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.

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.

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.

Photodynamic therapy for the treatment of port-wine stains in phakomatosis pigmentovascularis.

BACKGROUND: Phakomatosis pigmentovascularis (PPV) is a rare congenital syndrome. Only a few studies have reported the treatment of PPV, including a case using photodynamic therapy (PDT) to treat PPV-associated port-wine stains (PWS). OBJECTIVE: To investigating the efficacy and adverse effects of hemoporfin-PDT in PPV-associated PWS. METHODS: The efficacy and adverse effects in patients with PPV who underwent two sessions of hemoporfin-PDT from January 2019 to December 2022 were retrospectively analyzed. RESULTS: Twenty patients were included (13 females, 7 males, age range: 2-31 years; mean: 8.20 ± 8.92 years). Two, nine, seven, and two patients had PPV types Ia, IIa, IIb, and IIIa, respectively. After two treatments, the visual evaluation indicated the color of the PWS in 4, 5, 6, and 5 patients showed poor, fair, good, and excellent improvements, respectively. The combined good and excellent improvement rates in patients with PWS and pigmentary nevus overlapping in the same treatment area and in patients with PWS in the treatment areas only were 33.3% versus 87.5%, respectively, and were significantly different (p = 0.02). Minor side effects, such as edema, scabbing, hyperpigmentation, and blistering, were observed in some patients after PDT. CONCLUSION: Hemoporfin-PDT is an effective treatment for PPV-associated PWS. Patients with PWS and pigmentary nevus overlapping in the same treatment area showed poorer efficacy than patients with PWS in the treatment areas only.

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.

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.

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.

Photoradiation in the treatment of recurrent breast carcinoma.

Photoradiation, with the use of hematoporphyrin derivative (Hpd) activated by visible light in the red region of the spectrum, was an effective treatment for controlling local and regional chest wall recurrences of breast carcinoma. With sufficient time between iv injection of the drug and local activation with red light, cutaneous and subcutaneous masses were treated effectively without undue damage to overlying and adjacent skin. This high therapeutic ratio resulted from the ability to Hpd to accumulate and/or to be retained to a higher degree in malignant tissue than in many normal tissues. This technique can be used as a primary treatment or upon tumor recurrence following conventional modalities such as surgery, chemotherapy, and radiation therapy.

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.

Cutaneous porphyrin photosensitization: murine ear swelling as a marker of the acute response.

Acute cutaneous photosensitivity is a major manifestation of certain forms of human porphyria and also occurs in patients treated with hematoporphyrin derivative (HpD) photoradiation for the diagnosis and treatment of malignant tumors. In this study a quantitative animal model useful for in vivo studies of acute porphyrin photosensitization in cutaneous tissue was developed. C3H mice injected with HpD and irradiated 6 h later with 405 nm energy developed a 40-90% increase in ear thickness which was present immediately after irradiation and persisted for at least 24 h. No ear swelling occurred in animals receiving 405 nm radiation alone or HpD alone. Histologically, this photosensitivity reaction was manifest as edema, vascular dilatation, and mast cell degranulation immediately after irradiation followed by an influx of polymorphonuclear leukocytes and epidermal necrosis 24 h later. Tissue injury evoked by HpD and light was accompanied by extravasation of intravenously administered 125I-labeled albumin in the irradiated ears, indicating that photosensitization was accompanied by transudation of serum into the site of tissue injury. An in vivo correlation of this approach was verified by detection of measurable increase in ear thickness in irradiated mice rendered porphyric by the ingestion of a griseofulvin-containing diet. The mouse ear swelling model offers a useful system with which to study acute porphyrin photosensitization in the skin, and may lead to important new insights into the pathogenesis and prevention of this form of phototoxicity.

Delayed phase of hematoporphyrin-induced phototoxicity: modulation by complement, leukocytes, and antihistamines.

We have investigated the role of complement, leukocytes, and histamine in the delayed phase of hematoporphyrin-induced phototoxicity in guinea pigs. The phototoxic response was quantified by the accumulation of intravenously injected [125I]bovine serum albumin in the skin. There was a greater than 6-fold increase in the vascular response at the completion of irradiation, which subsided partially to reach a plateau of twice the preirradiation level between 0.5 h and 12 h. At 18 h, the vascular responsiveness returned to the baseline value. The 7 h timepoint was selected in this study to evaluate the modulation of the delayed phase. In complement-depleted guinea pigs, as well as in leukopenic animals, the enhancement in the vascular response was significantly suppressed (p vs control, less than 0.0001 and 0.0022, respectively). Cimetidine, when administered prior to irradiation, significantly suppressed the phototoxic response (p vs control, 0.0365). The combination of diphenhydramine and cimetidine, administered 6 h after the induction of phototoxicity, also suppressed the vascular response (p vs control, less than 0.0001). These data indicate that the expression of the delayed phase of hematoporphyrin-induced phototoxicity, similar to the early phase, requires the presence of an intact complement system, leukocytes, and histamine.

Participation of mast cells and complement in the immediate phase of hematoporphyrin-induced phototoxicity.

We have investigated the roles of mast cells and the complement system in the immediate phase of hematoporphyrin-induced phototoxicity in guinea pigs. Clinically, i.v. injection of hematoporphyrin, followed by irradiation with a light source containing 400-405 nm wavelength, resulted in the immediate onset of erythema and edema, which subsided partially in 30-60 min. This was followed by the appearance of delayed erythema and edema, which peaked at 6-12 h after irradiation. Histologic examination of the response of the immediate phase, using a 1 micron-thick section, revealed eosinophil infiltration and mast cell degranulation. The immediate phase of the clinical response was further quantitated by the extravasation of intravenously injected [125I]bovine serum albumin. Pretreatment of the guinea pig skin with the intradermal injection of compound 48/80 significantly suppressed the increase in vascular permeability induced by hematoporphyrin and irradiation (p less than 0.05). This hematoporphyrin-induced alteration in vascular permeability was also significantly inhibited by antihistamines, either H1 receptor antagonist alone (p less than 0.05) or a combination of H1 and H2 receptor antagonists (p less than 0.05). Guinea pigs depleted of complement also showed significantly less vascular permeability changes (p less than 0.05). These results indicate that functionally intact mast cells, and the complement system, are required for the full development of the immediate phase of phototoxicity induced by hematoporphyrin.

[Problems posed by the therapeutic use of photosensitizers in dermatology]. / Problèmes posés par l'utilisation thérapeutique des photosensibilisateurs en dermatologie.

Three phototherapeutic regimens with photosensitization are now used in dermatology: PUVA (psoralen + UVA), TUV (crude coaltar + UV), PRT (phototherapy with hematoporphyrin derivative). The efficiency of PUVA and TUV is well known in several dermatoses. PRT is now being tested experimentally. For TUV, the lack of a standardized regimen does not allow a clear-cut evaluation of the therapy. For PUVA, late side-effects, particularly carcinogenicity have to be considered. To improve efficiency and minimize the side-effects of PUVA some procedures, such as association with retinoïds, pharmaco-kinetic studies for individual adaptation of the therapeutic regimen and the use of new less mutagenic psoralens are helpful. The persistent phototoxicity following treatments with hematoporphyrin derivative constitutes the major side-effect observed, for this phototherapy.

Effect of hematoporphyrin derivative on rabbit corneal endothelial cell function and ultrastructure.

Hematoporphyrin derivative (HpD) is a systemically administered photosensitizing agent that may be of value in the treatment of solid tumors. When corneal endothelial cells were perfused in the specular microscope with HpD and exposed to a 25-W incandescent light at 5 cm (5.5 mW/cm2) there was anatomic disruption of corneal endothelial cells and swelling of the corneal stroma. Perfusion with 0.2 microliter/ml (1.0 microgram/ml) HpD and 5 min exposure to light resulted in a corneal swelling of 71 +/- 4 microns after 3 hr, whereas perfusion with 0.2 microliter/ml HpD and a 1-min exposure to light resulted in a corneal swelling of 36 +/- 4 microns after 3 hr. Perfusion with 0.2 microliter/ml HpD with no light exposure resulted in a corneal swelling of 22 +/- 4 microns after 3 hr. Inclusion of 100 micrograms/ml catalase in the perfusion solution resulted in a significant 38% reduction of the corneal swelling. The inclusion of either 100 micrograms/ml superoxide dismutase, 15 mM D-mannitol, 5 mM ascorbic acid, 1/4% DMSO, 50 microns EDTA, 50 microns DETAPAC, 10 mM L-histidine, or 1 mM sodium azide did not modify the corneal swelling induced by the photosensitization reaction. Perfusion of corneal endothelial cells with 2 microliters/ml (10 micrograms/ml) HpD and exposure to 25-W incandescent light for 5 min resulted in swelling of mitochondria, the appearance of vacuoles in the cytoplasm, and rapid corneal swelling. The data suggests that corneal endothelial cells can be damaged by hydrogen peroxide generated by the dismutation of superoxide anion produced during the photoreaction. Superoxide anion itself and hydroxyl-free radical do not appear to participate in causing the endothelial cell damage. The role of singlet oxygen remains somewhat unclear. The data suggests that further in vivo studies should be performed to delineate precautions that should be taken to protect the corneal endothelium during photoradiation therapy.

Hematoporphyrin derivative photochemotherapy of spontaneous animal tumors: clinical results with optimized drug dose.

Hematoporphyrin derivative (HpD) photochemotherapy was performed on 13 primary spontaneous tumors in dog and cat. The animals received an optimized drug dose of 5 mg/kg body wt i.v. 48 h before the first treatment with laser light at 631 nm. An evaluation of the clinical results is presented and discussed. Complete disappearance of the primary tumors was obtained in all cases with one or more light irradiations. Five cases presented recurrences that were cured with a further treatment. In 4 cases treated after surgical exeresis of the primary tumors, this therapy resulted in complete cure.

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.

Hematoporphyrin photoradiation therapy for intraocular and orbital malignant melanoma.

Photoradiation therapy (PRT) is a new technique that is currently under investigation for the treatment of a variety of solid malignant tumors. The technique involves systemic administration of hematoporphyrin derivative (HpD), a photosensitizing compound that is preferentially retained by malignant cells and photoactivation of the neoplasm with red light (630 nm) to achieve selective destruction of cancer cells. We used HpD PRT for seven patients with malignant melanoma of the uvea and conclude that initial results of HpD PRT for uveal malignant melanoma are encouraging and justify further investigation.

Neovascular glaucoma after photoradiation therapy for uveal melanoma.

We describe two patients (two eyes) with neovascular glaucoma following photoradiation therapy (PRT) for ciliary body and iris melanoma. Histopathologic examination in one eye eight months after treatment disclosed widespread tumor necrosis. The second patient with iris melanoma showed total clinical disappearance of the lesion and regression of iris neovascularization six months later. The cause of the neovascular glaucoma is uncertain. The marked tumor necrosis induced by PRT might have resulted in release of a vasoproliferative factor that, in turn, led to the development of rubeosis and neovascular glaucoma.

Induction of drug photosensitization in man after parenteral exposure to hematoporphyrin.

Two patients had acute phototoxic reactions after intravenous injections of hematoporphyrin (7 mg/kg) and exposure to light. These reactions were characterized by pain, redness, and swelling of affected sites. Controlled clinical studies were instituted using known types and amounts of light to ascertain the degree of photosensitivity at various time intervals after drug administration. In addition, action spectrum studies elicited a peak response at 405 nm (+/- 5 nm). Plasma hematoporphyrin concentration was approximately 520 microgram/100 ml one hour after hematoporphyrin infusion and it gradually declined during a period of 42 days with a biphasic diminution that suggested the existence of at least two pools of hematoporphyrin with half-life decay times of 16 hours and 12 days. beta-carotene was administered to ascertain whether or not the phototoxic response could be modified. It is suggested that a degree of protection was obtained that was insufficient to protect the patient.

Development of a protocol for photoradiation therapy of malignant brain tumors: part 1. Photosensitization of normal brain tissue with hematoporphyrin derivative.

The successful application of phototherapy to subcutaneous tumors has suggested that a similar procedure should be developed for treating gliomas. As a result, attempts are being made to determine a set of conditions that would optimize the destruction of tumor cells while minimizing injury to surrounding brain tissue. To initiate this task, we developed a novel assay method to assess the amount of phototoxicity induced in normal brain by light exposure of mice treated with hematoporphyrin derivative (HPD). The application of this procedure demonstrated that a sufficient amount of HPD was retained in brain tissue, even 72 hours after injection, to cause severe cerebral damage in light-treated mice.