scholarly journals An Orally Bioavailable (Mice) Prodrug of Glutathione

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 939
Author(s):  
Daune L. Crankshaw ◽  
Jacquie E. Briggs ◽  
Robert Vince ◽  
Herbert T. Nagasawa
Keyword(s):  
Oral Bioavailability ◽  
Toxic Dose ◽  
Mixed Disulfide ◽  
Wide Range ◽  
Orally Bioavailable

L-Cysteine-glutathione mixed disulfide (CySSG), a prodrug of glutathione (GSH), was found to be orally bioavailable in mice, and protected mice against a toxic dose of acetaminophen. If oral bioavailability can also be demonstrated in humans, a wide range of applicability for CySSG can be envisioned.

scholarly journals An Orally Bioavailable (Mice) Prodrug of Glutathione

2021 ◽  
Author(s):  
Herbert T. Nagasawa ◽  
Daune L. Crankshaw ◽  
Jacquie E. Briggs ◽  
Robert Vince
Keyword(s):  
Oral Bioavailability ◽  
Toxic Dose ◽  
Mixed Disulfide ◽  
Wide Range ◽  
Orally Bioavailable

Cysteine-glutathione mixed disulfide (CySSG), a prodrug of glutathione (GSH) --the “Master Antioxidant”, was found to be orally bioavailable in mice, and protected against a toxic dose of acetaminophen. If oral bioavailability can also be demonstrated in humans, this suggests a wide range of applicability for CySSG.

DIGITALIS TOLERANCE IN YOUNG PUPPIES

PEDIATRICS ◽  
1970 ◽  
Vol 46 (5) ◽  
pp. 730-736
Author(s):  
Katherine H. Halloran ◽  
Steven C. Schimpff ◽  
Jean G. Nicolas ◽  
Norman S. Talner
Keyword(s):  
Blood Gases ◽  
Acid Base Balance ◽  
Acid Base ◽  
Littermate Control ◽  
Premature Ventricular Contractions ◽  
Toxic Dose ◽  
Arterial Blood ◽  
Wide Range ◽  
Base Balance ◽  
The Mean

Tolerance to acetyl strophanthidin, a rapid-acting cardiac aglycone, was determined in 28 anesthetized mongrel puppies, ages 16 to 56 days, and compared to tolerance in 16 littermate puppies in whom acute hypercapnic acidemia was produced. The tolerance was also compared to that of four adult mongrel dogs. The toxic dose was defined as the intravenous amount required to produce four consecutive premature ventricular contractions. A marked variation in the toxic dose was found in the 28 control puppies (range 83 to 353 µg/kg, mean 169 µg/kg) which could not be correlated with age, arterial blood gases or pH, serum potassium or sodium, arterial pressure, or heart rate. The toxic dose was significantly greater in the puppies than in the adult dogs, in whom the mean toxic dose was 64 µg/kg (range 50 to 89 µg/kg). A significant increase in tolerance was also observed in the puppies with hypercapnic acidemia (mean toxic dose 220 µg/kg, range 93 to 375 µg/kg) in comparison to tolerance in the control puppies and despite the wide range of tolerance, each of the puppies with hypercapnic acidemia showed greater tolerance than its littermate control puppy. Assessment of the clinical implications of these findings will require study of the effects of alterations in acid-base balance on the inotropic effect of acetyl strophanthidin in addition to the toxic electrophysiologic effects.

scholarly journals Identification of GS 4104 as an Orally Bioavailable Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071

1998 ◽  
Vol 42 (3) ◽  
pp. 647-653 ◽  
Author(s):  
Weixing Li ◽  
Paul A. Escarpe ◽  
Eugene J. Eisenberg ◽  
Kenneth C. Cundy ◽  
Clive Sweet ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Ethyl Ester ◽  
Oral Bioavailability ◽  
Influenza A ◽  
Neuraminidase Inhibitor ◽  
Virus Infections ◽  
Neuraminidase Activity ◽  
Orally Bioavailable ◽  
Influenza Virus Neuraminidase

ABSTRACT GS 4071 is a potent carbocyclic transition-state analog inhibitor of influenza virus neuraminidase with activity against both influenza A and B viruses in vitro. GS 4116, the guanidino analog of GS 4071, is a 10-fold more potent inhibitor of influenza virus replication in tissue culture than GS 4071. In this study we determined the oral bioavailabilities of GS 4071, GS 4116, and their respective ethyl ester prodrugs in rats. Both parent compounds and the prodrug of the guanidino analog exhibited poor oral bioavailability (2 to 4%) and low peak concentrations in plasma (C maxs; C max<0.06 μg/ml). In contrast, GS 4104, the ethyl ester prodrug of GS 4071, exhibited good oral bioavailability (35%) as GS 4071 and high C maxs of GS 4071 (Cmax = 0.47 μg/ml) which are 150 times the concentration necessary to inhibit influenza virus neuraminidase activity by 90%. The bioavailability of GS 4104 as GS 4071 was also determined in mice (30%), ferrets (11%), and dogs (73%). The plasma of all four species exhibited high, sustained concentrations of GS 4071 such that at 12 h postdosing the concentrations of GS 4071 in plasma exceeded those necessary to inhibit influenza virus neuraminidase activity by 90%. These results demonstrate that GS 4104 is an orally bioavailable prodrug of GS 4071 in animals and that it has the potential to be an oral agent for the prevention and treatment of influenza A and B virus infections in humans.

scholarly journals Rethinking Remdesivir: Synthesis of Lipid Prodrugs that Substantially Enhance Anti-Coronavirus Activity

2020 ◽  
Author(s):  
Robert T. Schooley ◽  
Aaron F. Carlin ◽  
James R. Beadle ◽  
Nadejda Valiaeva ◽  
Xing-Quan Zhang ◽  
...  
Keyword(s):  
Early Treatment ◽  
Oral Bioavailability ◽  
Advanced Disease ◽  
Metabolic Activation ◽  
Single Step ◽  
Hospitalized Patients ◽  
Activation Pathway ◽  
Clinical Recovery ◽  
Infected Cells ◽  
Orally Bioavailable

ABSTRACTThe FDA has granted Remdesivir (RDV, GS-5734) an emergency use authorization on the basis of an acceleration of clinical recovery in hospitalized patients with COVID-19. Unfortunately, the drug must be administered intravenously, restricting its use to those with relatively advanced disease. RDV is also unstable in plasma and has a complex activation pathway which may contribute to its highly variable antiviral efficacy in SARS-CoV-2 infected cells. A potent orally bioavailable antiviral for early treatment of SARS-CoV-2 infection is needed. We focused on making simple orally bioavailable lipid analogs of Remdesivir nucleoside (RVn, GS-441524) that are processed to RVn-monophosphate, the precursor of the active RVn-triphosphate, by a single step intracellular cleavage. In addition to likely improved oral bioavailability and simpler metabolic activation, two of the three new lipid prodrugs of RVn had anti-SARS-CoV-2 activity 9 to 24 times greater than that of RDV in Vero E6 cells

Phase 1 Assessment of an Orally Bioavailable Formulation of Gallium Nitrate (G4544).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4455-4455
Author(s):  
Thomas Julian ◽  
Shingai Majuru ◽  
Moses Oyewumi ◽  
Steven Novick ◽  
Miriam Mangelus ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Clinical Studies ◽  
Oral Bioavailability ◽  
Oral Absorption ◽  
Phase 1 ◽  
Clinical Samples ◽  
Gallium Nitrate ◽  
Low Doses ◽  
Metabolic Markers ◽  
Orally Bioavailable

Abstract Background: High intravenous doses of gallium nitrate (GN) (200–300 mg/m2/day for 5–7 days) are extremely effective for treatment of patients (pts) with cancer-related hypercalcemia, and preliminary studies have shown consistent anticancer activity in pts with relapsed non-Hodgkin’s lymphoma (NHL). In preclinical studies, low concentrations of GN act as a potent inhibitor of osteoclast-mediated bone resorption, and the agent may also have anabolic effects on bone formation. Clinical studies have shown that low doses of GN (0.25–0.5 mg/kg/day x 14 days) administered by subcutaneous (SC) injection significantly reduced metabolic markers of disordered bone turnover in advanced Paget’s disease. Moreover, a multi-year longitudinal study in pts with advanced multiple myeloma showed that similarly low doses of GN administered by intermittent SC injection significantly reduced bone loss in pts receiving M-2 chemotherapy, and this therapy may have been associated with increased survival (Niesvizky R, Semin Oncol30 (Suppl. 5): 20–4, 2003). GN has low oral bioavailability, and in order to improve dosing convenience over extended periods, we have investigated the oral absorption of numerous gallium-containing compounds. We have successfully developed a novel formulation of GN (G4544) that has acceptable oral bioavailability, and this formulation has now advanced into initial clinical studies. Methods: GN was formulated with a proprietary functional excipient (Emisphere Technologies, Inc.), and compressed into tablets containing 30 mg of elemental gallium by weight (G4544). Oral availability of the formulation was tested in comparison with a control formulation without the functional excipient in dogs. G4544 was then examined in a dose-ranging study to assess safety and pharmacokinetics (PK) following administration of single oral doses to healthy male volunteers. Individual patient cohorts (6 subjects per level) received doses starting at 30 mg gallium and increasing to 60, 90, 120, and 150 mg. Plasma samples were assayed periodically to evaluate PK. Results: Non-clinical studies showed that tablets containing the functional excipient significantly increased gallium absorption compared to controls lacking excipient. The increase in plasma gallium exposure was up to 2.2-fold in AUC and 2.8-fold in Cmax. After a single dose of G4544, the observed mean Cmax and mean AUC0-inf for G4544 was 1.5 ug/mL and 33.0 hr*mg/mL, respectively, compared to 0.5 ug/mL and 14.8 hr*mg/mL for the control formulation. PK assays of clinical samples are pending and will be presented. Conclusions: Low doses of GN have highly potent anti-resorptive effects on bone, and potentially direct activity against myeloma and NHL cells. G4544 markedly increases the oral absorption of GN and may extended oral dosing for treatment of diseases associated with accelerated bone resorption. Follow-up clinical trials are planned to establish the bioequivalence of G4544 to the currently available parenteral formulation for acute treatment of cancer-related hypercalcemia.

Potent and Orally Bioavailable HIV-1 Proteinase Inhibitors Containing the 2-aminobenzylstatine Moiety

1995 ◽  
Vol 6 (5) ◽  
pp. 327-336 ◽  
Author(s):  
A. Billich ◽  
D. Scholz ◽  
B. Charpiot ◽  
H. Gstach ◽  
P. Lehr ◽  
...  
Keyword(s):  
Oral Bioavailability ◽  
Proteinase Inhibitor ◽  
Proteinase Inhibitors ◽  
Infected Cells ◽  
Orally Bioavailable ◽  
Derivatives Of ◽  
Hiv 1 ◽  
Good Oral Bioavailability

In order to design HIV proteinase inhibitors which combine antiviral potency in HIV-infected cells with good oral bioavailability, new derivatives of 2-aminobenzylstatine containing HIV-1 proteinase inhibitors were synthesized. Compounds showing the desired profile emerged from a series of modifications at the P3′ moiety of the parent inhibitor [1], and are characterized by the presence of hydroxy or methoxy substituents at the C-terminal benzylamide. The most potent congeners, compounds [15] and [19], were evaluated in more detail and proved inhibitory to HIV-1 replication in primary T4 lymphocytes with EC90 = 2.2 and 2.7 nM, respectively. They also exhibited adequate oral bioavailability in the range of [13] to 42% in mice and rats. Thus, further investigation of this type of HIV proteinase inhibitor seems warranted.

scholarly journals Screening, Optimization, and Bioavailability Research of Natural Deep Eutectic Solvent Extracts from Radix Pueraria

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 729
Author(s):  
Yan Huang ◽  
Jiehong Yang ◽  
Yu Zhao ◽  
Li Yu ◽  
Yu He ◽  
...  
Keyword(s):  
Oral Bioavailability ◽  
Extraction Efficiency ◽  
Biological Activities ◽  
Deep Eutectic Solvent ◽  
Relative Bioavailability ◽  
Pharmacokinetic Analysis ◽  
Optimal Conditions ◽  
Solubility In Water ◽  
Wide Range ◽  
Natural Deep Eutectic Solvent

Natural deep eutectic solvent (NaDES) is generally considered as a greener alternative to fossil solvent, with great potential in various areas. In the present work, 25 different NaDESs were screened for the extraction of puerarin (PUE) and its two natural derivatives from Radix Pueraria (RP). As the main isoflavone in RP, PUE has a wide range of biological activities. However, its application is restricted due to its poor solubility in water and low oral bioavailability. In this study, the extraction of PUE with NaDESs showed significant advantages compared with traditional solvents. While using L-Pro-Maa (L-proline-malic acid) under optimal conditions, the optimized yields of PUE, 3-MPR and PRX were 98.7 mg/g, 16.3 mg/g and 9.9 mg/g, respectively, which were 2.2-, 2.9- and 3.4-fold higher than that of water. Furthermore, the oral bioavailability of PUE in NaDES extracts was comparatively investigated in rats with HPLC-MS technique. Pharmacokinetic analysis revealed that the relative bioavailability of PUE in L-Pro-Maa extract is 323%. The result indicated that NaDES is not only a sustainable ionic liquid with higher extraction efficiency, but also an enhancer of oral bioavailability of specific natural products.

scholarly journals Phase Ib trial of reformulated niclosamide with abiraterone/prednisone in men with castration-resistant prostate cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mamta Parikh ◽  
Chengfei Liu ◽  
Chun-Yi Wu ◽  
Christopher P. Evans ◽  
Marc Dall’Era ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Plasma Levels ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Castration Resistant Prostate Cancer ◽  
Phase Ib ◽  
Castration Resistant ◽  
Wide Range ◽  
Orally Bioavailable ◽  
Group 2

AbstractNiclosamide has preclinical activity against a wide range of cancers. In prostate cancer, it inhibits androgen receptor variant 7 and synergizes with abiraterone. The approved niclosamide formulation has poor oral bioavailability. The primary objective of this phase Ib trial was to identify a maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of a novel reformulated orally-bioavailable niclosamide/PDMX1001 in combination with abiraterone and prednisone in men with castration-resistant prostate cancer (CRPC). Eligible patients had progressing CRPC, adequate end-organ function, and no prior treatment with abiraterone or ketoconazole. Patients were treated with escalating doses of niclosamide/PDMX1001 and standard doses of abiraterone and prednisone. Peak and trough niclosamide plasma levels were measured. Common Terminology Criteria for Adverse Events (CTCAE) v4.0 and Prostate Cancer Working Group 2 criteria were used to evaluate toxicities and responses. Nine patients with metastatic CRPC were accrued, with no dose-limiting toxicities observed at all dose levels. The recommended Phase II dose of niclosamide/PDMX1001 was 1200 mg orally (PO) three times daily plus abiraterone 1000 mg PO once daily and prednisone 5 mg PO twice daily. Trough and peak niclosamide concentrations exceeded the therapeutic threshold of > 0.2 µM. The combination was well tolerated with most frequent adverse effects of diarrhea. Five out of eight evaluable patients achieved a PSA response; two achieved undetectable PSA and radiographic response. A novel niclosamide/PDMX1001 reformulation achieved targeted plasma levels when combined with abiraterone and prednisone, and was well tolerated. Further study of niclosamide/PDMX1001 with this combination is warranted.

Pharmacologic Evaluation of Orally Bioavailable Inhibitors of the 20S Proteasome.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3581-3581
Author(s):  
Christopher J. Kirk ◽  
Monette A. Aujay ◽  
Mark Ho ◽  
Jing Jiang ◽  
Guy J. Laidig ◽  
...  
Keyword(s):  
Oral Bioavailability ◽  
Proteasome Inhibitors ◽  
Systemic Exposure ◽  
Proteasome Inhibition ◽  
Cell Permeability ◽  
Intestinal Cell ◽  
Pharmacokinetic Analysis ◽  
20S Proteasome ◽  
Orally Bioavailable

Abstract Clinical application of proteasome inhibitors in the treatment of hematologic malignancies such as myeloma and lymphoma is restricted in part by the necessity of frequent IV administration and would be improved by oral (PO) administration. Selective inhibitors of the protease subunits of the 20S proteasome can be generated from peptidyl aldehydes, boronates, vinyl sulfones, and epoxyketones. Many of these peptide based proteasome inhibitors are cell permeant and capable of systemic proteasome inhibition upon intravenous (IV) administration to experimental animals such as mice and rats. In the cases of the peptidyl boronate bortezomib (Velcade™) and the epoxyketone PR-171, proteasome inhibition can be achieved in patients with IV administration. However, systemic exposure following PO administration of these inhibitors may be limited by several factors including gastric pH, gastric and intestinal peptidases, efflux pumps, biliary excretion and intestinal and hepatic metabolic activities. We have tested over 80 peptide epoxyketones with potent (IC50 <100 nM) in vitro inhibitory activity against the chymotrypsin-like activity of the 20S proteasome for bioavailability following PO administration in mice. Systemic exposure was monitored by measuring chymotrypsin-like inhibition in a number of tissues and an approximation of the relative bioavailability for selected compounds was measured by comparing the pharmacodynamics of IV and PO administration using a range of doses. These compounds were also tested in vitro for solubility, intestinal cell permeability, intestinal and hepatic metabolism, and sensitivity to the multidrug resistance protein 1 (MDR1) efflux pump in order to determine which properties were associated with oral bioavailability. We have found that oral bioavailability in mice is associated with increased intrinsic solubility and metabolic stability and reduced MDR1 sensitivity. Proteasome inhibition following PO administration is rapid, resulting in maximal proteasome inhibition within 15 minutes. Rapid absorption and clearance of selected compounds was also confirmed in mice and rats by pharmacokinetic analysis. Repeated oral administration was well tolerated at doses that resulted in significant (>80%) proteasome inhibition in most tissues. The anti-tumor efficacy of these orally bioavailable proteasome inhibitors are being assessed in both human tumor xenograft and mouse syngeneic models. The results from these studies will enable further pre-clinical development of potent, orally bioavailable proteasome inhibitors for the treatment of malignant diseases.

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