title: In vitro permeation and biological activity of punicalagin and zinc (II) across skin and mucous membranes prone to Herpes simplex virus infection.
abstract: Coadministration of pomegranate rind extract (PRE) and zinc (II) ions has recently been reported as a potential new topical treatment for Herpes simplex virus (HSV) infections. In the current work we examined the in vitro topical delivery of punicalagin (major phytochemical of PRE) and zinc from hydrogels across epithelial membranes that can become infected with HSV. Porcine epidermal, buccal and vaginal mucous membranes were excised and mounted in Franz diffusion cells and dosed with a simple hydrogel containing PRE and zinc sulphate (ZnSO4). The permeation of punicalagin and zinc were determined by HPLC and ICPMS respectively; punicalagin was also determined in the basal layers by reverse tape stripping. Receptor phases from the epidermal membrane experiment were also used to challenge HSV-1 in Vero host cells, and ex vivo porcine skin was used to probe COX-2 modulation. Punicalagin and zinc permeated each of the three test membranes, with significantly greater amounts of both delivered across the epidermal membrane. The amounts of punicalagin permeating the buccal and vaginal membranes were similar, although the amount of zinc permeating the vaginal membrane was comparatively very large - it is known that zinc interacts with vaginal mucosa. The punicalagin recovered by reverse tape stripping of the epidermal, buccal and vaginal membranes gave 0.47±0.016, 0.45±0.052 and 0.51±0.048nMcm-2respectively, and were statistically the same (p<0.05). A 2.5 log reduction was achieved against HSV-1 using diffusion cell receptor phase, and COX-2 expression was reduced by 64% in ex vivo skin after 6h. Overall, a hydrogel containing 1.25mgmL-1PRE and 0.25M ZnSO4was able to topically deliver both the major bioactive compound within PRE and Zn (II) across all membranes and into the site specific region of Herpes simplex vesicular clusters, while maintaining potentiated virucidal and anti-inflammatory properties. This novel therapeutic system therefore has potential for the topical treatment of HSV infections.
authors: Cardiff School of Pharmacy & Pharmaceutical Science, Cardiff University, Cardiff CF10 3NB, Wales, United Kingdom; Department of Microbiology & Infectious Diseases, School of Medicine, Cardiff University, Cardiff CF14 4XW, Wales, United Kingdom.
authors: David M J
authors: DMJ
authors: Houston
authors: Cardiff School of Pharmacy & Pharmaceutical Science, Cardiff University, Cardiff CF10 3NB, Wales, United Kingdom.
authors: Bethan
authors: B
authors: Robins
authors: Department of Microbiology & Infectious Diseases, School of Medicine, Cardiff University, Cardiff CF14 4XW, Wales, United Kingdom; Institute of Microbiology, Armed Forces Medical Academy, Neuherbergstraße 11, 80937 München, Germany.
authors: Joachim J
authors: JJ
authors: Bugert
authors: Cardiff School of Pharmacy & Pharmaceutical Science, Cardiff University, Cardiff CF10 3NB, Wales, United Kingdom; University of Brighton, Mithras House, Lewes Road, Brighton BN2 4AT, United Kingdom.
authors: Stephen P
authors: SP
authors: Denyer
authors: Cardiff School of Pharmacy & Pharmaceutical Science, Cardiff University, Cardiff CF10 3NB, Wales, United Kingdom. Electronic address: heard@cardiff.ac.uk.
authors: Charles M
authors: CM
authors: Heard
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000494:pharmacology; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005260:Female; D006561:Herpes Simplex; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000254:growth & development; D020100:Hydrogels / Q000008:administration & dosage* / Q000494:pharmacology; D047348:Hydrolyzable Tannins / Q000008:administration & dosage* / Q000494:pharmacology; D065347:Hypromellose Derivatives; D066298:In Vitro Techniques; D009092:Mucous Membrane / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D013552:Swine; D014709:Vero Cells; D019287:Zinc Sulfate / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D000998:Antiviral Agents; D020100:Hydrogels; D047348:Hydrolyzable Tannins; D065347:Hypromellose Derivatives; C115642:punicalagin; D019287:Zinc Sulfate; D051546:Cyclooxygenase 2
keywords: Anti-inflammatory; Buccal cavity; Drug delivery; Herpes simplex virus; Pomegranate rind extract; Punica granatum L.; Punicalagin; Reverse tape stripping; Skin; Vagina; Virucidal; Zinc