Photosensitizing activity of hypericin and hypericin acetate after topical application on normal mouse skin

Boiy, Annelies; Roelandts, Rik; Oord, Joost van den; Witte, Peter de

doi:10.1111/j.1365-2133.2007.08329.x

Cited by 27 publications

(18 citation statements)

References 40 publications

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“…These results are consistent with previous studies of penetration and distribution of hypericin in mice, where after application on the skin, hypericin penetrated after 4 h and was retained mainly in the stratum corneum (44). A previous study showed that the passage of hypericin into the circulatory system is minimal, with undetectable levels in plasma or serum (45). Retention of hypericin in the skin guarantees a treatment that targets the affected area, thus avoiding possible systemic toxic effects, as happens with other drugs used for the treatment of CL or even with other photosensitizers used to treat other diseases (46,47).…”

Section: Discussionsupporting

confidence: 82%

Development of a Novel Formulation with Hypericin To Treat Cutaneous Leishmaniasis Based on Photodynamic Therapy inIn VitroandIn VivoStudies

Montoya

Daza

Muñoz

et al. 2015

Antimicrob Agents Chemother

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An evaluation of the leishmanicidal activity in vitro and in vivo of hypericin, an expanded-spectrum photosensitizer found in Hypericum perforatum, is presented. Hypericin was evaluated against intracellular amastigotes in vitro of Leishmania (Viannia) panamensis. A topical formulation containing 0.5% hypericin was developed and assayed in vivo in a hamster model of cutaneous leishmaniasis. Results demonstrate that hypericin induces a significant antiamastigote effect in vitro against L. panamensis by decreasing the number of parasites inside infected cells. The topical formulation of 0.5% hypericin allows healing of L. panamensis-induced lesions upon a topical application of 40 mg/day plus visible-light irradiation (5 J/cm 2 , 15 min), twice a week for 3 weeks. Cutaneous leishmaniasis (CL) is a parasitic disease caused by protozoa of the genus Leishmania, which manifests as a chronic infection affecting mainly mononuclear phagocytes of the skin (1). The disease affects the poorest populations in 99 countries in tropical and subtropical regions of the world (2, 3). It is estimated that 14 million people are infected, 350 million are at risk, and there are about 1.5 million new cases per year (3, 4). The parasite is transmitted by the bite of an insect vector belonging to the genus Lutzomyia (in America) or Phlebotomus (in Europe, Asia, and Africa) in the subfamily Phlebotominae (5).Only three types of drugs are available to treat CL. They are the pentavalent antimonials (meglumine antimoniate and sodium stibogluconate), pentamidine isethionate, and miltefosine. Miltefosine is the only one available for oral administration (4). These medications are delivered at high doses and for long periods, thus leading to high toxicity. Therefore, their use is contraindicated in pregnant women, in patients with cardiovascular, renal, or hepatic disease, and in children with low body weight (6). Overall, the efficacy of these drugs varies between 55 and 98% depending on the compound and on the Leishmania species causing the clinical manifestation (7,8). However, their elevated toxicity encourages abandonment of treatment and consequently a decrease in the efficacy (9).More recently, photodynamic therapy (PDT) has emerged as an alternative to treat CL (10). This therapy is based on the application of a photosensitizing agent (PA) that, when excited by light of a certain wavelength, induces the production of reactive oxygen species (ROS) that can destroy the microorganism or the target cell (11). In spite of its potential, only a few PAs have been tested against CL in animal models, and only one in humans. Topical application of 5-aminolevulinic acid (ALA) and light in a murine model of CL caused by L. major showed a significant reduction of the parasitic load and the size of lesions (12). Intralesional administration of ALA (one to three PDT sessions) in a patient with CL by L. major produced a 10 to 20% cure, although it is probable that clinical outcome resulted from nonspecific destruction of infected macrophages instead of...

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Section: Discussionsupporting

confidence: 82%

Development of a Novel Formulation with Hypericin To Treat Cutaneous Leishmaniasis Based on Photodynamic Therapy inIn VitroandIn VivoStudies

Montoya

Daza

Muñoz

et al. 2015

Antimicrob Agents Chemother

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“…Phototoxic reactions mainly occur in the skin and eyes; thus, dermal and ocular exposure to compounds can be a predictive factor for in vivo phototoxicity as well as systemic exposure (Boiy et al, 2008;Seto et al, 2009). PK characterizations of compounds were conducted with a focus on plasma, skin, and eyes ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In this context, FA might be a major contributor to FFinduced phototoxicity after metabolism of FF. For photosafety assessments, exposure of compounds and their retention to dermal/ocular tissues can also be a key consideration because phototoxic reactions typically occur in the skin and eyes (Boiy et al, 2008;Seto et al, 2009). Therefore, in this study, the PK behavior of FF and its metabolites was assessed with a focus on plasma and skin/eyes in rats after oral administration of FF.…”

Section: Discussionmentioning

confidence: 99%

New Photosafety Assessment Strategy Based on the Photochemical and Pharmacokinetic Properties of Both Parent Chemicals and Metabolites

et al. 2015

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Photoreactivity and dermal/ocular deposition of compounds have been recognized as key considerations for evaluating the phototoxic risk of compounds. Because some drugs are known to cause phototoxic reactions via generation of potent phototoxic metabolites, photosafety assessments on parent drugs alone may lead to false predictions about their photosafety. This study aimed to establish a new photosafety assessment strategy for evaluating the in vivo phototoxic potential of both a parent substance and its metabolites. The in vivo phototoxic risk of fenofibrate (FF) and its metabolites, fenofibric acid (FA) and reduced fenofibric acid, were evaluated based on photochemical and pharmacokinetic analyses. FF and FA exhibited intensive UV absorption, with molar extinction coefficient values of 17,000 (290 nm) and 14,000 M 21 cm 21 (295 nm), respectively. Superoxide generation from FA was significantly higher than from FF, and a marked increase in superoxide generation from FF was observed after incubation with rat hepatic S9 fractions, suggesting enhanced photoreactivity of FF after metabolism. FA showed high dermal/ocular deposition after oral administration (5 mg/kg, p.o.) although the concentration of FF was negligible, suggesting high exposure risk from FA. On the basis of these findings, FA was deduced to be a major contributor to phototoxicity induced by FF taken orally, and this prediction was in accordance with the results from in vitro/in vivo phototoxicity tests. Results from this study suggest that this new screening strategy for parent substances and their metabolites provides reliable photosafety information on drug candidates and would be useful for drug development with wide safety margins.

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“…However, the concentration gap of hypericin affinities in the micromolar range for binding these receptors and nanomolar plasma concentrations measured in humans after intake of therapeutic doses made it unlikely to account for the antidepressive principle (Staffeldt et al 1994;Kerb et al 1996;Brockm€ oller et al 1997). Phototoxicity is a feature attracting attention to hypericin (Boiy et al 2008;Davids et al 2008), being currently under investigation regarding its antimetastatic and antiangiogenic properties in the treatment of glioblastomas or melanoma (Davids et al 2008;Barliya et al 2011;Dror et al 2013). The flavonoids, biapigenine, hyperoside, and isoquercitrin, showed moderate antidepressive activity in the forced swim test, a behavioral animal model for depression (N€ oldner and Sch€ otz 2002;Paulke et al 2008) with yet unknown mechanism.…”

Section: Introductionmentioning

confidence: 97%

Hyperforin: To Be or Not to Be an Activator of TRPC(6)

Friedland

Harteneck

2015

Reviews of Physiology, Biochemistry and Pharmacology

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Meantime, it is well accepted that hyperforin, the chemical instable phloroglucinol derivative of Hypericum perforatum, St. John's wort, is the pharmacophore of St. John's wort extracts. With the decline of this scientific discussion, another controversial aspect has been arisen, the question regarding the underlying mechanism leading to the pharmacological profile of the plant extract used in therapy of depression. We will summarize the different concepts described for hyperforin's antidepressive activity. Starting with unspecific protein-independent mechanisms due to changes in pH, we will summarize data of protein-based concepts beginning with concepts based on involvement of a variety of proteins and will finally present concepts based on the modulation of a single protein.

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Photosensitizing activity of hypericin and hypericin acetate after topical application on normal mouse skin

Cited by 27 publications

References 40 publications

Development of a Novel Formulation with Hypericin To Treat Cutaneous Leishmaniasis Based on Photodynamic Therapy inIn VitroandIn VivoStudies

Development of a Novel Formulation with Hypericin To Treat Cutaneous Leishmaniasis Based on Photodynamic Therapy inIn VitroandIn VivoStudies

New Photosafety Assessment Strategy Based on the Photochemical and Pharmacokinetic Properties of Both Parent Chemicals and Metabolites

Hyperforin: To Be or Not to Be an Activator of TRPC(6)

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