scholarly journals Antifungal Activity of LY303366, a Novel Echinocandin B, in Experimental Disseminated Candidiasis in Rabbits

1999 ◽  
Vol 43 (9) ◽  
pp. 2148-2155 ◽  
Author(s):  
Ruta Petraitiene ◽  
Vidmantas Petraitis ◽  
Andreas H. Groll ◽  
Myrna Candelario ◽  
Tin Sein ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Vena Cava ◽  
Study Groups ◽  
Disseminated Candidiasis ◽  
Echinocandin B ◽  
Time Kill ◽  
Dose Dependent ◽  
The Brain

ABSTRACT The safety and antifungal activity of LY303366 (LY), a new broad-spectrum semisynthetic echinocandin, were studied against disseminated candidiasis in persistently neutropenic rabbits. In vitro time-kill assays demonstrated that LY has concentration-dependent fungicidal activity. The pharmacokinetics of LY in the plasma of nonneutropenic rabbits suggested a linear relationship between dose and area under the curve (AUC). The times spent above the MIC during the experimental dosing interval of 24 h were 4 h for LY at 0.1 mg/kg of body weight/day (LY0.1), 8 h for LY at 0.25 mg/kg/day (LY0.25), 12 h for LY at 0.5 mg/kg/day (LY0.5), and 20 h for LY at 1 mg/kg/day (LY1). Antifungal therapy was administered to infected rabbits for 10 days starting 24 h after the intravenous (i.v.) inoculation of 103 Candida albicansblastoconidia. Study groups consisted of untreated controls (UCs) and animals treated with amphotericin B (AmB; 1 mg/kg/day i.v.), fluconazole (FLU; 10 mg/kg/day i.v.), and LY0.1, LY0.25, LY0.5, or LY1 i.v. Rabbits treated with LY0.5, LY1, AmB, and FLU had similarly significant clearance of C. albicans from the liver, spleen, kidney, lung, vena cava, and brain in comparison to that for UCs. There was a dose-dependent clearance of C. albicansfrom tissues in response to LY. Among rabbits treated with LY0.1 there was a significant reduction of C. albicans only in the spleen. In animals treated with LY0.25 there was a significant reduction in all tissues but the brain. By comparison, LY0.5 and LY1 cleared all tissues, including the brain, of C. albicans. These in vivo findings were consistent with the results of in vitro time-kill assays. A dose-dependent effect of altered cell wall morphology was observed among UCs and animals treated with LY0.1, and LY0.25, with a progressive transition from hyphal structure to disrupted yeast forms. Serum creatinine levels were higher and serum potassium levels were lower in AmB-treated rabbits than in UCs and LY- and FLU-treated rabbits. LY0.5 and LY1 were well tolerated, displayed predictable pharmacokinetics in plasma, and had activities comparable to those of AmB and FLU in the treatment of disseminated candidiasis in persistently neutropenic rabbits.

scholarly journals The Antiviral Effect of Novel Steroidal Derivatives on Flaviviruses

2021 ◽  
Vol 12 ◽  
Author(s):  
Luping Zhang ◽  
Dengyuan Zhou ◽  
Qiuyan Li ◽  
Shuo Zhu ◽  
Muhammad Imran ◽  
...  
Keyword(s):  
Antiviral Effect ◽  
Therapeutic Drug ◽  
Dependent Manner ◽  
Design And Synthesis ◽  
Invasion Stage ◽  
Synthetic Derivatives ◽  
Dose Dependent ◽  
The Brain

Flaviviruses are the major emerging arthropod-borne pathogens globally. However, there is still no practical anti-flavivirus approach. Therefore, existing and emerging flaviviruses desperately need active broad-spectrum drugs. In the present study, the antiviral effect of steroidal dehydroepiandrosterone (DHEA) and 23 synthetic derivatives against flaviviruses such as Japanese encephalitis virus (JEV), Zika virus (ZIKV), and Dengue virus (DENV) were appraised by examining the characteristics of virus infection both in vitro and in vivo. Our results revealed that AV1003, AV1004 and AV1017 were the most potent inhibitors of flavivirus propagation in cells. They mainly suppress the viral infection in the post-invasion stage in a dose-dependent manner. Furthermore, orally administered compound AV1004 protected mice from lethal JEV infection by increasing the survival rate and reducing the viral load in the brain of infected mice. These results indicate that the compound AV1004 might be a potential therapeutic drug against JEV infection. These DHEA derivatives may provide lead scaffolds for further design and synthesis of potential anti-flavivirus potential drugs.

scholarly journals Dosage-Dependent Antifungal Efficacy of V-Echinocandin (LY303366) against Experimental Fluconazole-Resistant Oropharyngeal and Esophageal Candidiasis

2001 ◽  
Vol 45 (2) ◽  
pp. 471-479 ◽  
Author(s):  
Vidmantas Petraitis ◽  
Ruta Petraitiene ◽  
Andreas H. Groll ◽  
Tin Sein ◽  
Robert L. Schaufele ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Study Groups ◽  
Esophageal Candidiasis ◽  
Echinocandin B ◽  
Hepatic Transaminase ◽  
Fluconazole Resistant ◽  
Semisynthetic Derivative ◽  
Antifungal Efficacy

ABSTRACT V-echinocandin (VER-002; LY303366) is a semisynthetic derivative of echinocandin B and a potent inhibitor of fungal (1, 3)-β-d-glucan synthase. We studied the antifungal efficacy, the concentrations in saliva and tissue, and the safety of VER-002 at escalating dosages against experimental oropharyngeal and esophageal candidiasis caused by fluconazole-resistant Candida albicans in immunocompromised rabbits. Study groups consisted of untreated controls, animals treated with VER-002 at 1, 2.5, and 5 mg/kg of body weight/day intravenously (i.v.), animals treated with fluconazole at 2 mg/kg/day i.v., or animals treated with amphotericin B at 0.3 mg/kg/day. VER-002-treated animals showed a significant dosage-dependent clearance of C. albicans from the tongue, oropharynx, esophagus, stomach, and duodenum in comparison to that for untreated controls. VER-002 also was superior to amphotericin B and fluconazole in clearing the organism from all sites studied. These in vivo findings are consistent with the results of in vitro time-kill assays, which demonstrated that VER-002 has concentration-dependent fungicidal activity. Esophageal tissue VER-002 concentrations were dosage proportional and exceeded the MIC at all dosages. Echinocandin concentrations in saliva were greater than or equal to the MICs at all dosages. There was no elevation of serum hepatic transaminase, alkaline phosphatase, bilirubin, potassium, or creatinine levels in VER-002-treated rabbits. In summary, the echinocandin VER-002 was well tolerated, penetrated the esophagus and salivary glands, and demonstrated dosage-dependent antifungal activity against fluconazole-resistant esophageal candidiasis in immunocompromised rabbits.

scholarly journals Efficacy, Plasma Pharmacokinetics, and Safety of Icofungipen, an Inhibitor of Candida Isoleucyl-tRNA Synthetase, in Treatment of Experimental Disseminated Candidiasis in Persistently Neutropenic Rabbits

2005 ◽  
Vol 49 (5) ◽  
pp. 2084-2092 ◽  
Author(s):  
Ruta Petraitiene ◽  
Vidmantas Petraitis ◽  
Amy M. Kelaher ◽  
Alia A. Sarafandi ◽  
Diana Mickiene ◽  
...  
Keyword(s):  
Amphotericin B ◽  
High Performance ◽  
Central Nervous System Infection ◽  
Vena Cava ◽  
Study Groups ◽  
Trna Synthetase ◽  
Time Curve ◽  
Disseminated Candidiasis ◽  
Plasma Pharmacokinetics ◽  
Dose Dependent

ABSTRACT Icofungipen (formerly PLD-118) is a synthetic derivative of the naturally occurring β-amino acid cispentacin that blocks isoleucyl-tRNA synthetase, resulting in the inhibition of protein synthesis and growth of fungal cells. We investigated the efficacy, plasma pharmacokinetics, and safety of icofungipen in escalating dosages for the treatment of experimental subacute disseminated candidiasis in persistently neutropenic rabbits. Icofungipen was administered for 10 days starting 24 h after the intravenous inoculation of 103 Candida albicans blastoconidia. Study groups consisted of rabbits treated with icofungipen at 4 (ICO-4), 10 (ICO-10), and 25 (ICO-25) mg/kg of body weight/day in two divided dosages, rabbits treated with fluconazole at 10 mg/kg/day, rabbits treated with amphotericin B at 1 mg/kg/day, and untreated controls. Levels of icofungipen in plasma were derivatized by phthaldialdehyde and quantified by high-performance liquid chromatography with fluorescence detection. Rabbits treated with ICO-10 (P < 0.01) and ICO-25 (P < 0.001) showed significant dosage-dependent tissue clearance of C. albicans from the liver, spleen, kidney, brain, vitreous, vena cava, and lung in comparison to untreated controls. ICO-25 cleared C. albicans from all tissues and had activity comparable to that of amphotericin B versus untreated controls (P < 0.001). Pharmacokinetics of icofungipen in plasma approximated a dose-dependent relationship of the maximum concentration of drug in serum and the area under the concentration-time curve. There was no significant elevation of the levels of hepatic transaminases, alkaline phosphatase, bilirubin, urea nitrogen, or creatinine in icofungipen-treated rabbits. Icofungipen followed dose-dependent pharmacokinetics and was effective in the treatment of experimental disseminated candidiasis, including central nervous system infection, in persistently neutropenic rabbits.

scholarly journals Strong Antifungal Activity of SS750, a New Triazole Derivative, Is Based on Its Selective Binding Affinity to Cytochrome P450 of Fungi

2002 ◽  
Vol 46 (2) ◽  
pp. 308-314 ◽  
Author(s):  
Masaru Matsumoto ◽  
Kazuya Ishida ◽  
Akihiro Konagai ◽  
Kazunori Maebashi ◽  
Takemitsu Asaoka
Keyword(s):  
Cytochrome P450 ◽  
Antifungal Activity ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Strong Affinity ◽  
Dose Dependent ◽  
Potent Inhibitory Activity ◽  
In Vitro Antifungal Activity

ABSTRACT SS750 [(R)-(−)-2-(2,4-difluorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol] is a new triazole, and its potential as an antifungal agent was evaluated by in vitro and in vivo studies. In a comparison of the MICs at which 50% of isolates are inhibited (MIC50s) for all strains of Candida species and Cryptococcus neoformans tested, SS750 was four times or more active than fluconazole and had activity comparable to that of itraconazole. The most important advantage of SS750 was that, when the MIC90s were compared, SS750 had 64 and 32 times greater antifungal activities than fluconazole against Candida krusei and Candida glabrata, respectively, which are intrinsically less susceptible to fluconazole. In cyclophosphamide-immunosuppressed mouse models of systemic and pulmonary candidiasis caused by C. albicans, oral SS750 prolonged the number of days of survival of infected animals in a dose-dependent manner and was 4 and ≥64 times more potent than fluconazole and itraconazole, respectively. In a safety profile, SS750, like fluconazole, had less of an affinity for binding to mammalian cytochrome P450 compared with that of ketoconazole, despite its strong affinity for binding to fungal cytochrome P450. The mechanism for the increased in vitro antifungal activity of SS750 against C. krusei is partially due to the potent inhibitory activity (3.7 times versus that of fluconazole) of C. krusei cytochrome P450 sterol 14α-demethylase; SS750 showed a strong affinity for binding to cytochrome P450 of C. krusei, indicating that SS750 acts by inhibiting the cytochrome P450 sterol 14α-demethylase of fungal cells.

scholarly journals Brain Alanine Formation as an Ammonia-Scavenging Pathway during Hyperammonemia: Effects of Glutamine Synthetase Inhibition in Rats and Astrocyte—Neuron Co-Cultures

2013 ◽  
Vol 33 (8) ◽  
pp. 1235-1241 ◽  
Author(s):  
Sherry Dadsetan ◽  
Eva Kukolj ◽  
Lasse K Bak ◽  
Michael SØrensen ◽  
Peter Ott ◽  
...  
Keyword(s):  
Hepatic Encephalopathy ◽  
Glutamine Synthetase ◽  
Drug Target ◽  
Methionine Sulfoximine ◽  
Concerted Action ◽  
N Incorporation ◽  
Dose Dependent ◽  
The Brain

Hyperammonemia is a major etiological toxic factor in the development of hepatic encephalopathy. Brain ammonia detoxification occurs primarily in astrocytes by glutamine synthetase (GS), and it has been proposed that elevated glutamine levels during hyperammonemia lead to astrocyte swelling and cerebral edema. However, ammonia may also be detoxified by the concerted action of glutamate dehydrogenase (GDH) and alanine aminotransferase (ALAT) leading to trapping of ammonia in alanine, which in vivo likely leaves the brain. Our aim was to investigate whether the GS inhibitor methionine sulfoximine (MSO) enhances incorporation of 15NH4+ in alanine during acute hyperammonemia. We observed a fourfold increased amount of 15NH4 incorporation in brain alanine in rats treated with MSO. Furthermore, co-cultures of neurons and astrocytes exposed to 15NH4Cl in the absence or presence of MSO demonstrated a dose-dependent incorporation of 15NH4 into alanine together with increased 15N incorporation in glutamate. These findings provide evidence that ammonia is detoxified by the concerted action of GDH and ALAT both in vivo and in vitro, a mechanism that is accelerated in the presence of MSO thereby reducing the glutamine level in brain. Thus, GS could be a potential drug target in the treatment of hyperammonemia in patients with hepatic encephalopathy.

scholarly journals Synergistic Activity of Capsaicin and Colistin Against Colistin-Resistant Acinetobacter baumannii: In Vitro/Vivo Efficacy and Mode of Action

2021 ◽  
Vol 12 ◽  
Author(s):  
Tingting Guo ◽  
Mengying Li ◽  
Xiaoli Sun ◽  
Yuhang Wang ◽  
Liying Yang ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Opportunistic Pathogen ◽  
Antibacterial Activities ◽  
Synergistic Activity ◽  
Alternative Medicines ◽  
New Treatment ◽  
Time Kill ◽  
Dose Dependent

Acinetobacter baumannii is an opportunistic pathogen predominantly associated with nosocomial infections. With emerging resistance against polymyxins, synergistic combinations of drugs are being investigated as a new therapeutic approach. Capsaicin is a common constituent of the human diet and is widely used in traditional alternative medicines. The present study evaluated the antibacterial activities of capsaicin in combination with colistin against three unrelated colistin-resistant Acinetobacter baumannii strains in vitro and in vivo, and then further studied their synergistic mechanisms. Using the checkerboard technique and time-kill assays, capsaicin and colistin showed a synergistic effect on colistin-resistant A. baumannii. A mouse bacteremia model confirmed the in vivo effects of capsaicin and colistin. Mechanistic studies shown that capsaicin can inhibit the biofilm formation of both colistin-resistant and non-resistant A. baumannii. In addition, capsaicin decreased the production of intracellular ATP and disrupted the outer membrane of A. baumannii. In summary, the synergy between these drugs may enable a lower concentration of colistin to be used to treat A. baumannii infection, thereby reducing the dose-dependent side effects. Hence, capsaicin–colistin combination therapy may offer a new treatment option for the control of A. baumannii infection.

scholarly journals Comparative Antifungal Activities and Plasma Pharmacokinetics of Micafungin (FK463) against Disseminated Candidiasis and Invasive Pulmonary Aspergillosis in Persistently Neutropenic Rabbits

2002 ◽  
Vol 46 (6) ◽  
pp. 1857-1869 ◽  
Author(s):  
Vidmantas Petraitis ◽  
Ruta Petraitiene ◽  
Andreas H. Groll ◽  
Kristin Roussillon ◽  
Melissa Hemmings ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Invasive Pulmonary Aspergillosis ◽  
Vena Cava ◽  
Pulmonary Aspergillosis ◽  
Pulmonary Infarction ◽  
Pulmonary Tissue ◽  
Disseminated Candidiasis ◽  
Antifungal Activities

ABSTRACT Micafungin (FK463) is an echinocandin that demonstrates potent in vitro antifungal activities against Candida and Aspergillus species. However, little is known about its comparative antifungal activities in persistently neutropenic hosts. We therefore investigated the plasma micafungin pharmacokinetics and antifungal activities of micafungin against experimental disseminated candidiasis and invasive pulmonary aspergillosis in persistently neutropenic rabbits. The groups with disseminated candidiasis studied consisted of untreated controls (UCs); rabbits treated with desoxycholate amphotericin B (DAMB) at 1 mg/kg of body weight/day; or rabbits treated with micafungin at 0.25, 0.5, 1, and 2 mg/kg/day intravenously. Compared with the UCs, rabbits treated with micafungin or DAMB showed significant dosage-dependent clearance of Candida albicans from the liver, spleen, kidney, brain, eye, lung, and vena cava. These in vivo findings correlated with the results of in vitro time-kill assays that demonstrated that micafungin has concentration-dependent fungicidal activity. The groups with invasive pulmonary aspergillosis studied consisted of UCs; rabbits treated with DAMB; rabbits treated with liposomal amphotericin B (LAMB) at 5 mg/kg/day; and rabbits treated with micafungin at 0.5, 1, and 2 mg/kg/day. In comparison to the significant micafungin dosage-dependent reduction of the residual burden (in log CFU per gram) of C. albicans in tissue, micafungin-treated rabbits with invasive pulmonary aspergillosis had no reduction in the concentration of Aspergillus fumigatus in tissue. DAMB and LAMB significantly reduced the burdens of C. albicans and A. fumigatus in tissues (P < 0.01). Persistent galactomannan antigenemia in micafungin-treated rabbits correlated with the presence of an elevated burden of A. fumigatus in pulmonary tissue. By comparison, DAMB- and LAMB-treated animals had significantly reduced circulating galactomannan antigen levels. Despite a lack of clearance of A. fumigatus from the lungs, there was a significant improvement in the rate of survival (P < 0.001) and a reduction in the level of pulmonary infarction (P < 0.05) in micafungin-treated rabbits. In summary, micafungin demonstrated concentration-dependent and dosage-dependent clearance of C. albicans from persistently neutropenic rabbits with disseminated candidiasis but not of A. fumigatus from persistently neutropenic rabbits with invasive pulmonary aspergillosis.

Effect of pH and inhibitors on beta-amyloid fibril assembly

1996 ◽  
Vol 54 ◽  
pp. 752-753
Author(s):  
Beverly E. Maleeff ◽  
Timothy K. Hart ◽  
Stephen J. Wood ◽  
Ronald Wetzel
Keyword(s):  
Amyloid Fibril ◽  
Peptide Fragment ◽  
Hydrophobic Peptides ◽  
Amyloid Fibril Formation ◽  
Effects Of Ph ◽  
Severity Of The Disease ◽  
Kinetics Of ◽  
The Brain

Alzheimer's disease is characterized post-mortem in part by abnormal extracellular neuritic plaques found in brain tissue. There appears to be a correlation between the severity of Alzheimer's dementia in vivo and the number of plaques found in particular areas of the brain. These plaques are known to be the deposition sites of fibrils of the protein β-amyloid. It is thought that if the assembly of these plaques could be inhibited, the severity of the disease would be decreased. The peptide fragment Aβ, a precursor of the p-amyloid protein, has a 40 amino acid sequence, and has been shown to be toxic to neuronal cells in culture after an aging process of several days. This toxicity corresponds to the kinetics of in vitro amyloid fibril formation. In this study, we report the biochemical and ultrastructural effects of pH and the inhibitory agent hexadecyl-N-methylpiperidinium (HMP) bromide, one of a class of ionic micellar detergents known to be capable of solubilizing hydrophobic peptides, on the in vitro assembly of the peptide fragment Aβ.

Soluble Thrombomodulin Purified from Human Urine Exhibits a Potent Anticoagulant Effect In Vitro and In Vivo

1995 ◽  
Vol 73 (05) ◽  
pp. 805-811 ◽  
Author(s):  
Yasuo Takahashi ◽  
Yoshitaka Hosaka ◽  
Hiromi Niina ◽  
Katsuaki Nagasawa ◽  
Masaaki Naotsuka ◽  
...  
Keyword(s):  
Human Urine ◽  
Specific Activity ◽  
Anticoagulant Activity ◽  
Rabbit Lung ◽  
Soluble Thrombomodulin ◽  
Molecular Weights ◽  
Dose Dependent Fashion ◽  
Dose Dependent

SummaryWe examined the anticoagulant activity of two major molecules of soluble thrombomodulin purified from human urine. The apparent molecular weights of these urinary thrombomodulins (UTMs) were 72,000 and 79,000, respectively. Both UTMs showed more potent cofactor activity for protein C activation [specific activity >5,000 thrombomodulin units (TMU)/mg] than human placental thrombomodulin (2,180 TMU/mg) and rabbit lung thrombomodulin (1,980 TMU/mg). The UTMs prolonged thrombin-induced fibrinogen clotting time (>1 TMU/ml), APTT (>5 TMU/ml), TT (>5 TMU/ml) and PT (>40 TMU/ml) in a dose-dependent fashion. These effects appeared in the concentration range of soluble thrombomodulins present in human plasma and urine. In the rat DIC model induced by thromboplastin, administration of UTMs by infusion (300-3,000 TMU/kg) restored the hematological abnormalities derived from DIC in a dose-dependent fashion. These results demonstrate that UTMs exhibit potent anticoagulant and antithrombotic activities, and could play a physiologically important role in microcirculation.

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