High-Dose Intravenous Ribavirin Therapy for Subacute Sclerosing Panencephalitis

ABSTRACT Two patients with subacute sclerosing panencephalitis (SSPE) were treated safely and effectively with high doses of intravenous ribavirin combined with intraventricular alpha interferon. The ribavirin concentrations maintained in the serum and cerebrospinal fluid were higher than those which inhibit SSPE virus replication in vitro and in vivo.

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Effective ribavirin concentration in hamster brains for antiviral chemotherapy for subacute sclerosing panencephalitis.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.1.241 ◽

1996 ◽

Vol 40 (1) ◽

pp. 241-243 ◽

Cited By ~ 15

Author(s):

T Ishii ◽

M Hosoya ◽

S Mori ◽

S Shigeta ◽

H Suzuki

Keyword(s):

Cerebrospinal Fluid ◽

High Performance ◽

Subacute Sclerosing Panencephalitis ◽

Effective Concentration ◽

Intraventricular Administration ◽

Sspe Virus ◽

Antiviral Chemotherapy ◽

Potential Use

The ribavirin concentration in hamster brains was measured by a high-performance liquid chromatography (HPLC) system and a bioassay system. When ribavirin was administered intracranially at a dosage of 10 mg/kg of body weight per day for 10 days, a dosage which results in 100% survival of hamsters infected with subacute sclerosing panencephalitis (SSPE) virus and which inhibits the replication of SSPE virus in hamster brains, the ribavirin concentration in the brains estimated by HPLC and bioassay was kept higher than 50 micrograms/g for 10 days. The effective concentration in vivo corresponds to the concentration at which ribavirin completely inhibits the replication of SSPE virus in vitro. The maximal tolerable ribavirin concentration for hamsters was calculated to be 150 micrograms/g. Although ribavirin shows toxicity to the animals at a relatively low concentration (250 to 400 micrograms/g), intrathecal or intraventricular administration of ribavirin should be explored for potential use in the treatment of patients with SSPE, while the ribavirin concentration in cerebrospinal fluid or brain tissue should be monitored.

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Toll-Like Receptor Signaling in Airborne Burkholderia thailandensis Infection

Infection and Immunity ◽

10.1128/iai.00618-09 ◽

2009 ◽

Vol 77 (12) ◽

pp. 5612-5622 ◽

Cited By ~ 17

Author(s):

T. Eoin West ◽

Thomas R. Hawn ◽

Shawn J. Skerrett

Keyword(s):

Low Dose ◽

Inflammatory Responses ◽

High Dose ◽

Tlr Signaling ◽

Necrosis Factor Alpha ◽

Airborne Infection ◽

Essential Components ◽

High Doses

ABSTRACT Melioidosis is a tropical disease endemic in southeast Asia and northern Australia caused by the gram-negative soil saprophyte Burkholderia pseudomallei. Although infection is often systemic, the lung is frequently involved. B. thailandensis is a closely related organism that at high doses causes lethal pneumonia in mice. We examined the role of Toll-like receptors (TLRs), essential components of innate immunity, in vitro and in vivo during murine B. thailandensis pneumonia. TLR2, TLR4, and TLR5 mediate NF-κB activation by B. thailandensis in transfected HEK293 or CHO cells. In macrophages, TLR4 and the adaptor molecule MyD88, but not TLR2 or TLR5, are required for tumor necrosis factor alpha production induced by B. thailandensis. In low-dose airborne infection, TLR4 is needed for early, but not late, bacterial containment, and MyD88 is essential for control of infection and host survival. TLR2 and TLR5 are not necessary to contain low-dose infection. In high-dose airborne infection, TLR2 deficiency confers a slight survival advantage. Lung and systemic inflammatory responses are induced by low-dose inhaled B. thailandensis independently of individual TLRs or MyD88. These findings suggest that redundancy in TLR signaling or other MyD88-dependent pathways may be important in pneumonic B. thailandensis infection but that MyD88-independent mechanisms of inflammation are also activated. TLR signaling in B. thailandensis infection is substantially comparable to signaling induced by virulent B. pseudomallei. These studies provide additional insights into the host-pathogen interaction in pneumonic Burkholderia infection.

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Immunotherapy of a murine tumor with interleukin 2. Increased sensitivity after MHC class I gene transfection.

Journal of Experimental Medicine ◽

10.1084/jem.166.6.1716 ◽

1987 ◽

Vol 166 (6) ◽

pp. 1716-1733 ◽

Cited By ~ 61

Author(s):

J S Weber ◽

G Jay ◽

K Tanaka ◽

S A Rosenberg

Keyword(s):

T Cells ◽

Mhc Class I ◽

Interleukin 2 ◽

Class I ◽

High Dose ◽

Class I Mhc ◽

High Doses ◽

I Gene

We have shown that two weakly immunogenic MCA sarcomas developed in our laboratory that are sensitive to high-dose IL-2 immunotherapy express class I MHC in vivo and in vitro. Two nonimmunogenic MCA sarcomas are relatively insensitive to IL-2 therapy and express minimal or no class I MHC molecules in vivo and in vitro. To study the role of MHC in the therapy of tumors with IL-2, a class I-deficient murine melanoma, B16BL6, was transfected with the Kb class I gene. Expression of class I MHC rendered B16BL6 advanced pulmonary macrometastases sensitive to IL-2 immunotherapy. 3-d micrometastases of CL8-2, a class I transfected clone of B16BL6, were significantly more sensitive to IL-2 therapy than a control nontransfected line. Expression of Iak, a class II MHC molecule, had no effect on IL-2 therapy of transfectant pulmonary micrometastases in F1 mice. By using lymphocyte subset depletion with mAbs directed against Lyt-2, therapy of class I transfectant macrometastases with high-dose IL-2 was shown to involve an Lyt-2 cell. In contrast, regression of micrometastases treated with low-dose IL-2 involved Lyt-2+ cells, but regression mediated by high doses of IL-2 did not. We hypothesize that both LAK and Lyt-2+ T cells effect IL-2-mediated elimination of micrometastases, but only Lyt-2+ T cells are involved in macrometastatic regression. Low doses of IL-2 stimulate Lyt-2+ cells to eliminate class I-expressing micrometastases, but high doses of IL-2 can recruit LAK cells to mediate regression of micrometastases independent of class I expression. Only high-dose IL-2, mediating its effect predominantly via Lyt-2+ cells, is capable of impacting on MHC class I-expressing macrometastases. Macrometastases devoid of class I MHC antigens appear to be resistant to IL-2 therapy.

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Dose-Dependent Differential Effect of Neurotrophic Factors on In Vitro and In Vivo Regeneration of Motor and Sensory Neurons

Neural Plasticity ◽

10.1155/2016/4969523 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 28

Author(s):

Daniel Santos ◽

Francisco Gonzalez-Perez ◽

Xavier Navarro ◽

Jaume del Valle

Keyword(s):

Neurite Outgrowth ◽

Functional Recovery ◽

Neurotrophic Factors ◽

Collagen Matrix ◽

High Dose ◽

Organotypic Cultures ◽

High Doses ◽

Dose Dependent

Although peripheral axons can regenerate after nerve transection and repair, functional recovery is usually poor due to inaccurate reinnervation. Neurotrophic factors promote directional guidance to regenerating axons and their selective application may help to improve functional recovery. Hence, we have characterized in organotypic cultures of spinal cord and dorsal root ganglia the effect of GDNF, FGF-2, NGF, NT-3, and BDNF at different concentrations on motor and sensory neurite outgrowth. In vitro results show that GDNF and FGF-2 enhanced both motor and sensory neurite outgrowth, NGF and NT-3 were the most selective to enhance sensory neurite outgrowth, and high doses of BDNF selectively enhanced motor neurite outgrowth. Then, NGF, NT-3, and BDNF (as the most selective factors) were delivered in a collagen matrix within a silicone tube to repair the severed sciatic nerve of rats. Quantification of Fluorogold retrolabeled neurons showed that NGF and NT-3 did not show preferential effect on sensory regeneration whereas BDNF preferentially promoted motor axons regeneration. Therefore, the selective effects of NGF and NT-3 shown in vitro are lost when they are applied in vivo, but a high dose of BDNF is able to selectively enhance motor neuron regeneration both in vitro and in vivo.

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C1-esterase inhibitor treatment: preclinical safety aspects on the potential prothrombotic risk

Thrombosis and Haemostasis ◽

10.1160/th13-06-0469 ◽

2014 ◽

Vol 112 (11) ◽

pp. 960-971 ◽

Cited By ~ 12

Author(s):

Elmar Raquet ◽

Marc Nolte ◽

Frauke May ◽

Jochen Müller-Cohrs ◽

Jenny Björkqvist ◽

...

Keyword(s):

Thrombus Formation ◽

Venous Stasis ◽

High Dose ◽

In Vivo Models ◽

C1 Esterase Inhibitor ◽

Activity Measurements ◽

High Doses ◽

Esterase Inhibitor

SummaryHuman plasma-derived C1-esterase inhibitor (C1–INH) is an efficacious and safe treatment for hereditary angioedema. However, thrombotic events in subjects treated with C1–INH at recommended or offlabel, high doses have been reported. In this study, we addressed the potential prothrombotic risk of C1–INH treatment in high doses using a non-clinical rabbit model. Following intravenous infusion of C1–INH to rabbits at doses up to 800 IU/kg, the exposure and the pharmacodynamic efficacy of C1–INH in rabbits were confirmed by activity measurements of C1-esterase, and coagulation factors XIa and XIIa, respectively. Potential prothrombotic effects were assessed following induction of venous and arterial thrombosis using in vivo models of venous and arterial stasis, complemented by various in vitro assays of coagulation markers. Administration of C1–INH at doses up to 800 IU/ kg did not potentiate thrombus formation during venous stasis. In contrast, inhibition of arterial occlusion was observed upon C1–INH administration when compared with isotonic saline treatment, indicating antithrombotic rather than prothrombotic activity of high dose C1–INH treatment in vivo. This was further confirmed in vitro by decreased thrombin generation, increased activated partial thromboplastin time, clotting time and clot formation time, and inhibition of platelet aggregation. No relevant changes in fibrinolysis or in the levels of thrombin-antithrombin complexes, and prothrombin fragment 1+2 were observed upon high dose C1–INH treatment. The data suggest that treatment of healthy rabbits with high doses of C1–INH could potentially inhibit coagulation and thrombus formation rather than induce a prothrombotic risk.

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In Vivo Exposure to Bisphenol-A Altered the Reproductive Functionality in Male Coturnix Coturnix Japonica

10.21203/rs.3.rs-124102/v1 ◽

2020 ◽

Author(s):

SUTHAN PERMUAL ◽

GAUTHAM KOLLURI ◽

JAG MOHAN ◽

RAM SINGH ◽

JAGBIR TYAGI

Keyword(s):

Bisphenol A ◽

Sperm Quality ◽

Quality Attributes ◽

High Dose ◽

Japanese Quails ◽

High Doses ◽

Dose Dependent

Abstract Bisphenol-A, is one of the most characterized endocrine disruptors on the reproductive functions in humans and animals. We have previously reported in vitro and in vivo effects of bisphenol-A on functional role of sperm in chicken. Here, the effects of 1 and 5 mg/kg bisphenol-A daily administered by gavage for 3 wk to adult male Japanese quails on reproductive functionality was investigated. Cloacal index and foam frequency were greatly reduced at high dose. Sperm quality attributes were affected at both doses. Sperm quality attributes were affected at both doses. Alkaline phosphatase showed most significant reduction among seminal enzymes. Dose dependent response (P < 0.01) of bisphenol-A was noticed with modulating testosterone concentrations at low and high doses. Disturbances regarding fertility and hatchability traits were prominent in high and low dose groups. The current study confirms the compromising actions of bisphenol-A on reproductive success in male Japanese quails at lower doses that are considered to be safe (50 mg/kg BW/d) under in vivo exposure module. These results indicate higher sensitivity of quails to bisphenol-A toxicity and explores the possibility of using quail subjects as an accurate toxic indicators.

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Dose-Dependent Outcome of EBV Infection of Humanized Mice Based on Green Raji Unit (GRU) Doses

Viruses ◽

10.3390/v13112184 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2184

Author(s):

Haiwen Chen ◽

Ling Zhong ◽

Wanlin Zhang ◽

Shanshan Zhang ◽

Junping Hong ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Cd8 T Cells ◽

Humanized Mice ◽

High Dose ◽

Ebv Infection ◽

High Doses ◽

Dose Dependent

Humanized mouse models are used as comprehensive small-animal models of EBV infection. Previously, infectious doses of EBV used in vivo have been determined mainly on the basis of TD50 (50% transforming dose), which is a time-consuming process. Here, we determined infectious doses of Akata-EBV-GFP using green Raji units (GRUs), and characterized dose-dependent effects in humanized mice. We defined two outcomes in vivo, including an infection model and a lymphoma model, following inoculation with low or high doses of Akata-EBV-GFP, respectively. Inoculation with a low dose induced primary B cells to become lymphoblastoid cell lines in vitro, and caused latent infection in humanized mice. In contrast, a high dose of Akata-EBV-GFP resulted in primary B cells death in vitro, and fatal B cell lymphomas in vivo. Following infection with high doses, the frequency of CD19+ B cells decreased, whereas the percentage of CD8+ T cells increased in peripheral blood and the spleen. At such doses, a small part of activated CD8+ T cells was EBV-specific CD8+ T cells. Thus, GRUs quantitation of Akata-EBV-GFP is an effective way to quantify infectious doses to study pathologies, immune response, and to assess (in vivo) the neutralizing activity of antibodies raised by immunization against EBV.

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In vitro and In vivo Susceptibility of Baboons (Papio sp.) to Infection with and Apparent Antibody Reactivity to Simian Betaretrovirus (SRV)

Comparative Medicine ◽

10.30802/aalas-cm-19-000014 ◽

2020 ◽

Vol 70 (1) ◽

pp. 75-82

Author(s):

JoAnn L Yee ◽

Richard F Grant ◽

Koen K A Van Rompay ◽

Jeffrey A Roberts ◽

LaRene Kuller ◽

...

Keyword(s):

Tissue Culture ◽

Mononuclear Cells ◽

In Vivo Studies ◽

High Dose ◽

Peripheral Blood Mononuclear ◽

Antibody Reactivity ◽

High Doses ◽

Culture Virus

Despite the lack of confirmed reports of an exogenous Simian betaretrovirus (SRV) isolated from baboons (Papio sp.), reports of simian endogenous gammaretrovirus (SERV) in baboons with complete genomes suggest that such viruses may be potentially infectious. In addition, serologic tests have repeatedly demonstrated antibody reactivity to SRV in baboons from multiple colonies. These findings complicate the management and use of such animals for research. To provide further insight into this situation, we performed in vitro and in vivo studies to determine if baboons are or can be infected with SRV. In our initial experiment, we were not able to isolate SRV from 6 seropositive or sero-indeterminate baboons by coculturing their peripheral blood mononuclear cells (PBMC) with macaque PBMC or permissive cell lines. In a subsequent experiment, we found that baboon PBMC infected in vitro with high dose SRV were permissive to virus replication. To test in vivo infectibil- ity, groups of naive baboons were infused intravenously with either (i) the same SRV tissue culture virus stocks used for the in vitro studies, (ii) SRV antibody positive and PCR positive macaque blood, (iii) SRV antibody positive or indeterminate, but PCR negative baboon blood, or (iv) SRV antibody and PCR negative baboon blood. Sustained SRV infection, as defined by reproducible PCR detection and/or antibody seroconversion, was confirmed in 2 of 3 baboons receiving tissue culture virus but not in any recipients of transfused blood from seropositive macaques or baboons. In conclusion, the data indicate that even though baboon cells can be infected experimentally with high doses of tissue culture grown SRV, baboons that are repeatedly SRV antibody positive and PCR negative are unlikely to be infected with exogenous SRV and thus are unlikely to transmit a virus that would threaten the SPF status of captive baboon colonies.

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