scholarly journals Efficacy of Oral Cochleate-Amphotericin B in a Mouse Model of Systemic Candidiasis

2000 ◽  
Vol 44 (9) ◽  
pp. 2356-2360 ◽  
Author(s):  
Rosaria Santangelo ◽  
Padmaja Paderu ◽  
Guillaume Delmas ◽  
Zi-Wei Chen ◽  
Raphael Mannino ◽  
...  
Keyword(s):  
Mouse Model ◽  
Amphotericin B ◽  
Delivery System ◽  
Oral Delivery ◽  
Experimental Period ◽  
Oral Formulation ◽  
Systemic Candidiasis ◽  
Log Reduction ◽  
Cell Counts

ABSTRACT Amphotericin B (AMB) remains the principal therapeutic choice for deep mycoses. However, its application is limited by toxicity and a route of administration requiring slow intravenous injection. An oral formulation of this drug is desirable to treat acute infections and provide prophylactic therapy for high-risk patients. Cochleates are a novel lipid-based delivery system that have the potential for oral administration of hydrophobic drugs. They are stable phospholipid-cation crystalline structures consisting of a spiral lipid bilayer sheet with no internal aqueous space. Cochleates containing AMB (CAMB) inhibit the growth of Candida albicans, and the in vivo therapeutic efficacy of CAMB administered orally was evaluated in a mouse model of systemic candidiasis. The results indicate that 100% of the mice treated at all CAMB doses, including a low dosage of 0.5 mg/kg of body weight/day, survived the experimental period (16 days). In contrast, 100% mortality was observed with untreated mice by day 12. The fungal tissue burden in kidneys and lungs was assessed in parallel, and a dose-dependent reduction in C. albicansfrom the kidneys was observed, with a maximum 3.5-log reduction in total cell counts at 2.5 mg/kg/day. However, complete clearance of the organism from the lungs, resulting in more than a 4-log reduction, was observed at the same dose. These results were comparable to a deoxycholate AMB formulation administered intraperitoneally at 2 mg/kg/day (P < 0.05). Overall, these data demonstrate that cochleates are an effective oral delivery system for AMB in a model of systemic candidiasis.

Formulation, Characterization and In Vivo Evaluation of Self-Nanoemulsifying Drug Delivery System for Oral Delivery of Valsartan

2014 ◽  
Vol 10 (2) ◽  
pp. 263-270 ◽  
Author(s):  
Maulick Chopra ◽  
Usha Y. Nayak ◽  
Aravind Kumar Gurram ◽  
M. Sreenivasa Reddy ◽  
K.B. Koteshwara
Keyword(s):  
Drug Delivery ◽  
Drug Delivery System ◽  
Delivery System ◽  
Oral Delivery ◽  
In Vivo Evaluation

scholarly journals In-vitro and in-vivo evaluation of a new amphotericin B emulsion-based delivery system

1996 ◽  
Vol 38 (3) ◽  
pp. 485-497 ◽  
Author(s):  
Eryvaldo Sόcrates Tabosa Do Egito ◽  
Martine Appel ◽  
Hatem Fessi ◽  
Gillian Barrett ◽  
Francis Puisieux ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Delivery System ◽  
In Vivo Evaluation

scholarly journals Development of Piperine-Loaded Solid Self-Nanoemulsifying Drug Delivery System: Optimization, In-Vitro, Ex-Vivo, and In-Vivo Evaluation

Nanomaterials ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 2920
Author(s):  
Ameeduzzafar Zafar ◽  
Syed Sarim Imam ◽  
Nabil K. Alruwaili ◽  
Omar Awad Alsaidan ◽  
Mohammed H. Elkomy ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Drug Delivery System ◽  
Delivery System ◽  
Oral Delivery ◽  
Ex Vivo ◽  
In Vitro Release ◽  
System Optimization ◽  
Globule Size

Hypertension is a cardiovascular disease that needs long-term medication. Oral delivery is the most common route for the administration of drugs. The present research is to develop piperine self-nanoemulsifying drug delivery system (PE-SNEDDS) using glyceryl monolinoleate (GML), poloxamer 188, and transcutol HP as oil, surfactant, and co-surfactant, respectively. The formulation was optimized by three-factor, three-level Box-Behnken design. PE-SNEDDs were characterized for globule size, emulsification time, stability, in-vitro release, and ex-vivo intestinal permeation study. The optimized PE-SNEDDS (OF3) showed the globule size of 70.34 ± 3.27 nm, percentage transmittance of 99.02 ± 2.02%, and emulsification time of 53 ± 2 s Finally, the formulation OF3 was transformed into solid PE-SNEDDS (S-PE-SNEDDS) using avicel PH-101 as adsorbent. The reconstituted SOF3 showed a globule size of 73.56 ± 3.54 nm, PDI of 0.35 ± 0.03, and zeta potential of −28.12 ± 2.54 mV. SEM image exhibited the PE-SNEDDS completely adsorbed on avicel. Thermal analysis showed the drug was solubilized in oil, surfactant, and co-surfactant. S-PE-SNEDDS formulation showed a more significant (p < 0.05) release (97.87 ± 4.89% in 1 h) than pure PE (27.87 ± 2.65% in 1 h). It also exhibited better antimicrobial activity against S. aureus and P. aeruginosa and antioxidant activity as compared to PE dispersion. The in vivo activity in rats exhibited better (p < 0.05) antihypertensive activity as well as 4.92-fold higher relative bioavailability than pure PE dispersion. Finally, from the results it can be concluded that S-PE-SNEDDS might be a better approach for the oral delivery to improve the absorption and therapeutic activity.

scholarly journals Formulation, Stability, Pharmacokinetic, and Modeling Studies for Tests of Synergistic Combinations of Orally Available Approved Drugs Against Ebola Virus In Vivo

2021 ◽  
Author(s):  
Courtney L. Finch ◽  
Julie Dyall ◽  
Shuang Xu ◽  
Elizabeth A. Nelson ◽  
Elena Postnikova ◽  
...  
Keyword(s):  
Mouse Model ◽  
Oral Delivery ◽  
Ebola Virus ◽  
Cost Effective ◽  
High Morbidity ◽  
Strong Activity ◽  
Approved Drugs ◽  
Formulation Stability ◽  
Synergistic Combinations

Outbreaks of Ebola ebolavirus (EBOV) have been associated with high morbidity and mortality. Milestones have been reached recently in the management of EBOV disease (EVD) with licensure of an EBOV vaccine and two monoclonal antibody therapies. However, neither vaccines nor therapies are available for other disease-causing filoviruses. In preparation for such outbreaks, and for more facile and cost-effective management of EVD, we seek a cocktail containing orally available and room temperature stable drugs with strong activity against multiple filoviruses. We previously showed that (bepridil + sertraline) and (sertraline + toremifene) synergistically suppress EBOV in cell cultures. Here we describe steps towards testing these combinations in a mouse model of EVD. We identified a vehicle suitable for oral delivery of the component drugs and determined that, thus formulated the drugs are equally active against EBOV as preparations in DMSO, and they maintain activity upon storage in solution for up to seven days. Pharmacokinetic (PK) studies indicated that the drugs in the oral delivery vehicle are well tolerated in mice at the highest doses tested. Collectively the data support advancement of these combinations to tests for synergy in a mouse model of EVD. Moreover, mathematical modeling based on human oral PK projects that the combinations would be more active in humans than their component single drugs.

scholarly journals Combination therapy with amphotericin B and fluconazole against invasive candidiasis in neutropenic-mouse and infective-endocarditis rabbit models.

1997 ◽  
Vol 41 (6) ◽  
pp. 1345-1348 ◽  
Author(s):  
H Sanati ◽  
C F Ramos ◽  
A S Bayer ◽  
M A Ghannoum
Keyword(s):  
Infective Endocarditis ◽  
Combination Therapy ◽  
Mouse Model ◽  
Amphotericin B ◽  
Antifungal Agents ◽  
Combined Therapy ◽  
Rabbit Model ◽  
Model Treatment ◽  
The Brain

Although there are an increasing number of new antifungal agents available, the morbidity and mortality due to invasive mycoses remain high. The high rates of polyene toxicities and the development of azole resistance have raised the issue of using antifungal agents of these classes in combination, despite theoretical concerns regarding antagonism between such agents. This study was designed to evaluate the in vivo efficacy of combined therapy with amphotericin B and fluconazole against Candida albicans. Two distinct animal models were used in this study: a neutropenic-mouse model of hematogenously disseminated candidiasis and the infective-endocarditis rabbit model. Treatment efficacy was assessed by determining reductions in mortality as well as decreases in tissue fungal densities. In the neutropenic-mouse model, amphotericin B, as well as combination therapy, significantly prolonged survival compared to untreated controls (P < 10(-5) and P = 0.001, respectively). The fungal densities in the kidneys of neutropenic mice were significantly reduced with either amphotericin B monotherapy or amphotericin B-fluconazole combined therapy compared to those of controls (P < 10(-6)). Fluconazole monotherapy also reduced fungal densities in the kidneys; however, this decrease was not statistically significant (P = 0.17). In contrast, treatment with either fluconazole alone or combined with amphotericin B (but not amphotericin B monotherapy) significantly decreased fungal densities in the brain (P = 0.025). In the rabbit endocarditis model, amphotericin B monotherapy or combined therapy significantly decreased fungal densities in cardiac vegetations (P < 0.01 versus the controls). Although no significant antagonism was seen when fluconazole was given in combination with amphotericin B, combination therapy did not augment the antifungal activity of amphotericin B.

scholarly journals Efficacy of Oral Encochleated Amphotericin B in a Mouse Model of Cryptococcal Meningoencephalitis

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
R. Lu ◽  
C. Hollingsworth ◽  
J. Qiu ◽  
A. Wang ◽  
E. Hughes ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Oral Absorption ◽  
Oral Formulation ◽  
Significant Saving ◽  
Content Type ◽  
Cryptococcal Meningoencephalitis ◽  
Cryptococcal Disease ◽  
The Impact

ABSTRACT Cryptococcus neoformans is an encapsulated yeast responsible for approximately a quarter of a million deaths worldwide annually despite therapy, and upwards of 11% of HIV/AIDS-related deaths, rivaling the impact of tuberculosis and malaria. However, the most effective antifungal agent, amphotericin B, requires intravenous delivery and has significant renal and hematopoietic toxicity, making it difficult to utilize, especially in resource-limited settings. The present studies describe a new nanoparticle crystal encapsulated formulation of amphotericin B known as encochleated amphotericin B (CAmB) that seeks to provide an oral formulation that is low in toxicity and cost. Using a 3-day delayed model of murine cryptococcal meningoencephalitis and a large inoculum of a highly virulent strain of serotype A C. neoformans, CAmB, in combination with flucytosine, was found to have efficacy equivalent to parental amphotericin B deoxycholate with flucytosine and superior to oral fluconazole without untoward toxicity. Transport of fluorescent CAmB particles to brain as well as significant brain levels of amphotericin drug was demonstrated in treated mice, and immunological profiles were similar to those of mice treated with conventional amphotericin B. Additional toxicity studies using a standardized rat model showed negligible toxicity after a 28-day treatment schedule. These studies thus offer the potential for an efficacious oral formulation of a known fungicidal drug against intrathecal cryptococcal disease. IMPORTANCE Cryptococcus neoformans is a significant global fungal pathogen that kills an estimated quarter of a million HIV-infected individuals yearly and has poor outcomes despite therapy. The most effective therapy, amphotericin B, is highly effective in killing the fungus but is available only in highly toxic, intravenous formulations that are unavailable in most of the developing world, where cryptococcal disease in most prevalent. For example, in Ethiopia, reliance on the orally available antifungal fluconazole results in high mortality, even when initiated as preemptive therapy at the time of HIV diagnosis. Thus, alternative agents could result in significant saving of lives. Toward this end, the present work describes the development of a new formulation of amphotericin B (CAmB) that encapsulates the drug as a crystal lipid nanoparticle that facilitates oral absorption and prevents toxicity. Successful oral absorption of the drug was demonstrated in a mouse model that, in combination with the antifungal flucytosine, provided efficacy equal to a parental preparation of amphotericin B plus flucytosine. These studies demonstrate the potential for CAmB in combination with flucytosine to provide an effective oral formulation of a well-known, potent fungicidal drug combination.

In vivo evaluation of an oral delivery system for P-gp substrates based on thiolated chitosan

Biomaterials ◽  
2006 ◽  
Vol 27 (23) ◽  
pp. 4250-4255 ◽  
Author(s):  
Florian Föger ◽  
Thierry Schmitz ◽  
Andreas Bernkop-Schnürch
Keyword(s):  
Delivery System ◽  
Oral Delivery ◽  
In Vivo Evaluation ◽  
Thiolated Chitosan ◽  
Oral Delivery System

Evidence for An Anti-Cancer Barrier in a Mixed Lineage Leukemia Mouse Model in Vivo.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3347-3347
Author(s):  
Sylvia Takacova ◽  
Jiri Bartek ◽  
Lucie Piterkova ◽  
Robert K. Slany ◽  
Vladimir Divoky
Keyword(s):  
Bone Marrow ◽  
Tumor Suppressor ◽  
Mouse Model ◽  
Peripheral Blood ◽  
Myeloid Cells ◽  
Mixed Lineage Leukemia ◽  
Cell Counts ◽  
Potential Tumor Suppressor

Abstract Mixed Lineage Leukemia (MLL) mutations identify a unique group of acute leukemias with distinct biological and clinical features. Although the role of MLL in leukemogenesis has been extensively studied, a precise mechanism regarding the leukemogenic potential of MLL mutations is not known. We generated a switchable MLL-ENL-ERtm mouse model, in which the MLL-ENL oncogene has been introduced by homologous recombination and is controlled by the endogenous MLL promoter, thus, expressed at physiological levels. Due to fusion with the estrogen receptor ligand binding domain (ERtm), the MLL-ENL-ERtm protein activity is dependent on continuous provision of tamoxifen or 4-hydroxytamoxifen. The MLL-ENL-ERtm mice have developed a myeloproliferative disorder (MPD) characterized by persistent mature neutrophilia after 484,5 +/− 75,68 days of latency on a tamoxifen diet, in association with high white cell counts in peripheral blood, splenomegaly and occasionally with anemia. Blood smears showed large numbers of mature myeloid elements consisting of 40–80% neutrophils (non-segmented forms in abundance), admixed with immature myeloid elements, 3–11% monocytes and 2–6% myeloblasts. The phenotype of MPD also involved myelomonocytic proliferation with 35% immature monocytic cells in one animal and severe anemia with increased numbers of immature erythroid cells in peripheral blood in another animal. Hematoxylin- and eosin-stained sections of the bone marrow from MLL-ENL-ERtm mice revealed expansion of myeloid cell population with no signs of progressive dysplasia. We observed massive infiltration of myeloid cells (positive for myeloperoxidase) into spleen with various degree of loss of normal splenic architecture depending on disease progression. FACS profiles of both bone marrow and spleen cells showed a typical pattern of granulocyte/macrophage/monocyte surface marker expression (CD34-CD43+Mac- 1+Gr-1+CD16/32+). In vitro evaluation of hematopoetic progenitors derived from bone marrow of leukemic mice at the terminal stage of the disease revealed decreased numbers of BFU-Es and increased numbers of CFU-GMs and CFU-Gs compared to matched controls. These results correlated with the expansion of the myelomonocytic and reduction of the erythroid compartment observed in the bone marrow of these animals. The average size (cellularity) of the mutant myeloid colonies was much smaller than the colonies derived from the wild-type controls, which could be caused by a partial block of terminal differentiation of myeloid progenitors in vitro. In vivo, MLL-ENL leads to expansion of differentiated myeloid cells in our model. High penetrance and long latency of leukemia in our model permits the study of early leukemia development. Our model revealed that MLL-ENL - induced myeloproliferation occurs as early as twelve weeks after MLL-ENL-ERtm activation in the bone marrow and infiltrates the spleen with a consequent decrease in lymphoid B220+CD19+IgM+ cells. Using the TUNEL assay on bone marrow sections, we observed induction of apoptosis in the highly proliferative bone marrow compartment compared to matched controls. These results suggest activation of a potential tumor suppressor mechanism by MLL-ENL in early stages of leukemia. We are currently investigating potential tumor suppressor pathways that might be involved in MLL-ENL - induced apoptosis in preleukemia.

scholarly journals In Vivo Activity of Posaconazole against Mucor spp. in an Immunosuppressed-Mouse Model

2002 ◽  
Vol 46 (7) ◽  
pp. 2310-2312 ◽  
Author(s):  
Qiu N. Sun ◽  
Laura K. Najvar ◽  
Rosie Bocanegra ◽  
David Loebenberg ◽  
John R. Graybill
Keyword(s):  
Body Weight ◽  
Mouse Model ◽  
Amphotericin B ◽  
Immunosuppressed Mouse ◽  
Tissue Burden

ABSTRACT The in vivo activities of posaconazole, itraconazole, and amphotericin B in neutropenic mice with zygomycosis were compared. The in vitro MICs of posaconazole and itraconazole for the strains of Mucor spp. used in this study ranged from 0.125 to 8 μg/ml and 0.25 to 8 μg/ml, respectively. The in vitro MIC range for amphotericin B is 0.125 to 0.25 μg/ml. At twice-daily doses of ≥15 mg/kg of body weight, posaconazole prolonged the survival of the mice and reduced tissue burden.

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