each with six high-potassium (HK) and six lowpotassium(LK) Chokla ewes were given water once in 24, 48 and 72 h respectively. In the next summer, seven ewes (4 HK and 3 LK) from each group I, II and III were switched over to a watering schedule of once in 24, 72 and 96 h respectively and were naturally bred. All the animals were maintained on grazing alone.Water deprivation for 72 h caused 18·8 and 19·2% body weight loss in HK and LKewes respectively; an overall average maintenance of weight loss in LK ewes was significantly higher than in HK ewes from the same group. There were significant differences in water intake due to treatments only. The HK and LK ewes from groups I and III showed a similar trend.Pregnant ewes of HK and LK types given water once in 96 h lost 21·7 and 23·8% of their body weights respectively. Corresponding weight loss in aborted ewes were 23·8 and 33·3%. Two ewes, each from 3 LK and 4 HK animals aborted owing to water deprivation for 96 h. The water intake reached 30 and 36·5% of body weight in LK and HK pregnant ewes given water intermittently.The wool attributes of non-pregnant ewes did not indicate a significant influence of blood potassium types. Four out of five ewes of the LK phenotype died during 3 years, irrespective of watering schedule.

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Investigating the Roles of Platelet PAR4 in Hemostasis, Thrombosis and Viral Infection Using a Newly Generated PAR4 Floxed Mouse

Blood ◽

10.1182/blood-2021-151121 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1000-1000

Author(s):

Robert H Lee ◽

Tomohiro Kawano ◽

Vanthana Bharathi ◽

David Martinez ◽

Dale O Cowley ◽

...

Keyword(s):

Weight Loss ◽

Body Weight ◽

Carotid Artery ◽

Viral Infection ◽

Saphenous Vein ◽

Influenza A ◽

Body Weight Loss ◽

Cell Type ◽

Laser Injury ◽

Plug Formation

Abstract Introduction: Protease-activated receptor 4 (PAR4) is expressed by a wide variety of cells, including megakaryocytes/platelets, immune cells, cardiomyocytes and lung epithelial cells, and activated by multiple ligands including thrombin and cathepsin G. Importantly, PAR4 is the only functional thrombin receptor on murine platelets. A global deficiency of PAR4 is associated with impaired hemostasis and protection from thrombosis which are attributed to loss of platelet PAR4, but this has not been specifically demonstrated in mice. Additionally, global PAR4 deficiency increases mortality after influenza A virus infection, but the cell type/s responsible for the enhanced mortality have not been determined. Here, we describe the generation of PAR4 floxed (PAR4 fl/fl) mice that can be used to delete PAR4 in a cell type-specific manner, and examine the effect of megakaryocyte/platelet-specific deletion of PAR4 on hemostasis, thrombosis and viral infection using PAR4 fl/fl;PF4Cre + mice. Methods: PAR4global knockout (PAR4 -/-), MK/platelet-specific knockout (PAR4 fl/fl;PF4Cre +) and appropriate littermate control mice were used for experiments. Platelet function was determined by light transmission aggregometry and flow cytometry. Hemostasis was assessed in the saphenous vein laser injury model. Platelet plug formation was visualized by intravital microscopy following saphenous vein laser ablation (~50 μm diameter injury), followed by 2 subsequent ablations to reinjure the same site unless on-going bleeding was occurring. Mice were treated with ibrutinib (12.5 mg/kg) to inhibit GPVI signaling, or dabigatran etexilate (chow containing 10 mg/g) or recombinant hirudin (50 mg/kg) to inhibit thrombin activity. Thrombosis was assessed in the carotid artery FeCl 3 model. The carotid artery was exposed and 8% FeCl 3 applied for 3 mins. Blood flow was observed for 30 mins and occlusion was defined as no blood flow for 2 mins. To study susceptibility to viral infection, mice were challenged intranasally with a mouse-adapted H1N1 influenza A virus (H1N1 IAV PR8; 0.02 hemagglutination assay units), which induces mortality in 20% of WT mice. Mortality was defined as body weight loss greater than 25%, which required euthanasia. Results: As expected, PAR4 fl/fl;PF4Cre + platelets were unresponsive to thrombin or PAR4-specific stimulation, while the response to other agonists was retained. In the saphenous vein laser injury hemostasis model, PAR4 fl/fl;PF4Cre + mice were able to rapidly form a hemostatic platelet plug, but the majority of plugs (7/8) were unstable and re-opened after several minutes, leading to severely prolonged total bleeding times. We observed similar findings in global PAR4 -/- mice with 8/12 plugs re-opening. To investigate the mechanism mediating initial platelet plug formation, we inhibited GPVI signaling in PAR4 fl/fl;PF4Cre + mice using the Btk inhibitor ibrutinib. Ibrutinib administration shortened time to plug re-opening in PAR4 fl/fl;PF4Cre + mice but plugs were still able to form, which is likely mediated by GPIbα/VWF. We observed a similar phenotype to PAR4 fl/fl;PF4Cre + mice in mice treated with the direct thrombin inhibitor hirudin, suggesting thrombin is the primary activator of PAR4 during hemostatic plug formation. In the FeCl 3-induced carotid artery thrombosis model, both PAR4 fl/fl;PF4Cre + and PAR4 -/- mice were significantly protected compared to controls. Finally, when challenged with the mouse-adapted H1N1 IAV PR8, PAR4 fl/fl;PF4Cre + mice demonstrated similar body weight loss and survival as littermate controls. Conclusions: Our results in mice demonstrate that 1) platelet PAR4 is not required for initial hemostatic plug formation but is necessary for maintaining hemostatic plug stability, 2) loss of platelet PAR4 protects from arterial thrombosis, and 3) platelet PAR4 does not alter the course of H1N1 IAV infection, at least at the virus dose used in this study. In summary, we generated a novel mouse line carrying a floxed PAR4 allele which can be used to investigate cell-specific roles of PAR4 in disease. Disclosures No relevant conflicts of interest to declare.

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Baicalin Downregulates RLRs Signaling Pathway to Control Influenza A Virus Infection and Improve the Prognosis

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/4923062 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Peng Pang ◽

Ke Zheng ◽

Sizhi Wu ◽

Huachong Xu ◽

Li Deng ◽

...

Keyword(s):

Body Weight ◽

Inflammatory Response ◽

Signaling Pathway ◽

Influenza A Virus ◽

Inflammatory Cytokines ◽

Influenza A ◽

Body Weight Loss ◽

High Viral Load ◽

High Expression ◽

Key Factors

The objective of this study is to investigate the effects of baicalin on controlling the pulmonary infection and improving the prognosis in influenza A virus (IAV) infection. PCR and western blot were used to measure the changes of some key factors in RLRs signaling pathway. MSD electrochemiluminescence was used to measure the expression of pulmonary inflammatory cytokines including IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, and KC/GRO. Flow cytometry was used to detect the proportion of Th1, Th2, Th17, and Treg. The results showed that IAV infection led to low body weight and high viral load and high expression of RIG-I, IRF3, IRF7, and NF-κB mRNA, as well as RIG-I and NF-κB p65 protein. However, baicalin reduced the rate of body weight loss, inhibited virus replication, and downregulated the key factors of the RLRs signaling pathway. Besides, baicalin reduced the high expression inflammatory cytokines in lung and decreased the ratios of Th1/Th2 and Th17/Treg to arouse a brief but not overviolent inflammatory response. Therefore, baicalin activated a balanced host inflammatory response to limit immunopathologic injury, which was helpful to the improvement of clinical and survival outcomes.

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Therapeutic Activity of Intramuscular Peramivir in Mice Infected with a Recombinant Influenza A/WSN/33 (H1N1) Virus Containing the H275Y Neuraminidase Mutation

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00753-12 ◽

2012 ◽

Vol 56 (8) ◽

pp. 4375-4380 ◽

Cited By ~ 14

Author(s):

Yacine Abed ◽

Andrés Pizzorno ◽

Guy Boivin

Keyword(s):

Weight Loss ◽

Body Weight ◽

Influenza A ◽

Low Dose ◽

Body Weight Loss ◽

High Dose ◽

Therapeutic Activity ◽

Enzymatic Assays ◽

Oseltamivir Resistance

ABSTRACTThe therapeutic activity of intramuscular (IM) peramivir was evaluated in mice infected with a recombinant influenza A/WSN/33 virus containing the H275Y neuraminidase (NA) mutation known to confer oseltamivir resistance. Regimens consisted of single (90 mg/kg of body weight) or multiple (45 mg/kg daily for 5 days) IM peramivir doses that were initiated 24 h or 48 h postinfection (p.i.). An oral oseltamivir regimen (1 or 10 mg/kg daily for 5 days) was used for comparison. Untreated animals had a mortality rate of 75% and showed a mean weight loss of 16.9% on day 5 p.i. When started at 24 h p.i., both peramivir regimens prevented mortality and significantly reduced weight loss (P< 0.001) and lung viral titers (LVT) (P< 0.001). A high dose (10 mg/kg) of oseltamivir initiated at 24 h p.i. also prevented mortality and significantly decreased weight loss (P< 0.05) and LVT (P< 0.001) compared to the untreated group results. In contrast, a low dose (1 mg/kg) of oseltamivir did not show any benefits. When started at 48 h p.i., both peramivir regimens prevented mortality and significantly reduced weight loss (P< 0.01) and LVT (P< 0.001) whereas low-dose or high-dose oseltamivir regimens had no effect on mortality rates, body weight loss, and LVT. Our results show that single-dose and multiple-dose IM peramivir regimens retain clinical and virological activities against the A/H1N1 H275Y variant despite some reduction in susceptibility when assessedin vitrousing enzymatic assays. IM peramivir could constitute an alternative for treatment of oseltamivir-resistant A/H1N1 infections, although additional studies are warranted to support such a recommendation.

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Rats eating and hoarding as a function of body weight and cost of foraging

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1989.257.4.r952 ◽

1989 ◽

Vol 257 (4) ◽

pp. R952-R957 ◽

Cited By ~ 4

Author(s):

M. Cabanac ◽

A. H. Swiergiel

Keyword(s):

Weight Loss ◽

Body Weight ◽

Body Weight Loss ◽

The Body ◽

Negative Slope ◽

Set Point ◽

Hoarding Behavior ◽

Body Weights ◽

Food Procurement ◽

Access To Food

Rats were trained to forage 2 h daily in a zigzag alley at -15 degrees C. On experimental days food was placed in large amounts at a 1-, 4-, or 16-m distance from a warm shelter. The mass of food ingested and hoarded in the shelter by the rats was then recorded. The rats' body weights were depressed progressively by spacing the sessions with access to food, and then the animals were allowed to recover their initial body weight. The results showed that 2-h food intake was constant and did not vary as a function of body weight loss or the distance to reach the food (cost). On the other hand, the mass of food hoarded was a linear increasing function of body weight loss below the hypothetical set point for body weight and a decreasing linear function of the distance to the food. The linear regression of the mass of food hoarded on body weight with a negative slope (b) adequately depicted the rat's hoarding behavior: mass hoarded = a + b (body wt). The slope of this function decreased with increasing cost of food procurement. It is concluded that 1) the main response of the rat to starvation is food hoarding rather than ingestion and 2) the estimation of the body weight set point from hoarding is not affected by the costs of food procurement.

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Developmental growth and body weight loss of cattle. I. Experimental design, body weight growth, and the effects of developmental growth and body weight loss on the dressed carcass and the offal

Australian Journal of Agricultural Research ◽

10.1071/ar9671015 ◽

1967 ◽

Vol 18 (6) ◽

pp. 1015 ◽

Cited By ~ 14

Author(s):

RM Seebeck

Keyword(s):

Weight Loss ◽

Body Weight ◽

Body Weight Loss ◽

Carcass Weight ◽

Weight Growth ◽

Developmental Growth ◽

Body Weights ◽

Group A ◽

Group B ◽

Full Body

At the age of approximately 11 months, 19 Angus steers were allotted to two experimental groups, namely, 10 to group A and 9 to group B. Group A animals were grown in pens and fed ad libitum. They were killed, two at each of the following of body weights: 250, 281, 316, 356, 400 kg. Group B animals were grown under similar conditions and killed at the same body weights as corresponding animals in group A; however, they were grown to weights 15% above their killing weights (growing-on phase) and then made to lose weight at 0.5 kg per day by restricting food intake until they reached their planned killing weights (weight loss phase). Huxley's (1932) allometric equation was used in logarithmic form as the basis for covariance analyses of the data. Empty body weight (EBW) increased as a proportion of full body weight as full body weight increased. EBW was higher in group A animals than in group B animals at the same full body weight, reflecting differences in weight of contents of the digestive tract. Dressed carcass weight increased as a proportion of EBW as EBW increased. Dressed carcass weight was higher in group B animals than in group A animals at the same EBW, indicating that the increase in carcass weight that occurred during the growing-on phase was not completely lost during the weight loss phase. During developmental growth, the weights of hide, feet, head, liver, gall bladder, heart, lungs, kidneys, and gut tissue decreased as proportions of EBW. The weight of abdominal fat increased as a proportion of EBW, while the weights of tail, spleen, and blood did not change significantly as proportions of EBW. During body weight loss, the weights of the feet, head, and tail remained close to the weights they had reached at the end of the growing-on phase, although, with the head, this varied considerably with the size of the animal before undergoing body weight loss. All other components lost weight during the weight loss phase. The hide, heart, lungs, and abdominal fat all reversed, approximately, the pattern of development that occurred during body weight growth. The liver, gall bladder, kidneys, gut tissue, spleen, blood, and thymus gland all lost more weight during the weight loss phase than they put on during the growing-on phase. With the liver, kidneys, and gut tissue, the proportion of weight lost varied according to the size of the animal before undergoing body weight loss.

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