scholarly journals The Antidepressant Sertraline Provides a Promising Therapeutic Option for Neurotropic Cryptococcal Infections

2012 ◽  
Vol 56 (7) ◽  
pp. 3758-3766 ◽  
Author(s):  
Bing Zhai ◽  
Cheng Wu ◽  
Linqi Wang ◽  
Matthew S. Sachs ◽  
Xiaorong Lin
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Fungal Infections ◽  
Therapeutic Option ◽  
Susceptibility Gene ◽  
Content Type ◽  
Fungal Burden ◽  
Cell Extracts ◽  
Cns Penetration

ABSTRACTTherapeutic treatment for systemic mycoses is severely hampered by the extremely limited number of antifungals. The difficulty of treatment of fungal infections in the central nervous system is further compounded by the poor central nervous system (CNS) penetration of most antifungals due to the blood-brain barrier. Only a few fungistatic azole drugs, such as fluconazole, show reasonable CNS penetration. Here we demonstrate that sertraline (Zoloft), the most frequently prescribed antidepressant, displays potent antifungal activity againstCryptococcus neoformans, the major causative agent of fungal meningitis. Inin vitroassays, this neurotropic drug is fungicidal to all naturalCryptococcusisolates tested at clinically relevant concentrations. Furthermore, sertraline interacts synergistically or additively with fluconazole againstCryptococcus. Importantly, consistent with ourin vitroobservations, sertraline used alone reduces the brain fungal burden at an efficacy comparable to that of fluconazole in a murine model of systemic cryptococcosis. It works synergistically with fluconazole in reducing the fungal burden in brain, kidney, and spleen. In contrast to its potency againstCryptococcus, sertraline is less effective against strains ofCandidaspecies and its interactions with fluconazole againstCandidastrains are often antagonistic. Therefore, our data suggest the unique application of sertraline against cryptococcosis. To understand the antifungal mechanisms of sertraline, we screened a whole-genome deletion collection ofSaccharomyces cerevisiaefor altered sertraline susceptibility. Gene ontology analyses of selected mutations suggest that sertraline perturbs translation.In vitrotranslation assays using fungal cell extracts show that sertraline inhibits protein synthesis. Taken together, our findings indicate the potential of adopting this antidepressant in treating cryptococcal meningitis.

scholarly journals In VitroandIn VivoEvaluation of APX001A/APX001 and Other Gwt1 Inhibitors againstCryptococcus

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Karen Joy Shaw ◽  
Wiley A. Schell ◽  
Jonathan Covel ◽  
Gisele Duboc ◽  
C. Giamberardino ◽  
...  
Keyword(s):  
Brain Tissue ◽  
Lung Tissue ◽  
Fungal Infections ◽  
Treatment Options ◽  
Content Type ◽  
Fungal Burden ◽  
Geographical Regions ◽  
Current Therapies

ABSTRACTCryptococcal meningitis (CM), caused primarily byCryptococcus neoformans, is uniformly fatal if not treated. Treatment options are limited, especially in resource-poor geographical regions, and mortality rates remain high despite current therapies. Here we evaluated thein vitroandin vivoactivity of several compounds, including APX001A and its prodrug, APX001, currently in clinical development for the treatment of invasive fungal infections. These compounds target the conserved Gwt1 enzyme that is required for the localization of glycosylphosphatidylinositol (GPI)-anchored cell wall mannoproteins in fungi. The Gwt1 inhibitors had low MIC values, ranging from 0.004 μg/ml to 0.5 μg/ml, against bothC. neoformansandC. gattii. APX001A and APX2020 demonstratedin vitrosynergy with fluconazole (fractional inhibitory concentration index, 0.37 for both). In a CM model, APX001 and fluconazole each alone reduced the fungal burden in brain tissue (0.78 and 1.04 log10CFU/g, respectively), whereas the combination resulted in a reduction of 3.52 log10CFU/g brain tissue. Efficacy, as measured by a reduction in the brain and lung tissue fungal burden, was also observed for another Gwt1 inhibitor prodrug, APX2096, where dose-dependent reductions in the fungal burden ranged from 5.91 to 1.79 log10CFU/g lung tissue and from 7.00 and 0.92 log10CFU/g brain tissue, representing the nearly complete or complete sterilization of lung and brain tissue at the higher doses. These data support the further clinical evaluation of this new class of antifungal agents for the treatment of CM.

Efficacy of LY233053, a competitive glutamate antagonist, in experimental central nervous system ischemia

1992 ◽  
Vol 76 (1) ◽  
pp. 106-110 ◽  
Author(s):  
Kenneth P. Madden ◽  
Wayne M. Clark ◽  
Abha Kochhar ◽  
Justin A. Zivin
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Side Effects ◽  
Excitatory Amino Acids ◽  
Neurological Damage ◽  
Content Type ◽  
Glutamate Antagonist ◽  
Fine Print

✓ Antagonists of excitatory amino acids appear to serve a neuroprotective role during ischemic conditions in a variety of in vivo and in vitro models. The usefulness of such agents in the clinical setting, however, may be limited by poor central nervous system (CNS) entry and intolerable side effects. The authors report high efficacy in reducing neurological damage and relatively limited side effects of LY233053, a novel competitive glutamate antagonist, in two models of experimental CNS ischemia in the rabbit.

Immunotoxins and central nervous system neoplasia

1992 ◽  
Vol 76 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Walter A. Hall ◽  
Øystein Fodstad
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Malignant Disease ◽  
High Specificity ◽  
Intrathecal Administration ◽  
Treatment Modalities ◽  
Content Type ◽  
Toxic Agents ◽  
Cns Malignancy

✓ The poor prognosis associated with central nervous system (CNS) malignancy has led investigators to seek new, innovative treatment modalities. Immunotoxins, carrier molecules linked to toxic agents, combine high specificity for tumor-associated antigens with extreme potency. The rationale for both the development of these compounds and for their application to CNS neoplasia is explained. This report discusses the design and construction of immunoconjugates, using toxins that differ in their mechanism of action bound to ligands directed against various antigens. A comparison is made between the in vitro efficacy of standard chemotherapy and immunotoxins in glioblastoma- and medulloblastoma-derived cell lines. A review is included of the results of experiments in animals with leptomeningeal neoplasia, where prolongation of survival following intrathecal administration of immunotoxins has been reported. The obstacles encountered in clinical trials with other types of cancer are addressed and approaches to optimize the use of these novel agents in the context of treating malignant disease of the CNS are suggested.

scholarly journals The Novel Fungal Cyp51 Inhibitor VT-1598 Is Efficacious in Experimental Models of Central Nervous System Coccidioidomycosis Caused by Coccidioides posadasii and Coccidioides immitis

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Nathan P. Wiederhold ◽  
Lisa F. Shubitz ◽  
Laura K. Najvar ◽  
Rosie Jaramillo ◽  
Marcos Olivo ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Plasma Concentrations ◽  
Coccidioides Immitis ◽  
Coccidioides Posadasii ◽  
Content Type ◽  
Fungal Burden ◽  
Content Model ◽  
Survival Studies

ABSTRACT Coccidioidal meningitis can cause significant morbidity, and lifelong antifungal therapy is often required. VT-1598 is a fungus-specific Cyp51 inhibitor that has potent in vitro activity against Coccidioides species. We evaluated the in vivo efficacy of VT-1598 in murine models of central nervous system coccidioidomycosis caused by C. posadasii and C. immitis . Infection was introduced via intracranial inoculation, and therapy began 48 h postinoculation. Oral treatments consisted of vehicle control, VT-1598, and positive controls of fluconazole in the C. immitis study and VT-1161 in the C. posadasii study. Treatment continued for 7 and 14 days in the fungal-burden and survival studies, respectively. Fungal burden was assessed in brain tissue collected 24 to 48 h posttreatment in the fungal-burden studies, on the days the mice succumbed to infection, or at prespecified endpoints in the survival studies. VT-1598 plasma concentrations were also measured in the C. posadasii study. VT-1598 resulted in significant improvements in survival in mice infected with either species. In addition, the fungal burden was significantly reduced in the fungal-burden studies. Plasma concentrations 48 h after dosing stopped remained above the VT-1598 MIC against the C. posadasii isolate, although levels were undetectable in the survival study after a 4-week washout. Whereas fungal burden remained suppressed after a 2-week washout in the C. immitis model, a higher fungal burden was observed in the survival arm of the C. posadasii model. This in vivo efficacy supports human studies to establish the utility of VT-1598 for the treatment of coccidioidomycosis.

Insulin and insulin-like growth factors in central nervous system tumors

1992 ◽  
Vol 77 (3) ◽  
pp. 445-450 ◽  
Author(s):  
Roberta P. Glick ◽  
Terry G. Unterman ◽  
Mary Van der Woude ◽  
Lisa Zollner Blaydes
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Growth Factor ◽  
Tumor Cell ◽  
Cns Tumors ◽  
Insulin Like Growth Factor ◽  
Content Type ◽  
Igf I ◽  
Fine Print

✓ The authors have previously reported the presence of insulin-like growth factor (IGF) receptors in central nervous system (CNS) tumors and the production of IGF's and their binding proteins by CNS tumors in situ. This study was designed to investigate whether CNS tumor cells are capable of autocrine secretion of IGF-I and IGF-II in vitro. Production of IGF's was studied by specific radioimmunoassay of tumor-cell-conditioned serum-free media from 34 CNS tumors: 12 gliomas, 12 meningiomas, and 10 miscellaneous tumors. Normal human serum and cerebrospinal fluid served as controls. Insulin-like growth factor I was detected in five of 12 meningiomas but in none of the gliomas studied. In contrast, IGF-II was detected in four of 12 gliomas and in six of 11 meningiomas studied. Four miscellaneous tumors produced IGF-I and/or IGF-II. These results suggest that CNS tumors differentially produce IGF-I and IGF-II in vitro. Preferential production of IGF's may be an important marker of the tumor-cell differentiation or malignancy and may be useful as a clinical diagnostic tool. These results add further support to the concept that IGF's may play a role in the regulation of the behavior of CNS tumors.

scholarly journals The Orotomide Olorofim Is Efficacious in an Experimental Model of Central Nervous System Coccidioidomycosis

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Nathan P. Wiederhold ◽  
Laura K. Najvar ◽  
Rosie Jaramillo ◽  
Marcos Olivo ◽  
Michael Birch ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Oral Therapy ◽  
Vehicle Control ◽  
Coccidioides Immitis ◽  
Central Nervous System Infections ◽  
Content Type ◽  
Highly Active

ABSTRACT Olorofim (formerly F901318) is an advanced analog of the orotomide class that inhibits fungal pyrimidine biosynthesis. We evaluated the in vitro and in vivo activities of olorofim against Coccidioides species. In vitro activity was assessed against 59 clinical Coccidioides isolates. Central nervous system infections were established in mice via intracranial inoculation with Coccidioides immitis arthroconidia. Oral therapy began 48 h postinoculation and consisted of vehicle control, olorofim daily doses of 20 mg/kg (6.67 mg/kg three times daily or 10 mg/kg twice daily) or 40 mg/kg (13.3 mg/kg three times daily or 20 mg/kg twice daily), or fluconazole (25 mg/kg twice daily). Treatment continued for 7 and 14 days in the fungal burden and survival arms, respectively. Fungal burdens were assessed by CFU counts in brains. Olorofim demonstrated potent in vitro activity (MIC range, ≤0.008 to 0.06 μg/ml). Survival was significantly enhanced in mice treated with olorofim. Reductions in brain tissue fungal burdens were also observed on day 9 in the olorofim-treated groups. Improvements in survival and reductions in fungal burdens also occurred with fluconazole. More frequent dosing of olorofim was associated with enhanced survival and greater reductions in fungal burdens. In the group treated with 13.3 mg/kg olorofim three times daily, fungal burdens remained low on day 30 (15 days after treatment was stopped), with undetectable levels in 7 of 10 mice. In contrast, fungal burdens rebounded in all other groups after therapy stopped. Olorofim was highly active in vitro and in vivo against Coccidioides. These results demonstrate that olorofim may have a role in the treatment of coccidioidomycosis.

scholarly journals Bis-Benzimidazole Hits against Naegleria fowleri Discovered with New High-Throughput Screens

2015 ◽  
Vol 59 (4) ◽  
pp. 2037-2044 ◽  
Author(s):  
Christopher A. Rice ◽  
Beatrice L. Colon ◽  
Mehmet Alp ◽  
Hakan Göker ◽  
David W. Boykin ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
High Throughput ◽  
Lead Optimization ◽  
New Drugs ◽  
Naegleria Fowleri ◽  
Onset Of Action ◽  
Content Type ◽  
Nægleria Fowleri

ABSTRACTNaegleria fowleriis a pathogenic free-living amoeba (FLA) that causes an acute fatal disease known as primary amoebic meningoencephalitis (PAM). The major problem for infections with any pathogenic FLA is a lack of effective therapeutics, since PAM has a case mortality rate approaching 99%. Clearly, new drugs that are potent and have rapid onset of action are needed to enhance the treatment regimens for PAM. Diamidines have demonstrated potency against multiple pathogens, including FLA, and are known to cross the blood-brain barrier to cure other protozoan diseases of the central nervous system. Therefore, amidino derivatives serve as an important chemotype for discovery of new drugs. In this study, we validated two newin vitroassays suitable for medium- or high-throughput drug discovery and used these forN. fowleri. We next screened over 150 amidino derivatives of multiple structural classes and identified two hit series with nM potency that are suitable for further lead optimization as new drugs for this neglected disease. These include both mono- and diamidino derivatives, with the most potent compound (DB173) having a 50% inhibitory concentration (IC50) of 177 nM. Similarly, we identified 10 additional analogues with IC50s of <1 μM, with many of these having reasonable selectivity indices. The most potent hits were >500 times more potent than pentamidine. In summary, the mono- and diamidino derivatives offer potential for lead optimization to develop new drugs to treat central nervous system infections withN. fowleri.

scholarly journals A Novel Tricyclic Ligand-Containing Nonpeptidic HIV-1 Protease Inhibitor, GRL-0739, Effectively Inhibits the Replication of Multidrug-Resistant HIV-1 Variants and Has a Desirable Central Nervous System Penetration PropertyIn Vitro

2015 ◽  
Vol 59 (5) ◽  
pp. 2625-2635 ◽  
Author(s):  
Masayuki Amano ◽  
Yasushi Tojo ◽  
Pedro Miguel Salcedo-Gómez ◽  
Garth L. Parham ◽  
Prasanth R. Nyalapatla ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Protease Inhibitor ◽  
Serum Proteins ◽  
Multidrug Resistant ◽  
Highly Active ◽  
Cns Penetration ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACTWe report here that GRL-0739, a novel nonpeptidic HIV-1 protease inhibitor containing a tricycle (cyclohexyl-bis-tetrahydrofuranylurethane [THF]) and a sulfonamide isostere, is highly active against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC50], 0.0019 to 0.0036 μM), with minimal cytotoxicity (50% cytotoxic concentration [CC50], 21.0 μM). GRL-0739 blocked the infectivity and replication of HIV-1NL4-3variants selected by concentrations of up to 5 μM ritonavir or atazanavir (EC50, 0.035 to 0.058 μM). GRL-0739 was also highly active against multidrug-resistant clinical HIV-1 variants isolated from patients who no longer responded to existing antiviral regimens after long-term antiretroviral therapy, as well as against the HIV-2RODvariant. The development of resistance against GRL-0739 was substantially delayed compared to that of amprenavir (APV). The effects of the nonspecific binding of human serum proteins on the anti-HIV-1 activity of GRL-0739 were insignificant. In addition, GRL-0739 showed a desirable central nervous system (CNS) penetration property, as assessed using a novelin vitroblood-brain barrier model. Molecular modeling demonstrated that the tricyclic ring and methoxybenzene of GRL-0739 have a larger surface and make greater van der Waals contacts with protease than in the case of darunavir. The present data demonstrate that GRL-0739 has desirable features as a compound with good CNS-penetrating capability for treating patients infected with wild-type and/or multidrug-resistant HIV-1 variants and that the newly generated cyclohexyl-bis-THF moiety with methoxybenzene confers highly desirable anti-HIV-1 potency in the design of novel protease inhibitors with greater CNS penetration profiles.

scholarly journals Detection of (1,3)-β-D-Glucan in Cerebrospinal Fluid in Histoplasma Meningitis

2018 ◽  
Vol 56 (10) ◽  
Author(s):  
Thein Myint ◽  
Felicia C. Chow ◽  
Karen C. Bloch ◽  
Luke Raymond-Guillen ◽  
Thomas E. Davis ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Fungal Infection ◽  
Fungal Infections ◽  
Biological Marker ◽  
Control Group ◽  
Limited Data ◽  
Content Type ◽  
Fungal Meningitis

ABSTRACT The diagnosis of central nervous system (CNS) histoplasmosis is often difficult. Although cerebrospinal fluid (CSF) (1,3)-β-d-glucan (BDG) is available as a biological marker for the diagnosis of fungal meningitis, there are limited data on its use for the diagnosis of Histoplasma meningitis. We evaluated CSF BDG detection, using the Fungitell assay, in patients with CNS histoplasmosis and controls. A total of 47 cases and 153 controls were identified. The control group included 13 patients with a CNS fungal infection other than histoplasmosis. Forty-nine percent of patients with CNS histoplasmosis and 43.8% of controls were immunocompromised. The median CSF BDG level was 85 pg/ml for cases, compared to <31 pg/ml for all controls (P < 0.05) and 82 pg/ml for controls with other causes of fungal meningitis (P = 0.27). The sensitivity for detection of BDG in CSF was 53.2%, whereas the specificity was 86.9% versus all controls and 46% versus other CNS fungal infections. CSF BDG levels of ≥80 pg/ml are neither sensitive nor specific to support a diagnosis of Histoplasma meningitis.

Dispersion of central nervous system tumors

1974 ◽  
Vol 41 (6) ◽  
pp. 691-698 ◽  
Author(s):  
Ulrich Batzdorf ◽  
Vivian Gold
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Central Nervous System Tumors ◽  
Tissue Cultures ◽  
Human Central Nervous System ◽  
Content Type ◽  
Nervous System Tumors ◽  
Mechanical Factors ◽  
Made In

✓ The phenomenon of tumor dispersion through cerebrospinal fluid is discussed in relation to observations made in tissue cultures of human central nervous system tumors. Satellite colony formation was observed in cultures of tumors that tend to spread through the CSF. Abnormalities of the tumor cell surface, particularly a reduction of cell-to-cell adhesiveness, probably are important. Although mechanical factors contribute to the formation of both CSF metastases and in vitro satellites, they do not offer a sufficient explanation for these phenomena.

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