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.

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 Neurons Are Host Cells for Mycobacterium tuberculosis

2014 ◽  
Vol 82 (5) ◽  
pp. 1880-1890 ◽  
Author(s):  
Philippa J. Randall ◽  
Nai-Jen Hsu ◽  
Dirk Lang ◽  
Susan Cooper ◽  
Boipelo Sebesho ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Mycobacterium Tuberculosis ◽  
Host Cells ◽  
Productive Infection ◽  
Target Cells ◽  
Dependent Manner ◽  
Content Type ◽  
The Central Nervous System

ABSTRACTMycobacterium tuberculosisinfection of the central nervous system is thought to be initiated once the bacilli have breached the blood brain barrier and are phagocytosed, primarily by microglial cells. In this study, the interactions ofM. tuberculosiswith neuronsin vitroandin vivowere investigated. The data obtained demonstrate that neurons can act as host cells forM. tuberculosis.M. tuberculosisbacilli were internalized by murine neuronal cultured cells in a time-dependent manner after exposure, with superior uptake by HT22 cells compared to Neuro-2a cells (17.7% versus 9.8%). Internalization ofM. tuberculosisbacilli by human SK-N-SH cultured neurons suggested the clinical relevance of the findings. Moreover, primary murine hippocampus-derived neuronal cultures could similarly internalizeM. tuberculosis. InternalizedM. tuberculosisbacilli represented a productive infection with retention of bacterial viability and replicative potential, increasing 2- to 4-fold within 48 h.M. tuberculosisbacillus infection of neurons was confirmedin vivoin the brains of C57BL/6 mice after intracerebral challenge. This study, therefore, demonstrates neurons as potential new target cells forM. tuberculosiswithin the central nervous system.

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.

Multiple intracranial aneurysms due to Coccidioides immitis infection

1987 ◽  
Vol 66 (3) ◽  
pp. 453-456 ◽  
Author(s):  
Mark N. Hadley ◽  
Neil A. Martin ◽  
Robert F. Spetzler ◽  
Peter C. Johnson
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Young Woman ◽  
Intracranial Aneurysms ◽  
Mycotic Aneurysm ◽  
Coccidioides Immitis ◽  
Content Type ◽  
Multiple Intracranial Aneurysms ◽  
Fine Print

✓ True mycotic (fungal) aneurysms are distinctly uncommon. The case of a young woman with multiple intracranial aneurysms of Coccidioides immitis origin is presented. Coccidioides immitis organisms are not uncommon central nervous system pathogens and usually cause basilar meningitis and hydrocephalus. There are no previous reports of a coccidioidal mycotic aneurysm. The management of intracranial coccidioidomycosis and fungal aneurysms is reviewed.

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 Myeloid Differentiation Factor 88 and Interleukin-1R1 Signaling Contribute to Resistance toCoccidioides immitis

2018 ◽  
Vol 86 (6) ◽  
Author(s):  
Suganya Viriyakosol ◽  
Lorraine Walls ◽  
Sharon Okamoto ◽  
Eyal Raz ◽  
David L. Williams ◽  
...  
Keyword(s):  
Pathogenic Fungi ◽  
Myeloid Differentiation ◽  
Coccidioides Immitis ◽  
High Concentration ◽  
Coccidioides Posadasii ◽  
Content Type ◽  
Differentiation Factor ◽  
Myeloid Differentiation Factor 88 ◽  
Myeloid Differentiation Factor

ABSTRACTRodents are a natural host for the dimorphic pathogenic fungiCoccidioides immitisandCoccidioides posadasii, and mice are a good model for human infection. Humans and rodents both express Dectin-1 and Toll-like receptor 2 (TLR2) on myeloid cells, and those receptors collaborate to maximize the cytokine/chemokine responses to spherules (the tissue form of the fungi) and to formalin-killed spherules (FKS). We showed that Dectin-1 is necessary for resistance to pulmonary coccidioidomycosis, but the importance of TLR2in vivois uncertain. Myeloid differentiation factor 88 (MyD88) is the adapter protein for TLR2 and -4, interleukin-1R1 (IL-1R1), and IL-18R1. MyD88/TRIF−/−and MyD88−/−mice were equally susceptible toC. immitisinfection, in contrast to C57BL/6 (B6) controls. Of the four surface receptors, only IL-1R1 was required for resistance toC. immitis, partially explaining the susceptibility of MyD88−/−mice. We also found that FKS stimulated production of IL-1Ra by bone marrow-derived dendritic cells (BMDCs), independent of MyD88 and Dectin-1. There also was a very high concentration of IL-1Ra in the lungs of infected B6 mice, supporting the potential importance of this regulatory IL-1 family protein in the largely ineffective response of B6 mice to coccidioidomycosis. These results suggest that IL-1R1 signaling is important for defense againstC. immitisinfection.

Successful treatment of spinal arachnoiditis due to coccidioidomycosis

1983 ◽  
Vol 59 (2) ◽  
pp. 328-331 ◽  
Author(s):  
Drew J. Winston ◽  
Terrance O. Kurtz ◽  
Jacob Fleischmann ◽  
David Morgan ◽  
Ulrich Batzdorf ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Unusual Case ◽  
Obstructive Hydrocephalus ◽  
Spastic Paraparesis ◽  
Coccidioides Immitis ◽  
Content Type ◽  
Spinal Arachnoiditis ◽  
The Central Nervous System ◽  
Fine Print

✓ An unusual case is reported of a patient with spastic paraparesis who was found to have severe spinal arachnoiditis due to Coccidioides immitis. Despite an obstructive hydrocephalus and a spinal subarachnoid block, the patient was treated effectively with surgery (shunting) and antifungal therapy (amphotericin and ketoconazole). He remains asymptomatic 3 years after diagnosis. Aggressive surgical and medical treatment of coccidioidal infection of the central nervous system can be beneficial, even in patients with the worst prognosis.

scholarly journals Promoter Sequence of Shiga Toxin 2 (Stx2) Is Recognized In Vivo, Leading to Production of Biologically Active Stx2

mBio ◽  
2013 ◽  
Vol 4 (5) ◽  
Author(s):  
Leticia V. Bentancor ◽  
Maria P. Mejías ◽  
Alípio Pinto ◽  
Marcos F. Bilen ◽  
Roberto Meiss ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Central Nervous System ◽  
Nervous System ◽  
Hemolytic Uremic Syndrome ◽  
Shiga Toxin ◽  
Biologically Active ◽  
Eukaryotic Cells ◽  
Content Type ◽  
Uremic Syndrome

ABSTRACTShiga toxins (Stx) are the main agent responsible for the development of hemolytic-uremic syndrome (HUS), the most severe and life-threatening systemic complication of infection with enterohemorrhagicEscherichia coli(EHEC) strains. We previously described Stx2 expression by eukaryotic cells after they were transfectedin vitrowith thestx2gene cloned into a prokaryotic plasmid (pStx2). The aim of this study was to evaluate whether mammalian cells were also able to express Stx2in vivoafter pStx2 injection. Mice were inoculated by hydrodynamics-based transfection (HBT) with pStx2. We studied the survival, percentage of polymorphonuclear leukocytes in plasma, plasma urea levels, and histology of the kidneys and the brains of mice. Mice displayed a lethal dose-related response to pStx2. Stx2 mRNA was recovered from the liver, and Stx2 cytotoxic activity was observed in plasma of mice injected with pStx2. Stx2 was detected by immunofluorescence in the brains of mice inoculated with pStx2, and markers of central nervous system (CNS) damage were observed, including increased expression of glial fibrillary acidic protein (GFAP) and fragmentation of NeuN in neurons. Moreover, anti-Stx2B-immunized mice were protected against pStx2 inoculation. Our results show that Stx2 is expressedin vivofrom the wildstx2gene, reproducing pathogenic damage induced by purified Stx2 or secondary to EHEC infection.IMPORTANCEEnterohemorrhagic Shiga toxin (Stx)-producingEscherichia coli(EHEC) infections are a serious public health problem, and Stx is the main pathogenic agent associated with typical hemolytic-uremic syndrome (HUS). In contrast to the detailed information describing the molecular basis for EHEC adherence to epithelial cells, very little is known about how Stx is released from bacteria in the gut, reaching its target tissues, mainly the kidney and central nervous system (CNS). In order to develop an efficient treatment for EHEC infections, it is necessary to understand the mechanisms involved in Stx expression. In this regard, the present study demonstrates that mammals can synthesize biologically active Stx using the natural promoter associated with the Stx-converting bacteriophage genome. These results could impact the comprehension of EHEC HUS, since local eukaryotic cells transduced and/or infected by bacteriophage encoding Stx2 could be an alternative source of Stx production.

Neuropharmacological Profile and Chemical Analysis of Moroccan Ormenis mixta L.

2018 ◽  
Vol 16 (S1) ◽  
pp. S55-S64
Author(s):  
G. Hajjaj ◽  
A. Bahlouli ◽  
M. Tajani ◽  
K. Alaoui ◽  
Y. Cherrah ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Body Weight ◽  
Traditional Medicine ◽  
Behavioral Tests ◽  
Phytochemical Screening ◽  
Activity Profile ◽  
Acute Toxicity Study ◽  
Pharmacological Studies

Ormenis mixta L. is traditionally used for central nervous system (CNS)-related diseases. Its anti-stress properties have received attention in Moroccan traditional medicine and aromatherapy. However, no pharmacological studies have yet been undertaken on this plant in Morocco. The present study provides a preliminary phytochemical screening and psychopharmacological profile of the essential oil and aqueous extract from Ormenis mixta L. by using behavioral tests in vivo, at graded doses. The result of this research shows that Ormenis mixta L. was safe up to 2 g/kg b.w. (body weight) in the acute toxicity study, possesses potential psychostimulant effect, and has antianxiety and antidepressant-like activity. This activity profile of Ormenis mixta L. was similar to the typical psychostimulant, caffeine. The exact mechanism of action underlying this stimulant-like effect should be clarified with further detailed studies. These results explained the extensive use of Ormenis mixta L. as a traditional medicine in Morocco.

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