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Photodynamic therapy of non-melanoma malignant tumours of the skin using topical delta-amino levulinic acid sensitization and laser irradiation.

Eighty basal cell carcinomas (BCCs) in 21 patients, 10 lesions of Bowen's disease in three patients, and four lesions of cutaneous T-cell lymphoma in two patients, were treated with photodynamic laser therapy (PDT), using topical application of the haem precursor delta-amino levulinic acid (ALA). The diagnoses were confirmed histologically prior to treatment. Fifty-five of the BCCs were superficial lesions, and 25 were nodular. Of the 80 BCCs, 39 (49%) were located on the trunk, 36 (45%) on the head and neck region, four (15%) on the leg and one on the arm. The two principal locations of the 10 Bowen's disease lesions were the leg (50%) and the trunk (40%). The T-cell lymphoma lesions were located on the shoulder and on the arm. A water-in-oil based cream containing 20% ALA was applied to the lesions, with a margin of about 10-20 mm beyond the visible tumour border, 4-6 h before the laser procedure. During this period of time the highly fluorescent and photodynamically active substance protoporphyrin IX (Pp IX) is synthesized via the haem cycle. Laser-induced fluorescence (LIF) was used for real-time monitoring of the Pp IX distribution in the tumour and in the normal surrounding skin, before and after treatment in all patients. Before laser treatment the Pp IX distribution demonstrated by LIF showed a demarcation between tumour and normal skin of about 15:1 for BCC and Bowen's disease, and 5:1 for T-cell lymphomas.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗

Blood lead levels and erythrocyte delta-amino-levulinic acid dehydratase activity of selected population groups in Helsinki.

The levels of lead in the blood of the adult general population in Helsinki were determined during the period May 1972-June 1973. The possibility of occupational exposure to lead was scrupulously excluded.As control groups rural population groups were sampled in the commune of Pertunmaa and the communes of Haapajärvi and Pyhäjärvi. The concentrations of air-suspended particulate lead were studied during 1 year in Helsinki and Pertunmaa; the population groups were sampled from the geographical vicinity of the sampling sites. Care was taken to ensure the accuracy and precision of the analytical methods at experienced laboratories. The annual mean concentration of lead in air in Helsinki ranged from 0.43 to 1.32 mug/m3. The corresponding mean at the rural sampling site (Pertunmaa) was 0.025 mug/m3. From an international standpoint, the Pb-B levels were low. The highest mean Pb-B value in groups of the general population occurred in the rural male group (12.3 mug/100 ml); and the lowest, in the female respondents of the Pertunmaa survey (7.9 mug/100 ml). A group comprising 86 male streetsweepers from Helsinki displayed a Pb-B mean value of 13.3 mug/100 ml, and 28 traffic-directing policemen displayed a mean of 13.5 mug/100 ml, a finding indicating a slight increase in lead absorption. No effect on the Pb-B levels of traffic alone was detectalbe within the general population; thus no statistically significant differences were found between downtown and rural or suburban Pb-B levels. The observation that the Pohjois-Haaga suburbanites disclosed higher Pb-B levels. The observation that the Pohjois-Haaga suburbanites disclosed higher Pb-B levels than did other suburbanites indicates that factors other than traffic should be borne in mind in the assessment of the effect of traffic on lead absorption. The delta-amino-levulinic acid dehydratase (ALAD) assay proved useful and reliable in the discrimination between separate groups whose Pb-B levels differed to a small but measurable extent. The negative correlation between Pb-B and ALAD activity was found to prevail at a statistically significant level still at Pb-B levels of 10 mug/100 ml or lower.

Adolescent↗

Photodynamic therapy of normal and balloon-injured rat carotid arteries using 5-amino-levulinic acid.

BACKGROUND: Although the management of atherosclerotic disease by the use of balloon angioplasty is widespread, the treatment is limited by restenosis in 30% to 50% of cases. Fibrocellular intimal hyperplasia, the main cause of restenosis, arises from proliferation and migration of medial smooth muscle cells (SMC) into the intimal layer. Factors leading to intimal hyperplasia are incompletely understood, and drugs have universally failed to influence clinical restenosis. Photodynamic therapy (PDT), the light activation of photosensitizing drugs to generate cytotoxic mediators, may have potential as prophylaxis for intimal hyperplasia. 5-Amino-levulinic acid-induced protoporphyrin IX (ALA-PPIX), a naturally occurring porphyrin precursor, and its product, -PPIX, offers a novel method of sensitization for PDT. We have investigated the pharmacokinetics of ALA in arteries and the effects of ALA-PPIX-sensitized PDT on normal and balloon-injured arteries. METHODS AND RESULTS: ALA (20 to 200 mg/kg) was injected into healthy rats, and PPIX fluorescence was measured in the carotid arteries. In a second group of rats, the exposed carotid artery was laser illuminated (50 J/cm2, 630 nm) 30 to 90 minutes after sensitization. Three and 14 days after PDT, histological sections from treated arteries were analyzed by light microscopy. Subsequently, two new groups of rats underwent PDT (ALA, 100 mg/kg; laser, 50 J/cm2, 630 nm [at 60 to 90 minutes]). The left carotid arteries underwent balloon angioplasty by intraluminal passage of a Fogarty FG2 catheter immediately before irradiation. These rats were killed at 14 and 28 days together with laser-only, ALA-only, and untreated control rats. The arteries were perfusion-fixed in vivo. ALA-PPIX induced arterial media fluorescence in a dose-dependent manner. In the normal arteries, PDT produced a dose-dependent cellular depletion in the treated arterial segment at 3 days, and this was complete with 100 and 200 mg/kg of ALA. At 14 days, the media remained acellular, although the endothelial lining had regenerated. In the balloon-injured arteries, PDT produced complete inhibition of intimal hyperplasia at both 14 and 28 days (0%). This was significantly greater than that produced by any of the control rats (34% to 69% and 37% to 66% at the two times, respectively). Significance was at 99% using ANOVA and Fisher's PLSD test. No hemorrhage, thrombosis, or aneurysm formation was seen. CONCLUSIONS: ALA-PPIX-sensitized PDT applied at the time of angioplasty effectively inhibits experimental intimal hyperplasia development in rats. This may offer a new approach to the management of angioplasty restenosis in patients.

Aminolevulinic Acid↗

Singlet oxygen luminescence as an in vivo photodynamic therapy dose metric: validation in normal mouse skin with topical amino-levulinic acid.

Although singlet oxygen ((1)O(2)) has long been proposed as the primary reactive oxygen species in photodynamic therapy (PDT), it has only recently been possible to detect it in biological systems by its luminescence at 1270 nm. Having previously demonstrated this in vitro and in vivo, we showed that cell survival was strongly correlated to the (1)O(2) luminescence in cell suspensions over a wide range of treatment parameters. Here, we extend this to test the hypothesis that the photobiological response in vivo is also correlated with (1)O(2) generation, independent of individual treatment parameters. The normal skin of SKH1-HR hairless mice was sensitised with 20% amino-levulinic acid-induced protoporophyrin IX and exposed to 5, 11, 22 or 50 J cm(-2) of pulsed 523 nm light at 50 mW cm(-2), or to 50 J cm(-2) at 15 or 150 mW cm(-2). (1)O(2) luminescence was measured during treatment and the photodynamic response of the skin was scored daily for 2 weeks after treatment. As observed by other authors, a strong irradiance dependence of the PDT effect was observed. However, in all cases the responses increased with the (1)O(2) luminescence, independent of the irradiance, demonstrating for the first time in vivo an unequivocal mechanistic link between (1)O(2) generation and photobiological response.

Aminolevulinic Acid↗

Comparative effect of oxygen and nitrate on protoporphyrin and heme synthesis from delta-amino levulinic acid in bacterial cultures.

Pseudomonas aeruginosa and P. denitrificans accumulate more protoheme and considerably more protoporphyrin during anaerobic growth under denitrifying conditions than during aerobic growth. In Escherichia coli, the small accumulation of protoporphyrin and protoheme which occurs during anaerobic growth is slightly stimulated by nitrate and markedly stimulated by oxygen.

Aerobiosis↗

GC/ITMS measurement of carbonyls and multifunctional carbonyls in PM2.5 particles emitted from motor vehicles.

A method was developed and tested to identify and quantitate carbonyls and multifunctional carbonyls in fine particulate matter (PM2.5; <2.5 microm aerodynamic diameter). The method relies on ultrasonic extraction of particulate matter on filters at -8 degrees C; derivatization with O-(2,3,4,5,6-pentafluorobenzyl) hydroxylamine (PFBHA), and PFBHA along with bis (trimethylsilyl) trifluoroacetamide (BSTFA); and detection of the derivatives by gas chromatography/ion trap mass spectrometry. Ultrasonic extraction of model compounds from enriched particles was affected by solvent polarity (water > methylene chloride > toluene-isopropanol (2 + 1, v/v). Water provided the highest recovery for dihydroxy acetone, pyruvic acid, and hydroxy acetone, compared to methylene chloride, and toluene-isopropanol. Lowering the ultrasonication bath temperature from 0 degrees to -8 degrees C improved the recoveries of the less water soluble and more volatile species-methacrolein, methyl vinyl ketone, 2,3-butanedione, and tolualdehyde. The power of the method was demonstrated by identification and quantitation of carbonyls and multifunctional carbonyls in sample extracts of fine particulate matter (PM2.5) collected in the Caldecott tunnel, CA. The identities of crotonaldehyde, 2,3-butanedione, glyoxal, 9H-fluoren-9-one, glycolaldehyde, glyoxylic acid, levulinic acid, and 3-hydroxybenzaldehyde were confirmed by comparing the relative retention time and mass spectra of the analyte in the sample extract with an authentic standard. Quantitation of crotonaldehyde, glyoxal, 2,3-butanedione, glyoxylic acid, and levulinic acid was accomplished. This is the first report of glyoxylic acid, levulinic acid, and 3-hydroxybenzaldheyde in PM2.5 particles sampled in a roadway tunnel. It is also the first report of a C10 carbonyl with the molecular formula of C10H16O2, a hydroxy carbonyl with the molecular formula of C17H21NO2, and a hydroxy or dihydroxy carbonyl with the molecular formula of C16H14O2 or C9H10O3. The high-molecular weight hydroxy carbonyls, which were found only in the heavy-duty (diesel) bore, may be tracers of diesel emissions in air.

Air Pollutants↗

[The relationship between zinc levels in blood and the activity of delta-amino-levulinic acid dehydratase in human erythrocytes (author's transl)].

The blood levels of zinc, lead, copper and albumin and the activity of erythrocyte delta-aminolevulinic acid dehydratase (ALA D), with and without addition of zinc in vitro, were measured in healthy subjects and in patients with cirrhosis. In cirrhosis there was a decrease, of zinc (-40%) albumin (-38%) and of activity of ALA D (-48%) and an increase in blood lead (+80%). Correlation between these results has been studied. The increase of blood lead is probably the result of zinc decrease. Moreover, as the urinary excretion of zinc is enhanced by chelation therapy, the prescription of zinc in lead intoxication is to be recommended. The activity of ALA D in patients with cirrhosis is less enhanced by addition of zinc in vitro than is the activity in patients intoxicated with lead. Probably in cirrhosis there is especially a decrease in the synthesis of ALA D, and lead intoxication the enzyme is inhibited.

Copper↗