Hematoporphyrin monomethyl ether photodynamic therapy for the treatment of Sturge-Weber syndrome and large segmental facial port-wine stain.

Hematoporphyrin monomethyl ether (HMME) is a newly authorized photosensitizer for the treatment of port-wine stain (PWS) in China. However, no research on its efficacy for treating PWS lesions of Sturge-Weber syndrome (SWS) has been made. To assess the efficacy and safety of HMME-photodynamic therapy (PDT) in the treatment of SWS and simple large segmental facial PWS. Medical records of patients with SWS and large segmental facial PWS were reviewed. Efficacy was evaluated according to color blanching and graded as excellent (≥75%), good (50%-74%), fair (25%-49%), and poor (≤24%). Adverse events were analyzed. Nineteen patients with SWS and 33 patients with large segmental facial PWS were analyzed. 52.6% SWS and 69.7% PWS patients (p > .05) achieved at least 25% improvement. Common adverse events included short-term pain, edema, pruritus, exudation, and scab. No severe adverse event occurred. HMME-PDT was effective and safe for SWS and large segmental facial PWS.

Clinical study on hemoporfin PDT for infant facial port-wine stains.

OBJECTIVE: To observe the clinical efficacy and therapeutic response of Hemoporfin photodynamic therapy (PDT) for infant facial port-wine stains (PWS). METHOD: Hemoporfin PDT was used to treat 100 cases of infant facial PWS. After receiving Hemoporfin skin test, the cases with a negative skin test result were intravenously injected with Hemippofen (5 mg/kg) and irradiated under 532 nm LED green light. After treatment, a follow-up visit was paid through WeChat and Dermlink PWS consulting platform, in order to observe the therapeutic response and clinical efficacy. RESULT: The follow-up visit showed an effective rate of 98%, including 85 cases of itching (85%), 100 cases of edema (100%), 89 cases of purpura-like change (89%), 33 cases of crust (33%), 2 cases of hyperpigmentation (2%) and 2 cases of scars (2%), with no allergy and other systematic adverse reaction. CONCLUSION: Hemoporfin PDT has a high clinical efficacy and response rate in treating infant facial PWS, with slight adverse reactions.

A dose-finding study for hemoporfin in photodynamic therapy for port-wine stain: A multicenter randomized double-blind phase IIb trial.

BACKGROUND/PURPOSE: Previous studies have shown that hemoporfin-mediated photodynamic therapy (PDT) was a treatment for port-wine stain (PWS). Our current study aimed to identify optimal hemoporfin dose. METHODS: A prospective, multicenter, double-blind, randomized clinical trial was conducted. Patients were assigned into low- or high-dose hemoporfin (2.5 mg/kg and 5 mg/kg intravenously, respectively), or control (placebo) group, at a rate of 2:2:1. Treatment efficacy was evaluated at week 8. Then, patients in control group were randomly assigned into either high- or low-dose hemoporfin group. Treatment reactions and adverse events were analyzed at week 16. RESULTS: A total of 100 patients (40, 40, 20 in low-, high-dose hemoporfin, and control group, respectively) were enrolled. Compared to low dose (40%) and control group (15%), a higher proportion of patients in high-dose group (75%) had achieved skin lesion improvements. Treatment satisfactions were graded highest in high-dose group. Compared to low-dose group (14.3%), high-dose group (46.0%) had more frequent skin hyperpigmentation, which disappeared 3-6 months after treatment. Other treatment reactions and adverse events were comparable between two groups. CONCLUSIONS: Photodynamic therapy with 5 mg/kg hemoporfin could be an effective and safe treatment for PWS.

Evaluation of the effect of photodynamic therapy with hematoporphyrin monomethyl ether on VX2 tumors implanted in the rectal submucosa of rabbits.

We evaluated the influence of the photodynamic therapy (PDT) dosage with hematoporphyrin monomethyl ether (HMME) on its therapeutic efficacy in a rabbit model of in situ rectal cancer. VX2 cells were injected into the rectal submucosa of a rabbit to establish a carcinoma model in situ. After 10-14days, the tumors were treated with PDT at three dosages: a low dose (5mg/kg HMME; 60J/cm(2) laser power), intermediate dose (5mg/kg; 240J/cm(2)), and high dose (10mg/kg; 360J/cm(2)). Tumor growth, animal survival, histopathological changes, general conditions, and adverse reactions were analyzed. PDT showed inhibitive effects on rectal cancer in all PDT groups, and the efficacy was correlated with the PDT dosage. The high dose PDT group had the best efficacy with a remarkable response rate of 20% and slight response rate of 80%, but it also had the highest death rate of 80% at day 7. The intermediate dose PDT group had a total response rate of 80% (60% remarkable plus 20% slight) and a 40% death rate. Comparably, the low dose PDT group had a 40% slight response rate and 60% death rate. Therefore, the intermediate dose of PDT was considered to be optimal among the three groups. Based on endoscopy findings, we also found that high dose PDT presented more side effects including inflammation, intestinal obstruction, rectal dysfunction, and death when PDT was performed on tumors inside the rectal tract. Our results indicate that a moderate PDT dose is more appropriate to treat tumors located in tract or cavity tissues.

The effect of bumetanide on photodynamic therapy-induced peri-tumor edema of C6 glioma xenografts.

OBJECTIVE: The aim of this study was to investigate the effect of bumetanide on peri-tumor edema caused by photodynamic therapy (PDT) of intraparenchymal C6 glioma xenografts. METHODS: Seven days after inoculation with C6 cells, rats with MRI-confirmed glioma received hematoporphyrin monomethyl ether (HMME)-mediated PDT, injection of bumetanide or a combination of the two treatments. After treatment, tumor volume, tumor weight, brain water content, microvessel density, expression of NKCC-1, Zonula occludens-1 (ZO-1), and animal survival time were examined. RESULTS: In the PDT group, tumor growth was significantly inhibited and survival prolonged. Bumetanide enhanced the efficacy of PDT and reduced PDT-induced peri-tumor edema in the combined PDT + bumetanide treatment group where NKCC-1 expression in response to PDT was significantly suppressed. ZO-1 expression was significantly suppressed in the PDT-only group. This suppression was not observed in the combined PDT + bumetanide treatment group. CONCLUSION: PDT, in combination with bumetanide was seen to significantly inhibit the growth of C6 glioma, relieve peri-tumor edema caused by PDT alone and prolong survival. These results suggest that PDT, in combination with bumetanide, may be a useful and promising strategy in the treatment of human glioma.

Adverse effects associated with photodynamic therapy (PDT) of port-wine stain (PWS) birthmarks.

BACKGROUND: Several Chinese studies suggest that Hemoporfin-mediated photodynamic therapy (PDT) is an alternative treatment for port-wine stain (PWS) birthmarks. OBJECTIVE: To evaluate treatment responses and adverse effects associated with Hemoporfin PDT for the treatment of PWS and their management. METHOD: The medical records of 700 patients who underwent PDT treatment in our center were retrospectively examined. Treatment-related reactions and adverse effects were reviewed. RESULT: Different types of PWS lesions and different individuals showed different immediate responses (e.g. swelling, color change, pain). To certain extents these reactions were a useful indicator of the treatment endpoint. Edema and scabbing were the most common post-treatment responses. Short-term (e.g. blister, eczematous dermatitis, cutaneous photosensitivity) and long-term (e.g. pigmentation change, scar formation) adverse effects were generally caused by the phototoxicity associated with the combination of photosensitizer and light exposure. CONCLUSION: Although PDT is a safe treatment alternative for PWS birthmarks, treatment parameters must be selected for each individual patient and cutaneous changes must be monitored during light irradiation to minimize the risk of adverse effects. Over estimation of required light dosage or failure to recognize cutaneous changes associated with adverse effects can increase the risk of a poor outcome.

Research progress of Hemoporfin--part one: preclinical study.

The second generation photosensitizer Hemoporfin (7(12)-(1-methoxyethyl) -12(7)-(1-hydroxyethyl)-3,8,13,17-tetramethyl-21H,23H-porphin-2,18-dipropionic acid) is a porphyrin derivative which processes a stable structure, high singlet oxygen yield, high photoactivity, low dark toxicity and fast clearance rate. Hemoporfin, also known as hematoporphyrin monomethyl ether (HMME) has been studied and used in photodynamic therapy (PDT) in China since 1989. This series of reports will provide an overview on the preclinical and clinical studies of this PDT photosensitizer. The first part of this series will highlight the results of preclinical studies that focused on the compound's optical characteristics, mechanism of the activities, pharmacological and toxicological properties.

Tolerance and pharmacokinetics of single-dose intravenous hemoporfin in healthy volunteers.

AIM: To investigate the safety, tolerability and pharmacokinetics of intravenous hemoporfin, a novel photosensitive drug for the treatment of port-wine stain (PWS), in healthy Chinese volunteers following single-dose administration. METHODS: Thirty-six healthy Chinese subjects were enrolled. The subjects were administered hemoporfin (2.5, 5, 7.5 or 10 mg/kg) via single-dose intravenous infusion. Pharmacokinetics of the drug were studied in the groups with doses of 2.5, 5 and 7.5 mg/kg, and tolerability was studied in all the 4 groups. Safety and tolerance were evaluated by monitoring adverse events and laboratory parameters, and pharmacokinetics were assessed by determining hemoporfin content with a validated high-performance liquid chromatography with fluorescence detection (HPLC/FLD) method. RESULTS: Mild and transient adverse events occurred in the trial (n=10), but none were serious, and no subjects were withdrawn from the trial. The gastrointestinal tract adverse events, such as nausea, stomach upset, abdominal pain and vomiting, were observed in the groups with doses of 7.5 and 10 mg/kg. Increased alanine aminotransferase (ALT) concentration was found in 3 subjects, and increased alkaline phosphatase (ALP) concentration in one subject. The half-life of hemoporfin for doses of 2.5, 5, and 7.5 mg/kg was 1.26 h, 1.31 h, and 1.70 h, respectively. C(max) and AUC increased with dose for intravenous single-dose administration of hemoporfin in the 2.5, 5, and 7.5 mg/kg groups. Urinary excretion of hemoporfin within 12 h was less than 0.2%. CONCLUSION: Hemoporfin is safe and well-tolerated in healthy Chinese volunteers at a single intravenous dose of up to 10 mg/kg. It was rapidly cleared from the blood and had a short half-life, which insures a short light-avoidance period.

Establishing an experimental model of photodynamically induced anterior ischemic optic neuropathy.

Numerous methods and drugs have been used to treat anterior ischemic optic neuropathy (AION); however, further investigations to determine the value of treatments for AION have been impeded by the lack of appropriate animal models of AION, significantly impacting on in-depth study of the disease. A rat model of AION was established, and corresponding functional changes of the fundus were observed using fundus fluorescein angiography (FFA), optical coherence tomography (OCT), and flash visual-evoked potential (F-VEP) in order to confirm the reliability of the AION model histopathologically. One day after model establishment, histopathology demonstrated that portions of the optic disc were highly edematous, with edema of nerve fibers and loose tissue, accompanied by displacement of the surrounding retina. At 23 days, the optic disc and surrounding nerve fiber layers had become thinner. None of the above-mentioned changes was observed in the laser, hematoporphyrin derivative (HPD), or naive groups. The results of fundus, FFA, F-VEP, and OCT-within 90 days after model establishment-confirmed that krypton red laser irradiation (647 nm), applied 2 h after HPD injection, can establish an ideal animal model of AION.

Tissue retention and adverse reaction after intravenous injection of hematoporphyrin derivatives in dogs.

We evaluated changes in hematology and chemical profile, and the tissue retention of hematoporphyrin derivative (HpD) following the intravenous injection in dogs. HpD at concentrations of 1, 5, 10, and 15 mg/kg was intravenously injected to 16 dogs (n=4 each) and complete blood count (CBC) and blood chemistry were performed on days 1, 3, 5, and 7 after the injection. To examine tissue retention, HpD (5 mg/kg) was administered to 15 dogs and 3 dogs were euthanized on days 1, 2, 7, 14, and 28 after the injection, respectively, to collect the skin, muscle, small intestine, spleen, kidney and liver as tissue samples. There were no significant changes in CBC and blood chemical profile except for an increase in LDH concentrations in dogs given 10 and 15 mg/kg of HpD at day 3. The levels of HpD retention in the tissues were ranked in the following order: liver > kidney > spleen > intestine > muscle > skin.

Does new photosensitizer improve photodynamic therapy in advanced esophageal carcinoma?

BACKGROUND AND OBJECTIVE: Polyhematoporphyrin (Photosan) as sensitizers for photodynamic therapy (PDT) in advanced esophageal cancer carry the risk of prolonged photosensitivity of the skin. New sensitizers such as 5-aminolaevulinic acid (ALA) with low rates of skin phototoxicity appear to be promising alternatives. The aim of this study was to evaluate the efficacy of ALA compared to Photosan for PDT in advanced esophageal carcinoma regarding phototoxicity of the skin, reduction of dysphagia, tumor stenosis, and tumor length and Karnovsky performance status. STUDY DESIGN/MATERIALS AND METHODS: After diagnostic work-up, photosensitization was done in 22 patients with ALA (60 mg/kg body weight, oral, 6-8 hours prior to PDT) and in 27 patients with Photosan (2 mg/kg body weight, i.v., 48 hours before PDT). The light dose was calculated as 300 J/cm fibre tip. Light at 630 nm was applied using a pumped dye laser. In both groups, additional hyperbaric oxygenation was applied at a level of 2 absolute atmospheric pressure. RESULTS: Improvement regarding dysphagia, stenosis diameter, and tumor length could be obtained in both treatment arms with a significant difference in favour of the Photosan-group, P = 0.02; P = 0.0000; and P = 0.000014, respectively. The Karnovsky performance status also improved in both groups and showed no significant difference (P = 0.12). The median survival time for the ALA-group was 8.0 months, compared with 9.0 months for the Photosan group. No sunburn or other major treatment related complication occurred in both treatment arms. Thirty-day mortality was 0%. CONCLUSION: Despite the limitations of a non-randomized study, photosensitzation with Photosan seems to be more effective in PDT of advanced esophageal carcinoma compared to ALA.

Functional and histological damage in the mouse bladder after photodynamic therapy.

Bladders of anaesthetised mice were illuminated with laser light of 630 nm at 24 h after intraperitoneal administration of the photosensitiser Photofrin II (10 mg kg-1). A range of light doses, at a power setting of 100 mW, was delivered intravesically by a fibre optic inserted into the centre of the bladder via the urethra. Functional bladder damage was assessed from increases in urination frequency and the presence of urethra. Functional bladder damage was assessed from increases in urination frequency and the presence of haematuria at 1 to 26 weeks after treatment. Whole bladder illumination with incident light doses exceeding 18.75 J cm-2 caused extensive oedema, haemorrhage and necrosis of the bladder wall and mice had to be sacrificed within 24 h. PDT with incident light doses of 3.75 to 15.0 J cm-2 caused haematuria and increased urination frequency during the first week in nearly all mice, but there was complete functional recovery by 6 to 10 weeks after doses of up to 7.5 J cm-2. Recovery was slower after higher doses and up to 50% of mice still had some increased urination frequency at 10 weeks after greater than or equal to 11.25 J cm-2, although haematuria was rare at this time. Histologically, early damage (one day after PDT) consisted of epithelial sloughing, submucosal oedema, fibrin imbibition, vascular ectasia and, rarely, thrombosis. Doses exceeding 7.5 J cm-2 were often associated with foci of necrosis. In some instances, necrosis was complicated by bacterial infection, resulting in an acute transmural inflammation with a tendency to suppuration. After doses of up to 11.25 J cm-2 there was a gradual recovery and only a mild degree of fibrosis of the bladder wall (with some increase in vascularity) remained at 6 months.

Intrathoracic organ injury associated with photodynamic therapy.

Photodynamic therapy has been proposed as a new modality for the local treatment of neoplasms limited to the pleural surface. Clinical use of photodynamic therapy will involve exposure of large surface areas of normal intrathoracic organs to tumoricidal doses of photodynamic therapy. This study details the pathologic changes that occur within the lung, heart, trachea, and diaphragm of Sprague-Dawley rats after administration of tumoricidal photodynamic therapy. Animals were injected with the photosensitizer Photofrin-II (Quadralogic Technologies, Vancouver, B.C., Canada), 10 mg/kg intraperitoneally, 24 hours before surface illumination of a portion of the target organ with gold vapor laser light (628 nm) (124 joules/cm2). Control animals were treated with light alone. After endotracheal intubation and mechanical ventilation, the lung and heart were exposed via left thoracotomy. The trachea was dissected in the neck, and the diaphragm was visualized via celiotomy. One site was treated per animal. Animals were killed at 24 hours, 48 hours, 72 hours, 1 week, 1 months, and 6 months after therapy. Histologic injury was numerically assessed by a single observer blinded to treatment and time of organ harvest. The Wilcoxon matched-pair signed-rank test was used to determine the statistical significance of differences between treated and control groups. Twenty-four hours after treatment the lung, heart, and trachea of rats subjected to photodynamic therapy demonstrated parenchymal injury (p less than 0.05). The diaphragm showed delayed injury 72 hours after therapy (p less than 0.05). Microscopic pulmonary changes included alveolar and endothelial disruption, intraalveolar hemorrhage, and fibrin deposition. Coagulation necrosis of myocardial fibers extending through the epicardium to involve up to 50% of myocardial thickness was observed. The diaphragm showed mesothelial hyperplasia with necrosis of superficial skeletal muscle. No similar gross or microscopic changes were present in the organs of control animals, or more than 48 hours after treatment in the trachea of animals that received photodynamic therapy. Photodynamic therapy induces a spectrum of tissue-specific injury, which may affect its usefulness in subsequent clinical trials.

[Photodynamic therapy in oncological digestive tract surgery]. / La thérapie photodynamique en chirurgie digestive oncologique.

Photodynamic therapy is a useful new antitumoral treatment, since it is relatively selective and noniatrogenic. The photosensitizers become preferentially localized in the tumoral tissue, where their excitation by light causes the production of free cytotoxic radicals. If haematoporphyrin derivatives are the most widely used photosensitizers, numerous molecules are being tested. Now used as a palliative photodynamic therapy could logically be used as adjuvant treatment in curative surgical excision. The practical utility of peroperative photodynamic therapy in gastroenterological surgery is being evaluated experimentally and clinically.

[Recent developments in anticancer photochemotherapy]. / Récents développements en photochimiothérapie anticancéreuse.

The photodynamic therapy of cancer (PDT) by porphyrins is now at a turning point with the advent of phase III clinical trials. The transport of photofrin II and its delivery to tumor cells and vasculature is believed to be a determinant of tumor necrosis by suppressing the oxygen supply. However, this treatment must be improved by increasing the selectivity of the photosensitizer uptake by tumors and also by using photosensitizers absorbing in the 700-800 nm range where tissues have the highest transmittance. In addition, these new photosensitizers (chlorines, phthalocyanines...) should be rapidly excreted to avoid the only secondary effect of the PDT: the long-lasting photosensitivity of the patient skin. Finally, the combination of PDT with other therapies or its chemopotentiation by "bioreductive" drugs which interfere with the metabolism of hypoxic cells resulting from the PDT are potential means for improving the effectiveness of this new modality for cancer treatment.

Photodynamic therapy for early gastric cancer using a pulsed gold vapor laser.

Endoscopic photodynamic therapy (PDT) using a pulsed gold vapor laser (wavelength 628 nm, LaserSonics Inc.) was performed on eight cases of early gastric cancer. Three patients refused to have surgery, and the others were in a high-risk group due to old age or complications with other diseases. Hematoporphyrin derivative (HpD I, 2.5-3 mg/kg, Photofrin Inc.) was injected intravenously, and 48-72 hours later, the entire cancer lesion and 5 mm width mucosa encircling it were irradiated with a gold vapor laser through a single quartz fiber. The irradiation was delivered at 300-330 mW for 5-20 minutes, which gave about 90 J/cm 2 dosage. In seven of eight cases, local cure was achieved. Recurrence was noted only in one patient. In one of eight patients, operation was carried out 1 month after PDT. Pathological examination of the resected stomach revealed that the effect of PDT extended into the tunica muscularis propria. Side effects of HpD, such as skin rash, were noted in two patients, but no serious complications of PDT were encountered. This suggests that PDT with a pulsed gold vapor laser is clinically useful in the treatment of early gastric cancer.

Photodynamic therapy in the treatment of malignant tumours: an analysis of 540 cases.

Malignant tumours (540 cases), including tumours of the lung, oesophagus, cardia, stomach, rectum, bladder, other urinary genital organs, face and mouth, eyes, ear, nose and throat (ENT), head and neck, breast and skin, were treated using photodynamic therapy (PDT) between 1982 and 1985 in Beijing. All of the cases were identified pathologically and the patients received haematoporphyrin derivative (HPD) (5 mg kg-1) intravenously 48-72 h prior to PDT. An argon-pumped dye laser emitting at 630 nm was used for the treatment. The results were as follows: complete response (CR) was obtained in 227 cases (42.1%), partial response (PR) was obtained in 114 cases (21.1%), mild response (MR) was obtained in 120 cases (22.2%) and 79 cases (14.6%) showed no response (NR). The effectiveness of PDT in the different organs was compared. HPD fluorescence was examined in 409 cases of malignant tumours: 344 lesions (84.1%) revealed red fluorescence (positive reaction), 32 gave an equivocal response and 33 gave a negative reaction. Positive fluorescence was seen in all types of malignant tumour in our study. Indications and limitations of PDT for the different organs are discussed and compared.

Dihematoporphyrin ether-induced photosensitivity in laryngeal papilloma patients.

Twenty-six patients with recurrent laryngeal papillomatosis received 2.5 mg/kg of Dihematoporphyrin Ether (DHE) intravenously prior to photodynamic therapy. All patients experienced some degree of photosensitivity, the only known side effect of DHE. Reported reactions included mild erythema and inflammation (88%), swelling (58%), blistering (23%), ocular discomfort (61.5%), pruritus (38%), and skin hyperpigmentation (46%). Length of sensitivity ranged from 4-17 weeks, with an average duration of 9 weeks. No long-term debilitating sequelae were noted. Degree of skin reaction mainly depended on how compliant the patient was in following precaution instructions. Although restrictive precautions were often difficult to strictly adhere to, most patients felt the potential benefits of the therapy far outweighed any inconvenience.

Cutaneous phototoxic occurrences in patients receiving Photofrin.

Incidence of cutaneous phototoxic reactions induced by intravenous injection of Photofrin polyporphyrin was assessed in a series of 180 patients (266 injections) undergoing photodynamic therapy (PDT) at Roswell Park Cancer Institute during the period 1986-1989. In addition to the usual verbal questions regarding phototoxic reactions solicited at follow-up, forty-two patients in this group also responded to a written questionnaire designed to solicit answers to specific questions. Photofrin doses ranged from 0.5 to 2.0 mg/kg. Overall, 20-40% of patients reported some type of phototoxic response.