Dye-sensitized destabilization of liposomes bearing photooxidizable lipid head groups.

Liposomes were prepared from mixtures of dipalmitoyl-L-alpha-phosphatidylcholine and up to 40% mol:mol of N-stearoyl-L-histidine (NSH) in the presence of the hydrophobic sensitizer DHE. In the dark such liposomes are stable and retain entrapped salts. On photolysis with visible light, liposomes leak trapped ions at NSH concentrations greater than 10% mol:mol. Up to 15% mol:mol NSH concentration leakage is seen only during the illumination period, whereas at higher concentration the liposomes continue to leak contents after illumination and fuse to form larger structures. Photolysis of the liposomes is accompanied by oxygen uptake in proportion to the NSH concentration within the bilayer. Photocontrol of liposome permeability through oxidation of membrane additives such as NSH offers a potential means for controlled drug delivery and might be useful as an adjunct to photodynamic therapy.

Influence of fluorocarbon emulsions on porphyrin-sensitised oxidation of histidine.

The influence of fluorocarbon emulsions on the efficiency of photosensitized oxidation of histidine in solution has been studied, using haematoporphyrin and dihaematoporphyrin derivatives as sensitisers. It is shown that the fluorocarbon emulsions at low concentrations efficiently disaggregate porphyrins, and thereby enhance photosensitised oxidation. The high solubility of oxygen in fluorocarbon emulsions maintains solution oxygen tension, optimising photooxidative damage. It is suggested that fluorocarbon emulsions might find a role in photodynamic therapy, both as carriers for sensitising dyes, and also to maintain tissue oxygenation in hypoxic regions of solid tumours.

Uptake of verteporfin by articular tissues following systemic and intra-articular administration.

Photodynamic therapy (PDT) using the photosensitizer BPD-Verteporfin (liposomal benzoporphyrin derivative-monoacid ring A) has been shown in previous studies to be effective in the amelioration of inflammatory arthritis in both the MRL-lpr mouse and the New Zealand White (NZW) rabbit models, and could potentially offer alleviation of certain inflammation-related symptoms of rheumatoid arthritis. Time and dose dependency of BPD-MA tissue uptake was carried out in the inflamed synovium and other articular and peri-articular tissues following intravenous and intra-articular administration in the NZW rabbit model. As some articular and peri-articular tissues are difficult to extract, this study uses a rapid fluorimetric sampling of tissues following dissolution in Soluene 350. Our results showed that i.v. injected BPD-MA preferentially distributed in the inflamed synovium, and in tissues with a high degree of vascularization. Little or no association was found with avascular tissues such as cartilage and tendons. Clearance from the synovium was rapid, supporting earlier rather than late light treatment. Much higher association of BPD-MA with the synovium was achieved using intra-articular injection, and BPD-MA concentrations were maintained at relatively steady levels for several hours. These observations support the possibility that PDT could offer a safe, highly versatile clinical option for the management of inflamed joints in autoimmune disorders.

Photodynamic therapy; a comparison with other immunomodulatory treatments of adjuvant-enhanced arthritis in MRL-lpr mice.

Although numerous experimental immunomodulatory regimens have been reported to be effective in the treatment of rheumatoid arthritis, they also produce undesirable side effects. An alternative specific modality of localized treatment is photodynamic therapy (PDT). In this study we treated 13-week-old MRL-lpr mice whose spontaneous arthritis was enhanced by intradermal injection of Freund's complete adjuvant (FCA). One group received transcutaneous photodynamic therapy at days 0, 10, and 20, following the FCA injection. The other groups were injected with 1 mg/kg per day indomethacin, 40 mg/kg per day cyclosporin A (CsA), or treated with 3 Gy sublethal whole body irradiation (WBI). The development of swelling was monitored for 1 month, at which time proteinuria, lymphadenopathy and the histopathology of the joints and kidneys were assessed. The results demonstrated that PDT and the conventional treatments significantly ameliorated swelling of the hindlimbs from 70% in the untreated FCA-injected animals to below the 19% level characteristic of the unmanipulated control. Histological examination showed a reduction in pannus formation, and cartilage and bone destruction, the characteristics of adjuvant-enhanced arthritis. PDT did not affect the survival rate, lymphoproliferation, or proteinuria of the treated animals. However, indomethacin increased proteinuria, and was less effective in preventing cartilage and bone destruction. Furthermore, lower doses of CsA and WBI exacerbated arthritis activity. These results indicate that photodynamic therapy can inhibit the development of adjuvant-enhanced arthritis in MRL-lpr mice with similar effectiveness to the conventional treatments, but without their negative side effects.

The use of transcutaneous photodynamic therapy in the prevention of adjuvant-enhanced arthritis in MRL/lpr mice.

The use of transcutaneous photodynamic therapy (PDT) has been investigated in the prevention of adjuvant enhanced arthritis in MRL/lpr mice. Mice receiving adjuvant were treated with PDT at 10-day intervals starting on the day of adjuvant administration. PDT was carried out by intravenous injection of the photosensitizer, benzoporphyrin derivative-monoacid ring A, followed by its transcutaneous activation with light. Adjuvant-injected animals displayed a delayed onset and reduced incidence and severity of arthritis when compared to untreated animals. Most importantly, inflammatory structural damage to cartilage and bone tissues was prevented by PDT. PDT was found to have no adverse effects on animals as assessed by mitogen responses, hematopoiesis, and serum enzyme levels. As mitogen-activated MRL/lpr splenocytes were shown to be more susceptible to in vitro photodynamic treatment, it is postulated that the observed effects were the result of selective destruction of adjuvant-activated lymphocytes in the circulation and/or joints.

Kala-azar epidemic in Varanasi district, India.

Reports at the Sir Sunder Lal Hospital, Banaras Hindu University, of a large number of kala-azar cases from one particular village in Varanasi district, Uttar Pradesh, led us to carry out an epidemiological study of the situation using standard techniques. The overall prevalence and case fatality of the disease were 12.9% and 10.5%, respectively. A history of fever and hepatosplenomegaly was noted for all the cases. The case definition was the presence of parasites in bone marrow or splenic aspirate smears. The disease was more prevalent among adults, but occurred also among children. However, there was no clear linear relationship between the prevalence of the disease and age group. Kala-azar occurred among males and females, and its prevalence did not correlate significantly with income. Since the disease vector continues to be present in the study area, the health authorities should take strong steps to control the disease.

PIP: The epidemiological characteristics of the kala-azar outbreak in Pandit Ka Purva, India, were investigated using standard techniques. A door-to-door survey of 518 persons in Pandit Ka Purva was carried out in November and December 1995, using a predesigned and pretested proforma. Independent variables such as age, sex, and literacy were considered in the survey. Results showed that the overall prevalence and case fatality of the disease were 12.9% and 10.5%, respectively, with a history of fever and hepatosplenomegaly noted for all cases. Culture and Giemsa staining confirmed indications of parasites in the bone marrow or splenic aspirate smears. The disease was more prevalent among adults, but it occurred also among children. However, there was no clear linear relationship between the prevalence of the disease and age group. Kala-azar was more prevalent among males, and its occurrence did not correlate significantly with income. In view of the outbreak of kala-azar in Pandit Ka Purva, it is essential for health authorities to take immediate measures to control the epidemic and prevent its spread to neighboring villages. This will necessitate the development of shorter treatment courses, the improvement of diagnostic methods, and close cooperation between universities, public health agencies, and the government.

Amelioration of antigen-induced arthritis in rabbits by induction of apoptosis of inflammatory cells with local application of transdermal photodynamic therapy.

OBJECTIVE: To study the efficacy and mechanism of local transdermal photodynamic therapy (tPDT) in rabbits with antigen-induced arthritis (AIA). METHODS: AIA in rabbits on day 14 postinduction was treated with an intravenous injection of benzoporphyrin-derivative monoacid ring A (BPD; Verteporfin) and subsequent transdermal exposure of the knee joint to light. BPD uptake and PDT-induced apoptosis of the synovium was studied applying fluorescence confocal microscopy and immunohistochemistry. The (histo)pathology of the joints was assessed at day 28. RESULTS: Treatment with tPDT resulted in significant amelioration of synovial inflammation and an almost complete prevention of pannus formation and bone and cartilage destruction. BPD uptake was detectable in activated T cells and macrophages, and there was significant PDT-induced increase in the number of apoptotic cells in the synovium. CONCLUSION: Because photodynamic therapy is both specific and noninvasive, our findings suggest that it could be used for treating arthritic joints in humans.