# Natural Photosensitizers in Clinical Trials
## 3 Natural Photosensitizers in Clinical Trials
### Hypericin  
Hypericin (HYP) is a hydroxylated phenanthroperylenediquinone derived from the well-known St. John's word (_Hypericum perforatum_) herb [42; 43; 44]. Due to its hydrophobic nature, hypericin accumulates mainly in the membranes of the endoplasmic reticulum (ER), lysosomes, Golgi apparatus, and mitochondria. When used in PDT, it can induce stress in the ER, leading to the release of calcium ions into the cytoplasm. In turn, increasing their levels can activate various enzymes and lead to mitochondrial damage. Moreover, HYP generates high levels of singlet oxygen and has minimal toxicity in the dark and excellent photosensitivity [45; 46]. HYP's photoactivation ability is induced by a delocalized \(\pi\) electron arrangement in its aromatic rings [47; 48; 46]. Studies in recent years have demonstrated the anticancer potential of hypericin for use as a photosensitizer in PDT in several types of cancer, including anaplastic thyroid cancer, pancreatic cancer, glioblastoma multiforme, nasopharyngeal carcinoma, and leukemia [49; 50; 51; 52; 53]. Hypericin in Clinical Trials of Photodynamic Therapy  
We located three clinical trials with this compound, with one using pure hypericin as a photosensitizer and two using _Hypericum perforatum_ extract. All focused on the treatment of skin lesions. The side effects of PDT with hypericin have been described, but they were not serious. [PERSON] et al. conducted a multicenter, placebo-controlled, double-blinded, randomized clinical trial testing the efficacy and safety of topical synthetic hypericin 0.25% visible light-activated ointment as non-mutagenic PDT in early-stage mycosis fungoides-cutaneous T-cell lymphoma. The treatment regimen consisted of applying 0.25% hypericin ointment to each index lesion, covering it with an opaque dressing or clothing for 18 to 24 h, and then irradiating it with visible light ranging from 500 to 650 nm. Light treatment began at 5 J/cm\({}^{2}\) and was increased by 1 J/cm\({}^{2}\) with each treatment until a mild skin reaction was observed in the treated lesions or until a maximum light dose of 12 J/cm\({}^{2}\) was reached. The lesions were treated twice a week for each 6-week cycle. Significant clinical responses were observed in both lobular and plaque-type lesions, and the response rate increased with the number of cycles received (up to a maximum of 49%). The most common treatment-related adverse events were mild local skin lesions and injection site reactions. No serious adverse events related to the drug occurred [54]. [PERSON] et al. conducted a study in which they evaluated the efficacy of _Hypercium perforatum_ extract in the treatment of solar keratosis, basal cell carcinoma, and [PERSON]'s disease (carcinoma in situ). The _H. perforatum_ extract used contained 32.5% hypericin and 67.5% pseudohypericin. The therapeutic regimen involved applying hypericin ointment with a concentration of 2 mg/mL to the lesion and 10 mm of surrounding skin in a 1 mm thick layer under an occlusive dressing, removing it after 2 h, and irradiating the area with a PDT lamp emitting incoherent red light with a wavelength of 580 to 680 nm. The total light dose was 75 J/cm\({}^{2}\) for 15-20 min. The above-mentioned lesions were treated with PDT at weekly intervals; the average treatment period was 6 weeks. The number of PDT treatments depended on the clinical features of the treated areas and persistent fluorescence during photodynamic diagnosis. The percentage of complete clinical response was 50% for cutaneous keratosis, 28% for patients with superficial basal cell carcinoma, and 40% for patients with [PERSON]'s disease. All patients complained of burning and pain during irradiation. No erythema or swelling was observed after treatment, and no other serious side effects were reported [55]. [PERSON] et al. tested PDT with St. John's wort extract for the treatment of acne in a prospective, double-blind, randomized study. The therapeutic regimen consisted of applying 1.5 mL of 0.5% _H.