scholarly journals Efficacious Treatment of Experimental Leishmaniasis with Amphotericin B-Arabinogalactan Water-Soluble Derivatives

1999 ◽  
Vol 43 (9) ◽  
pp. 2209-2214 ◽  
Author(s):  
Jacob Golenser ◽  
Shoshana Frankenburg ◽  
Tirtsa Ehrenfreund ◽  
Abraham J. Domb
Keyword(s):  
Amphotericin B ◽  
Leishmania Major ◽  
Water Soluble ◽  
In Vivo Experiments ◽  
Drug Concentrations ◽  
Efficacious Treatment ◽  
Lipid Formulations ◽  
Established Infection

ABSTRACT In this study, we tested the efficacy of amphotericin B (AmB)-arabinogalactan (AmB-AG) conjugates for the treatment of experimental leishmaniasis. Chemical conjugation of AmB to a water-soluble, biodegradable, and biocompatible polymer could present many advantages over presently available AmB formulations. Two conjugates were tested, a reduced (rAmB-AG) form and an unreduced (uAmB-AG) form. In vitro, the drug concentrations which lower the values of parasites (for promastigotes) or infected macrophages (for amastigotes) to 50% of the untreated values (ED50s) of uAmB-AG and rAmB-AG were 0.19 and 0.34 μg/ml, respectively, forLeishmania major promastigotes and 0.17 and 0.31 μg/ml, respectively, for amastigotes. The effect on Leishmania infantum-infected macrophages was more marked, with ED50s of 0.035 μg/ml for rAmB-AG and 0.027 μg/ml for uAmB-AG. In in vivo experiments, BALB/c mice injected with L. major were treated from day 2 onwards on alternate days for 2 weeks. Both conjugates, as well as liposomal AmB (all at 6 mg/kg of body weight) and Fungizone (1 mg/kg), significantly delayed the appearance of lesions compared to that in untreated mice. In addition, both conjugates, but not liposomal AmB, were significantly more effective than Fungizone. Subcutaneous injection of the conjugates (6 mg/kg) was significantly more effective than liposomal AmB in delaying the appearance of lesions. Higher AmB concentrations of up to 12 mg/kg could be administered by this route. When an established infection was treated, uAmB-AG was somewhat more effective than liposomal AmB. In summary, water-soluble polymeric AmB derivatives were found effective and safe for the treatment of leishmanial infections. The conjugates, which are stable and can be produced relatively cheaply (compared to lipid formulations), can be used in the future for the treatment of leishmaniasis infections.

scholarly journals Activity of Indenoisoquinolines against African Trypanosomes

2008 ◽  
Vol 53 (1) ◽  
pp. 123-128 ◽  
Author(s):  
Rahul P. Bakshi ◽  
Dongpei Sang ◽  
Andrew Morrell ◽  
Mark Cushman ◽  
Theresa A. Shapiro
Keyword(s):  
Anticancer Agents ◽  
Mammalian Cells ◽  
Sleeping Sickness ◽  
Water Soluble ◽  
African Trypanosomes ◽  
In Vivo Experiments ◽  
Topoisomerase Ib ◽  
Topoisomerase Poisons

ABSTRACT African trypanosomiasis (sleeping sickness), caused by protozoan Trypanosoma brucei species, is a debilitating disease that is lethal if untreated. Available drugs are antiquated, toxic, and compromised by emerging resistance. The indenoisoquinolines are a class of noncamptothecin topoisomerase IB poisons that are under development as anticancer agents. We tested a variety of indenoisoquinolines for their ability to kill T. brucei. Indenoisoquinolines proved trypanocidal at submicromolar concentrations in vitro. Structure-activity analysis yielded motifs that enhanced potency, including alkylamino substitutions on N-6, methoxy groups on C-2 and C-3, and a methylenedioxy bridge between C-8 and C-9. Detailed analysis of eight water-soluble indenoisoquinolines demonstrated that in trypanosomes the compounds inhibited DNA synthesis and acted as topoisomerase poisons. Testing these compounds on L1210 mouse leukemia cells revealed that all eight were more effective against trypanosomes than against mammalian cells. In preliminary in vivo experiments one compound delayed parasitemia and extended survival in mice subjected to a lethal trypanosome challenge. The indenoisoquinolines provide a promising lead for the development of drugs against sleeping sickness.

scholarly journals Formulation Development of Mucoadhesive Microparticle-Laden Gels for Oral Mucositis: An In Vitro and In Vivo Study

Pharmaceutics ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 603
Author(s):  
Hiroomi Sakurai ◽  
Yuri Ikeuchi-Takahashi ◽  
Ayaka Kobayashi ◽  
Nobuyoshi Yoshimura ◽  
Chizuko Ishihara ◽  
...  
Keyword(s):  
Oral Mucosa ◽  
Oral Mucositis ◽  
Formulation Development ◽  
Scanning Calorimetry ◽  
In Vivo Experiments ◽  
Drug Retention ◽  
Drug Concentrations ◽  
Diffraction Patterns

In order to relieve pain due to oral mucositis, we attempted to develop mucoadhesive microparticles containing indomethacin (IM) and gel preparations with IM microparticles that can be applied to the oral cavity. The mucoadhesive microparticles were prepared with a simple composition consisting of IM and polyvinyl alcohol (PVA). Two kinds of PVA with different block properties were used, and microparticles were prepared by heating-filtration and mixing-drying. From the X-ray powder diffraction patterns, differential scanning calorimetry thermograms, and morphological features of the IM microparticles, IM should exist as polymorphic forms in the microparticles. Rapid drug release properties were observed in the IM microparticles. Increased drug retention was observed in IM microparticles containing PVA, and the IM-NK(50) gel, using a common block character PVA and heating-filtration, showed good long-term drug retention properties. In vivo experiments showing significantly higher drug concentrations in the oral mucosa were observed with IM microparticles prepared by heating-filtration, and the IM-NK(50) gel maintained significantly higher drug concentrations in the oral mucosa. From these results, the IM-NK(50) gel may be useful as a preparation for relieving oral mucositis pain.

Development and Characterization of the Neuroregenerative Xanthohumol C/Hydroxypropyl-β-cyclodextrin Complex Suitable for Parenteral Administration

Planta Medica ◽  
2019 ◽  
Vol 85 (16) ◽  
pp. 1233-1241
Author(s):  
Michael Kirchinger ◽  
Lara Bieler ◽  
Julia Tevini ◽  
Michael Vogl ◽  
Elisabeth Haschke-Becher ◽  
...  
Keyword(s):  
Water Solubility ◽  
Pharmaceutical Research ◽  
Water Soluble ◽  
Complexing Agents ◽  
Cyclodextrin Complex ◽  
Scanning Calorimetry ◽  
In Vivo Experiments ◽  
Strong Candidate

AbstractThe chroman-like chalcone Xanthohumol C, originally found in hops, was demonstrated to be a potent neuroregenerative and neuroprotective natural product and therefore constitutes a strong candidate for further pharmaceutical research. The bottleneck for in vivo experiments is the low water solubility of this chalcone. Consequently, we developed and validated a suitable formulation enabling in vivo administration. Cyclodextrins were used as water-soluble and nontoxic complexing agents, and the complex of Xanthohumol C and 2-hydroxypropyl-β-cyclodextrin was characterized using HPLC, HPLC-MS, NMR, and differential scanning calorimetry. The water solubility of Xanthohumol C increases with increasing concentrations of cyclodextrin. Using 50 mM 2-hydroxypropyl-β-cyclodextrin, solubility was increased 650-fold. Furthermore, in vitro bioactivity of Xanthohumol C in free and complexed form did not significantly differ, suggesting the release of Xanthohumol C from 2-hydroxypropyl-β-cyclodextrin. Finally, a small-scaled in vivo experiment in a rat model showed that after i. p. administration of the complex, Xanthohumol C can be detected in serum, the brain, and the cerebrospinal fluid at 1 and 6 h post-administration. Mean (± SD) Xanthohumol C serum concentrations after 1, 6, and 12 h were determined as 463.5 (± 120.9), 61.9 (± 13.4), and 9.3 (± 0.8) ng/mL upon i. v., and 294.3 (± 22.4), 45.5 (± 0.7), and 13 (± 1.0) ng/mL after i. p. application, respectively. Accordingly, the formulation of Xanthohumol C/2-hydroxypropyl-β-cyclodextrin is suitable for further in vivo experiments and further pharmaceutical research aiming for the determination of its neuroregenerative potential in animal disease models.

scholarly journals Biodistribution and In Vivo Antileishmanial Activity of 1,2-Distigmasterylhemisuccinoyl-sn-Glycero-3-Phosphocholine Liposome-Intercalated Amphotericin B

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Maryam Iman ◽  
Zhaohua Huang ◽  
Seyedeh Hoda Alavizadeh ◽  
Francis C. Szoka ◽  
Mahmoud R. Jaafari
Keyword(s):  
Amphotericin B ◽  
Leishmania Major ◽  
Parasite Load ◽  
Tissue Concentrations ◽  
Content Type ◽  
Colloidal Properties ◽  
Covalently Linked ◽  
Antileishmanial Activities

ABSTRACT 1,2-Distigmasterylhemisuccinoyl-sn-glycero-3-phosphocholine (DSHemsPC) is a new lipid in which two molecules of stigmasterol (an inexpensive plant sterol) are covalently linked via a succinic acid to glycerophosphocholine. Our previous study revealed that liposome (Lip)-intercalated amphotericin B (AMB) prepared from DSHemsPC (DSHemsPC-AMB-Lip) possesses excellent colloidal properties and in vitro antifungal and antileishmanial activities similar to those of the liposomal AMB preparation AmBisome. The aim of this study was to determine the biodistribution and evaluate the antileishmanial effects of DSHemsPC-AMB-Lip in Leishmania major-infected BALB/c mice. The serum profile and tissue concentrations of AMB were similar in DSHemsPC-AMB-Lip- and AmBisome-treated mice after intravenous (i.v.) injection. Multiple i.v. doses of the micellar formulation of AMB (Fungizone; 1 mg/kg of body weight), DSHemsPC-AMB-Lip (5 mg/kg), and AmBisome (5 mg/kg) were used in L. major-infected BALB/c mouse models of early and established lesions. In a model of the early lesions of cutaneous leishmaniasis (CL), the results indicated that the level of footpad inflammation was significantly (P < 0.001) lower in mice treated with DSHemsPC-AMB-Lip and AmBisome than mice treated with empty liposomes or 5% dextrose. The splenic and footpad parasite load was also significantly (P < 0.001) lower in these groups of mice than in control mice that received 5% DW or free liposome. The in vivo activity of DSHemsPC-AMB-Lip was comparable to that of AmBisome, and both provided improved results compared to those achieved with Fungizone at the designated doses. The results suggest that systemic DSHemsPC-AMB-Lip administration may be useful for the treatment of leishmaniasis, and because it costs less to produce DSHemsPC-AMB-Lip than AmBisome, DSHemsPC-AMB-Lip merits further investigation.

Use of in vitro lipid digestion data to explain the in vivo performance of triglyceride-based oral lipid formulations of poorly water-soluble drugs: Studies with halofantrine

2004 ◽  
Vol 93 (5) ◽  
pp. 1110-1121 ◽  
Author(s):  
Christopher J.H. Porter ◽  
Ann Marie Kaukonen ◽  
Agnes Taillardat-Bertschinger ◽  
Ben J. Boyd ◽  
Jacquelyn M. O'Connor ◽  
...  
Keyword(s):  
Water Soluble ◽  
Lipid Digestion ◽  
Poorly Water Soluble Drugs ◽  
Water Soluble Drugs ◽  
Poorly Water Soluble ◽  
Lipid Formulations

scholarly journals Antileishmanial Activity, Uptake, and Biodistribution of an Amphotericin B and Poly(α-Glutamic Acid) Complex

2013 ◽  
Vol 57 (10) ◽  
pp. 4608-4614 ◽  
Author(s):  
Abeer H. A. Mohamed-Ahmed ◽  
Karin Seifert ◽  
Vanessa Yardley ◽  
Hollie Burrell-Saward ◽  
Stephen Brocchini ◽  
...  
Keyword(s):  
Glutamic Acid ◽  
Amphotericin B ◽  
Leishmania Donovani ◽  
Water Soluble ◽  
Molecular Weight Range ◽  
Acid Complex ◽  
Content Type ◽  
New Treatment

ABSTRACTA noncovalent, water-soluble complex of amphotericin B (AMB) and poly(α-glutamic acid) (PGA), with AMB loadings ranging from 25 to 55% (wt/wt) using PGA with a molecular weight range of 50,000 to 70,000, was prepared as a potential new treatment for visceral leishmaniasis (VL). The AMB-PGA complex was shown to be as active as Fungizone (AMB deoxycholate) against intracellularLeishmania donovaniamastigotes in differentiated THP-1 cells. Thein vitrouptake of the AMB-PGA complex by differentiated THP-1 cells was similar to that of Fungizone and higher than that of AmBisome (liposomal AMB). The AMB-PGA complex also displayed a dose-response profile similar to that of AmBisomein vivoin BALB/c mice againstL. donovani, with 50% effective doses (ED50s) of 0.24 ± 0.03 mg/kg of body weight for the AMB-PGA complex and 0.24 ± 0.06 mg/kg for AmBisome. A biodistribution study with mice indicated that the AMB-PGA complex cleared more rapidly from plasma than AmBisome, with a comparable low level of distribution to the kidneys.

Differential Effects of TPM, A Phosphorylated Tocopherol Mixture, and Other Tocopherol Derivatives as Excipients for Enhancing the Solubilization of Co-Enzyme Q10 as a Lipophilic Drug During Digestion of Lipid- Based Formulations

2019 ◽  
Vol 16 (7) ◽  
pp. 628-636
Author(s):  
Anna Pham ◽  
Paul D. Gavin ◽  
Roksan Libinaki ◽  
Gisela Ramirez ◽  
Jamal T. Khan ◽  
...  
Keyword(s):  
Medium Chain Triglyceride ◽  
In Vitro Digestion ◽  
Water Soluble ◽  
Strongly Correlated ◽  
Polyethylene Glycol 1000 ◽  
Exposure In Vivo ◽  
Poorly Water Soluble ◽  
Lipid Formulations

Background: The tocopherol-based excipient, TPM, when incorporated into a medium-chain triglyceride (MCT)-based lipid formulation, has been previously shown to improve the solubilization of Coenzyme Q10 (CoQ10) during in vitro digestion which is strongly correlated with enhanced exposure in vivo. Methods: The current study aimed to gain further understanding of the MCT + TPM co-formulation, by assessing the formulation performance under fasted and fed in vitro digestion conditions, with different drug and excipient loading levels. Natural and synthetic-derived TPM were equivalent, and with d-α- tocopherol polyethylene glycol 1000 succinate (TPGS) outperformed other derivatives in enhancing the solubilisation of CoQ10 during digestion. Results: Fed conditions significantly improved the solubility of CoQ10 during in vitro digestion of the formulation in comparison with fasted conditions. The addition of TPM at 10% (w/w) of the total MCT + TPM provided optimal performance in terms of CoQ10 solubilization during digestion. Conclusion: The results further highlights the potential of TPM as an additive in lipid formulations to improve the solubilization and oral bioavailability of poorly water-soluble compounds.

scholarly journals KY-62, a Polyene Analog of Amphotericin B, for Treatment of Murine Candidiasis

1998 ◽  
Vol 42 (1) ◽  
pp. 147-150 ◽  
Author(s):  
John R. Graybill ◽  
Laura K. Najvar ◽  
Annette Fothergill ◽  
Thomas Hardin ◽  
Michael Rinaldi ◽  
...  
Keyword(s):  
Body Weight ◽  
Candida Albicans ◽  
Amphotericin B ◽  
Clinical Development ◽  
Water Soluble ◽  
Clinical Isolates ◽  
In Vitro Testing ◽  
Immunocompetent Mice

ABSTRACT KY-62 is a water-soluble analog of amphotericin B. In vitro testing of five clinical isolates of Candida albicans showed KY-62 to have potency similar to that of amphotericin B. KY-62 was administered to mice infected intravenously with C. albicans. In vivo, KY-62 was effective in immunocompetent mice, with potency similar to that of amphotericin B. KY-62 was well tolerated up to 30 mg/kg of body weight per dose, an amount that would be lethal with amphotericin B. KY-62 was less effective in mice rendered neutropenic with 5-fluorouracil. The addition of flucytosine had little effect. KY-62 may have potential for clinical development.

scholarly journals In vitro activity of six antiviral drugs against equid alphaherpesvirus type 1 indicates ganciclovir as promising drug for in vivo studies

2018 ◽  
Vol 48 (12) ◽  
Author(s):  
Amanda Lovato de Oliveira ◽  
Juliana Felipetto Cargnelutti ◽  
Ana Paula Gnocato Mortari ◽  
Eduardo Furtado Flores ◽  
Rudi Weiblen
Keyword(s):  
Specific Treatment ◽  
Vitro Activity ◽  
In Vivo Studies ◽  
In Vitro Activity ◽  
In Vivo Experiments ◽  
Drug Concentrations ◽  
Viral Plaque

ABSTRACT: Equid alphaherpesvirus type 1 (EHV-1) is distributed worldwide and is a major agent of abortion, respiratory and neurological disease in horses. No specific treatment is available for EHV-1 infection, yet the potential of antiviral therapy has been explored. In this study we investigated the in vitro activity of Acyclovir, Ganciclovir, Foscarnet, Famciclovir, Vidarabina and Cidofovir against EHV-1. For this, the MTT test was performed, in which all the tested drugs showed no toxicity up to 200μg/mL. Subsequently, different drug concentrations were submitted to viral plaque reduction assays in cell culture. The selectivity index (SI) of the compounds was determined using the cytotoxic concentration for 50% of cells (CC50), obtained by MTT, and effective drug concentration to inhibit by 50% the number of viral plaques (EC50). Ganciclovir (SI: 490; EC50: 1.9 μg/mL) was the most efficient and safest drug against EHV-1, followed by Cidofovir (SI: 150, EC50: 5.7μg/mL), Acyclovir (SI: 37.4, EC50: 22.2μg/mL), Famciclovir (SI: 25.1, EC50: 24.5μg/mL), Vidarabine (SI: 12.2, EC50: 40.9μg/mL) and Foscarnet (SI: 6.9, EC50: 49.5 μg/mL), respectively. These results indicated that Ganciclovir (followed by Cidofovir), is a promising candidate for use in in vivo experiments.

scholarly journals In Vitro and In Vivo Anti-Parasitic Activity of Artemisinin Combined With Glucantime and Shark Cartilage Extract on Iranian Strain of Leishmania major (MRHO/IR/75/ER)

2021 ◽  
Vol 14 (3) ◽  
Author(s):  
Fatemeh Ghaffarifar ◽  
Soheila Molaei ◽  
Zuhair Mohammad Hassan ◽  
Mohammad Saaid Dayer ◽  
Abdolhossein Dalimi ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Human Subjects ◽  
Parasite Burden ◽  
Lesion Size ◽  
In Vivo Experiments ◽  
Parasitic Activity ◽  
Shark Cartilage ◽  
Immune System Modulation

Background: The adverse effects and increased resistance of drugs necessities the discovery of novel combination therapy. Objectives: This study aimed to examine the effects of Artemisinin plus glucantime or shark cartilage extract on the Iranian strain of Leishmania major (MRHO/IR/75/ER) in vitro and in vivo. Methods: In in vitro experiments, the effects of drugs and their combination in different concentrations (3.12 - 400 µg/mL) on the promastigotes, amastigotes, and un-infected macrophage cells were evaluated. In in vivo experiments, infected BALB/c mice were used as a cutaneous leishmaniasis model to evaluate the effects of the drugs and their combinations with different routes of administrations (namely Artemisinin: oral, ointment, and intraperitoneal; glucantime: intraperitoneal, intramuscular, intralesional, and subcutaneous; shark cartilage extract: oral) on parasite burden, lesion size, and immune system modulation. Results: The results revealed that Artemisinin and glucantime in combination with shark cartilage extract had greater effects on promastigotes than either Artemisinin or glucantime (P < 0.05), and that the combinations also had high cytotoxic effects on promastigotes and uninfected macrophages (P = 0.001). These combinations had more inhibitory effects on amastigotes and infected macrophages than promastigotes. The lesion sizes and parasite burden in the spleen decreased against the combinations of the drugs in different administrations. It was also noticed that the best combination administration route of Artemisinin and glucantime, as strong inducers of INF-γ and Th1 immune response, were ointment and IM, respectively (P < 0.05). Conclusions: The findings indicate that Artemisinin- glucantime or Artemisinin- Shark cartilage combinations are effective inhibitors of L. major. However, further clinical trials are recommended to evaluate the effects of these combinations in human subjects.

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