31 results about "Toxicity profile" patented technology

Imino sugars, such as deoxynojirimycin (DNJ), are glucose analogues that selectively inhibit cellular α-glucosidase I and II (enzymes that process N-linked glycans in glycoprotein) and exhibit broad spectrum antiviral activities against many enveloped viruses. Previously we have reported a novel DNJ derivative, OSL-95II, with antiviral activity and reduced cytotoxicity. In order to develop imino sugars with more potent antiviral activity as well as improved toxicity profile, OSL-95II was modified by diversifying the nitrogen linked alkylated side chain. The antiviral activities were initially tested in bovine viral diarrhea virus (BVDV) infected MDBK cells, yielding several imino sugar derivatives with novel structure and superior antiviral activity and toxicity profile. Furthermore, these new compounds were shown to be active against Dengue virus (DV) and West Nile virus (WNV) infection in BHK cells where potent anti-DV activity having submicromolar EC50 values and SI of greater than 900. These compounds represent a new generation of iminio sugars and their analogues, having application in the clinical treatment of infection of DV and other members of flaviviridae.

The present invention provides pyridopyrimidinone compounds with desirable biological activity and toxicity profiles for the enhanced treatment and prevention of malaria. The invention also relates to methods of making such molecules.

The present invention provides gapped oligomeric compounds. More particularly the gapped oligomeric compounds provided herein comprise at least one modified intemucleoside linkage in the gap region. Such gapped oligomeric compounds have one or more improved properties such as selectivity, potency, improved toxicity profile and or improved proinflammatory profile. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount activity or expression of the target nucleic acid in a cell.

Acetaminophen conjugates are provided, which have an acetaminophen moiety covalently linked to a second moiety. The conjugates provided may have one or more advantageous properties, including increased water solubility as compared to acetaminophen, reduced toxicity profile as compared to acetaminophen and an altered pharmacokinetic profile. Formulations comprising the conjugates are also provided, as are methods of using the conjugates and kits comprising the conjugates.

The present invention is in the field of polymer-based nano-carriers for the solubilization and delivery of hydrophobic drugs, and relates to methods of making said carriers, and to pharmaceutical compositions comprising said carriers. Novel PEO-b-PCL micelles and micelles containing cyclosporine A or analogs thereof are provided as well as a novel method for making said micelles that reduces aggregation and enhances delivery, the toxicity profile and biodistribution of hydrophobic drugs.

Acetaminophen conjugates are provided, which have an acetaminophen moiety covalently linked to a second moiety. The conjugates provided may have one or more advantageous properties, including increased water solubility as compared to acetaminophen, reduced toxicity profile as compared to acetaminophen and an altered pharmacokinetic profile. Formulations comprising the conjugates are also provided, as are methods of using the conjugates and kits comprising the conjugates.

Differential surface-charge-dependent localization of nanoceria in normal cells and cancer cells plays a critical role in the toxicity profile of a nanoceria particle. Engineered surface-coated cerium oxide nanoparticles with different surface charges that are positive, negative and neutral provide therapeutic results for normal and cancer cell lines. Results show that nanoceria with a positive or neutral charge enters most of the cell lines studied, while nanoceria with a negative charge internalizes mostly in the cancer cell lines. Moreover, upon entry into the cells, nanoceria is localized to different cell compartments (e.g. cytoplasm and lysosomes) depending on the nanoparticle surface charge. The internalization and subcellular localization of nanoceria plays a key role in the nanoparticle cytotoxicity profile, exhibiting significant toxicity when they localize in the lysosomes of the cancer cell lines. In contrast, minimal toxicity is observed when they localize into the cytoplasm or do not enter the cells.

The present invention provides new chemical compositions with desirable biological activity and toxicity profiles for the enhanced treatment of malaria.

The invention provides a prodrug platform technology for improving the therapeutic value of a variety of parent drug compounds by altering and improving drug characteristics such as aqueous solubility, hydrolytic stability, therapeutic index, toxicity profile, pharmacolcinetics and selectivity while allowing the potential for synthetic elaboration. The prodrug platform is particularly well suited for targeting therapeutic drugs, including anti-tumor drugs and antibiotics, to specific receptors on target cells (e.g., cancer cells and bacteria). The platform is a technology for providing an improved, preactivated form of a therapeutic drug, and for optionally targeting such drug to target cells or biological molecules. The invention is broadly applicable to many different therapeutic drugs, as well as to a variety of diseases and conditions, including a variety of forms of cancer and bacterial infections.

Enantiomers of 1′,6′-isoneplanocin, including derivatives of the enantiomers of 1′,6′-isoneplanocin, are disclosed along with novel synthetic methods. In particular, a substituted cyclopentane epoxide is synthesized into the enantiomers of 1′,6′-isoneplanocin. Enantiomers of carbocyclic nucleoside analogs of 3-deazaneplanocin to provide D- and L-like 1′,6′-iso-3-deazaneplanocin are also disclosed. The small molecule chemotherapeutic compounds beneficially provide DNA and RNA antiviral activity, demonstrating activity towards, for example, human cytomegalovirus, measles, Ebola, norovirus, dengue, vaccinia and HBV. Compounds exhibiting reduced S-adenosylhomocysteine hydrolase inhibitory effects are disclosed and provide improved toxicity profiles in comparison to neplanocin. The invention provides improved prophylactic and / or therapeutic antiviral efficacy.

The present invention provides new chemical compositions with desirable biological activity and toxicity profiles for the enhanced treatment of malaria.

The present invention provides oligomeric compounds comprising at least one neutral methoxypropyl phosphonate modified internucleoside linkage. Such oligomeric compounds have one or more improved properties such as selectivity, potency, improved toxicity profile and or improved proinflammatory profile. Such oligomeric compounds have enhanced stability to exposure to base during synthesis. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount activity or expression of the target nucleic acid in a cell.

The present invention provides new chemical compositions with desirable biological activity and toxicity profiles for the enhanced treatment of malaria.

Imino sugars, such as deoxynojirimycin (DNJ), are glucose analogues that selectively inhibit cellular α-glucosidase I and II (enzymes that process N-linked glycans in glycoprotein) and exhibit broad spectrum antiviral activities against many enveloped viruses. Previously we have reported a novel DNJ derivative, OSL-95II, with antiviral activity and reduced cytotoxicity. In order to develop imino sugars with more potent antiviral activity as well as improved toxicity profile, OSL-95II was modified by diversifying the nitrogen linked alkylated side chain. The antiviral activities were initially tested in bovine viral diarrhea virus (BVDV) infected MDBK cells, yielding several imino sugar derivatives with novel structure and superior antiviral activity and toxicity profile. Furthermore, these new compounds were shown to be active against Dengue virus (DV) and West Nile virus (WNV) infection in BHK cells where potent anti-DV activity having submicromolar EC50 values and SI of greater than 900. These compounds represent a new generation of iminio sugars and their analogues, having application in the clinical treatment of infection of DV and other members of flaviviridae.

The present disclosure relates to methods for treating cancer by intrapulmonary administration of a polynucleotide Toll-like receptor 9 agonist. The methods of the present disclosure are suitable fortreating primary cancer of the lung, as well as metastatic cancer to the lung and extra pulmonary cancers thereof. Additionally, the present disclosure provides polynucleotide Toll-like receptor 9 agonists with immune stimulatory and toxicity profiles suitable for intrapulmonary administration.

The invention provides transgenic animals that are heterozygous or homozygous for a nonfunctional allele of BACE-1. These animals show normal development indicating that BACE-1 is not necessary for development and hence is an appropriate therapeutic target. The transgenic animals are useful in various screening assays including identifying inhibitors of other enzymes involved in processing of APP to Aβ and determining a toxicity profile of inhibitors of BACE-1.

The present invention provides new chemical compositions with desirable biological activity and toxicity profiles for the enhanced treatment of malaria.

Methods of screening a compound for susceptibility to causing systemic or hepatic toxicity, using a hepatic cell system exposed to a range of concentrations of a bile acid in the absence or presence of a compound to determine a toxicity profile. In vitro systems for predicting in vivo hepatotoxic potential of a compound are also provided, and include in vitro cultured hepatic cell systems with a capacity for bile acid synthesis, bile acid transport and bile acid regulation.

The present invention relates to transgenic animals comprising a mutation or deletion to the ANF-RGC protein, particularly to its ARM and / or its ATS-ST region. Such animals may be used to study the effects on pathways associated with ANF-RGC activation, including, but not limited to, hypertension. Such animals may also be used in drug screen assays, to establish toxicity profiles, or other similar methods discussed herein known in the art.

The present invention provides new chemical compositions with desirable biological activity and toxicity profiles for the enhanced treatment of malaria.

The invention discloses a method for predicting the toxicity of novel pollutants of non-steroidal anti-inflammatory drugs to embryos in the early life stage of zebrafish. The present invention records the mortality and distortion rate of zebrafish embryos after exposure for 7 days by exposing the zebrafish embryos to the new pollutants of non-steroidal anti-inflammatory drugs in an equal logarithmic interval concentration; and then uses SPSS software to calculate the corresponding LC 50 and teratogenic EC 50 To evaluate the toxicity of novel pollutants of non-steroidal anti-inflammatory drugs. The method of the invention realizes the analysis, testing and quantitative description of the toxicity characteristics and toxicity levels of the new pollutants of the non-steroidal anti-inflammatory drugs, and can be used as an index for monitoring and evaluating the biological toxicity of the non-steroidal anti-inflammatory drug sewage. It provides a reference for the prediction and assessment of the potential ecotoxicity risk of such pollutants in China.

The present invention provides new chemical compositions with desirable biological activity and toxicity profiles for the enhanced treatment of malaria.

Differential surface-charge-dependent localization of nanoceria in normal cells and cancer cells plays a critical role in the toxicity profile of a nanoceria particle. Engineered surface-coated cerium oxide nanoparticles with different surface charges that are positive, negative and neutral provide therapeutic results for normal and cancer cell lines. Results show that nanoceria with a positive or neutral charge enters most of the cell lines studied, while nanoceria with a negative charge internalizes mostly in the cancer cell lines. Moreover, upon entry into the cells, nanoceria is localized to different cell compartments (e.g. cytoplasm and lysosomes) depending on the nanoparticle surface charge. The internalization and subcellular localization of nanoceria plays a key role in the nanoparticle cytotoxicity profile, exhibiting significant toxicity when they localize in the lysosomes of the cancer cell lines. In contrast, minimal toxicity is observed when they localize into the cytoplasm or do not enter the cells.

Enantiomers of 1′,6′-isoneplanocin, including derivatives of the enantiomers of 1′,6′-isoneplanocin, are disclosed along with novel synthetic methods. In particular, a substituted cyclopentane epoxide is synthesized into the enantiomers of 1′,6′-isoneplanocin. Enantiomers of carbocyclic nucleoside analogs of 3-deazaneplanocin to provide D- and L-like 1′,6′-iso-3-deazaneplanocin are also disclosed. The small molecule chemotherapeutic compounds beneficially provide DNA and RNA antiviral activity, demonstrating activity towards, for example, human cytomegalovirus, measles, Ebola, norovirus, dengue, vaccinia and HBV. Compounds exhibiting reduced S-adenosylhomocysteine hydrolase inhibitory effects are disclosed and provide improved toxicity profiles in comparison to neplanocin. The invention provides improved prophylactic and / or therapeutic antiviral efficacy.

A molecular model of pokeweed antiviral protein (PAP)-RNA interactions was used to rationally engineer FLP-102 (151AA152) and FLP-105 (191AG192) as nontoxic PAP proteins with potent anti-HIV activity. FLP-102 and FLP-105 have been produced in E. coli and tested both in vitro as well as in vivo. These proteins depurinate HIV-1 RNA much better than ribosomal RNA and are more potent anti-HIV agents than native PAP or recombinant wild-type PAP. They are substantially less toxic than native PAP in BALB / c mice and exhibit potent in vivo activity against genotypically and phenotypically NRTI-resistant HIV-1 in a surrogate Hu-PBL-SLID mouse model of human AIDS. Rationally engineered nontoxic recombinant PAP proteins such as FLP-102 and FLP-105 may provide the basis for effective salvage therapies for patients harboring highly drug resistant strains of HIV-1. The documented in vitro potency of FLP-102 and FLP-105, their in vivo antiretroviral activity in HIV-infected Hu-PBL SCID mice, and their favorable toxicity profile in BALB / c mice warrant the further development of these promising new biotherapeutic agents.

The present invention provides morpholino modified oligomeric compounds having at least one monomer subunit having Formula III, compounds having Formula I useful for making certain of the morpholino modified oligomeric compounds and methods of using the oligomeric compounds. In certain embodiments, the oligomeric compounds provided herein provide for an improved toxicity profile. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount of activity or expression of the target nucleic acid in a cell.

A compound of formula (I) with improved TGF Beta signaling pathway inhibitory activity, improved therapeutic efficacy and improved toxicity profile, as well as two prodrugs thereof are disclosed. Compositions comprising said TGF Beta signaling pathway inhibitor and prodrugs thereof are also disclosed. Additionally, present invention discloses said compound of formula (I) and prodrugs thereof for use in a method of treating diseases responsive to TGF Beta signaling pathway inhibition.

The present invention provides morpholino modified oligomeric compounds having at least one monomer subunit having Formula III, compounds having Formula I useful for making certain of the morpholino modified oligomeric compounds and methods of using the oligomeric compounds. In certain embodiments, the oligomeric compounds provided herein provide for an improved toxicity profile. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount of activity or expression of the target nucleic acid in a cell.