Experiences with local photodynamic therapy with TPPS4 and non-coherent light.
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Administration, Topical↗
Biomedical subjects
M Jirsa
Publications and source records attributed to M Jirsa.
The effect of the irradiation wavelength on the processes sensitized by protoporphyrin IX dimethyl ester.
The formation of triplet states of photosensitizers and singlet oxygen during reactions sensitized by protoporphyrin IX dimethyl ester (PPDME) and the products of its photo-oxidation in solution were studied by time-resolved spectroscopy. Irradiation with long-wavelength light (670 nm), which is absorbed by the products of photo-oxidation of PPDME, provides lower quantum yields of singlet oxygen than in sensitization with PPDME alone, which absorbs light with a wavelength of 630 nm. Spectroscopic measurements also confirmed the lower rate of sensitized photo-oxidation of bilirubin during irradiation with light with a wavelength of 670 nm.
Bilirubin↗
The localisation of TPPS4 in some organs and its possible nephrotoxicity in rats.
Photodynamic therapy (PDT) is now being used more frequently in carefully selected cases of malignancies. The drugs used for PDT are mostly derivatives of haematoporphyrine (HPD) and its active component photofrine II. Another compound prepared by total synthesis is meso-tetra-(4-sulfonatophenyl)-porphine (TPPS4) but its application in human medicine was rejected because of its neurotoxicity. Our TPPS4 was prepared by the method of Busby et al. in the modification of Jirsa and Kakac (1987). This product is purer and without neurotoxic effects. In this study, we concentrated our attention on the effect of TPPS4 on nephrotoxicity and its accumulation in some organs. As the parameters of toxic kidney damage we used urine levels of N-acetyl-beta-D-glucosaminidase (NAG), serum creatinine levels, glomerular filtration rate (GFR) and proteinuria. TPPS4 was administered i.v. in a dose of 25 mg/kg b.w. The animals were observed for 21 days after drug application. Urine and blood samples were collected over 24-hour periods on days 0, 5 and 21. The serum creatinine level was significantly higher only on day 5 (65.0+/-1.46 micromol/l vs 56.5+/-2.69 micromol/l on day 0, p<0.05). There were no significant changes in GFR, proteinuria or NAG activity in the urine during the experiment. AST serum activity was increased. We determined the concentration of TPPS4 (pmol/mg w.w.) in rat organs on the 21st day after the injection. The concentration of TPPS4 was high in kidneys (30.8+/-5.5), liver (13.5+/-2.0), lungs (11.7+/-4.6) and spleen (9.7+/-1.5), while the concentration in heart and brain was low. We conclude that TPPS4 has the highest concentration in the kidney 21 days after its administration and does not exert any nephrotoxic effects during this period.
Animals↗
[Long-term administration of cyclosporine A in patients with IgA nephropathy].
BACKGROUND: IgA nephropathy is the most common glomerulonephritis all over the world and a considerable proportion of the patients reaches end-stage renal failure. Yet the standard treatment for the patients with progressive course and/or great proteinuria is currently lacking. All suggested treatment protocols, including short-term treatment with cyclosporine A had equivocal results. Therefore we decided to try long-term cyclosporine treatment. METHODS AND RESULTS: We treated 6 patients (4 males, 2 females, age 21-31 years) with bioptically proven IgA nephropathy and proteinuria over 3.5 g/24 hrs with or without nephrotic syndrome non responding to corticosteroid therapy administered for at least 3 months. Patients with serum creatinine greater than 200 mumol/l and/or glomerulosclerosis in more than 50% of glomeruli in renal biopsy were excluded. Pts were given cyclosporine A in initial dose 5 mg/kg bw/day then titrated aiming to the serum concentration of 70-150 ng/ml. Prednisone 5-10 mg on alternate days was given with cyclosporine. Proteinuria decreased during first month of therapy from 4.66 +/- 0.43 g/day to 1.38 +/- 0.29 g/day (p < 0.01) and remained low after one year of treatment (0.59 +/- 0.14 g/day, p < 0.001). Glomerular filtration rate (creatinine clearance) did not change during first month of therapy (1.25 +/- 0.21 ml/s vs. 1.38 +/- 0.29 ml/s), but slightly decreased after one year of treatment (1.05 +/- 0.14 ml/s, p < 0.05). We also calculated ratio of proteinuria to glomerular filtration rate (g/l) to assess the role of hemodynamic changes in the decrease of proteinuria. This ratio was 53.80.10(-3) +/- 15.20.10(-3) before cyclosporin therapy, it decreased significantly after one month (11.56.10(-3) +/- 3.24.10(-3), p < 0.05) and achieved the lowest value after one year of therapy (6.78.10(-3) +/- 4.25 .10(-3) +/- 4.25.10(-3), p < 0.01). Serum cholesterol also significantly decreased after 12 months of therapy (6.21 +/- 0.62 vs. 5.41 +/- 0.45 mmol/l, p < 0.05). CONCLUSIONS: CyA significantly lowered moderate to high proteinuria with much less decrease of glomerular filtration rate in 6 patients with IgA. Significant decrease of proteinuria/GFR ratio strongly suggests some non-hemodynamic mechanisms of cyclosporine action in these patients. Therapy was well tolerated and side-effects were not so severe to require cyclosporine withdrawal.
Adult↗
[The first case of Crigler-Najjar syndrome in the Czech Republic].
BACKGROUND: Crigler-Najjar syndrome is a rare disease due to a congenital deficiency of bilirubin UDP glucuronosyl transferase in the liver tissue. It is characterised by high levels of unconjugated bilirubin in plasma through the whole life. The aim of the study was to confirm the clinical diagnosis of the first Crigler-Najjar syndrome case in our country. METHODS AND RESULTS: 34 years old Gypsy women was admitted to our GI clinic for clinical examination before scheduled cholecystectomy. The high plasmatic level of unconjugated bilirubin was found and therefore the diagnosis of Crigler-Najjar syndrome was anticipated. The diagnosis was based on the chromatographic analysis of biliary bile pigments. The amount of diconjugates was considerable decreased. In addition, the molecular analysis of DNA isolated from peripheral blood leukocyte was performed to confirm our conclusions. Our patients was found to be homozygous for a nucleotide shift in the unique exon of bilirubin UDP glucuronosyl transferase 1, substituting guanine into an adenine at position 211.
Adult↗
Photodynamic therapy of cutaneous metastases of breast cancer after local application of meso-tetra-(para-sulphophenyl)-porphin (TPPS4).
Nine patients with cutaneous metastases of breast cancer were treated using photodynamic therapy. Meso-tetra-(para-sulphophenyl)-porphin (TPPS4) was applied locally at a dose of 0.15-0.3 mg directly to the lesion. The light source was an argon dye laser emitting light of 630 nm at a fluence rate of 312-680 mW cm-2 and a fluence of 150 J cm-2. No signs of local or systemic side effects or toxicity of the photosensitizer were observed. Treatments were well tolerated with no photosensitivity of the skin. Complete destruction of the tumour was observed in three patients, reduction of the tumour size by more than 50% in two patients, reduction-of the tumour size by less than 50% in two patients and no regression in two patients. The advantages of this method include the high concentration of the photosensitizer in the tumour, the extremely low total dose and the lack of side effects. The disadvantages include the less homogeneous distribution of the photosensitizer in the tumour tissue compared with that obtained by intravenous application.
Aged↗
[Photodynamic therapy of malignant tumors].
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Animals↗
Hepatic biotransformation in rodents and physicochemical properties of 23(R)-hydroxychenodeoxycholic acid, a natural alpha-hydroxy bile acid.
The hepatic biotransformation in the rat and hamster of 23(R)-hydroxychenodeoxycholic acid (23(R)OH-CDCA), the alpha-hydroxy derivative of CDCA, was defined; some physiological and physicochemical properties were also assessed. 23(R)OH-CDCA was isolated from duck bile; [24-14C]23(R)OH-CDCA was synthesized. The compound was administered intravenously to anesthetized biliary fistula rats at doses of 1, 3, or 5 mu mol/kg-min and to hamsters at 3 mu mol/min-kg. Biliary bile acids and radioactivity were analyzed by thin-layer chromatography (TLC), high pressure liquid chromatography (HPLC), and gas chromatography-mass spectrometry (GC-MS). Recovery of radioactivity in bile was incomplete (50-70% of infused dose); some was also recovered as breath 14CO2. Radioactivity in bile was present as unchanged compound (25-50%, dose-dependent) and its conjugates (with taurine, with glycine, or with glucuronate). Nor-CDCA (C23) was present in bile (in both unconjugated and conjugated form), indicating that 23(R)OH-CDCA had undergone oxidative decarboxylation (alpha-oxidation) with loss of the C-24 carboxyl group. The alpha-oxidation was 20 +/- 5% (mean +/- SD) of administered dose in the rat and was not dose-dependent; in hamsters, alpha-oxidation was 35 +/- 8%. In rats, the S isomer of 23OH-CDCA also underwent alpha-oxidation (10 +/- 2%). Nor-CDCA also underwent 6beta-hydroxylation to form nor-alpha-muricholic acid, as well as reduction of its C-23 carboxyl group to form the C23 alcohol. The taurine conjugate of 23(R)OH-CDCA [23(R)OH-CDC-tau] was prepared synthetically and characterized by 1H-NMR. By surface tension measurements, it had a critical micellization concentration (CMC) of 3.5 mM (in 0.15 M Na+), as compared to 1.8 mM for CDC-taurine. Aqueous solubility of 23(R)OH-CDCA increased markedly above pH 5, compared to pH 7 for CDCA. When incubated with cholylglycine hydrolase, 23(R)OH-CDC-tau was deconjugated at a rate one-fourth that of CDC-tau. It is concluded that the presence of a 23(R)-hydroxyl group in a 3alpha, 7alpha-dihydroxy bile acid alters its metabolism in the rodent hepatocyte, as evidenced by inefficient conjugation with taurine or glycine, alpha-oxidation to nor (C23) bile acid, and reduction of the nor bile acid to the primary alcohol. The taurine conjugate of 23(R)OH-CDCA, a major biliary bile acid of marine mammals and wading birds, is a biological detergent with properties superior to those of the taurine conjugate of CDCA. Natural C23 nor-bile acids may be formed by alpha-oxidation of alpha-hydroxy C24 bile acids.
Animals↗
Vascular pattern in the chorioallantoic membrane (CAM) after laser/photosensitive compound treatment. II. Microscopic findings.
The formation of clusters of densely packed primitive erythrocytes in growing capillaries and primitive vascular stems of chicken chorioallantoic membrane (CAM) after laser/meso-tetra(sulfonatophenyl)porphine dodecahydrate tetra-sodium salt (TPPS4) was studied. The soluble TPPS4 penetrates easily through the CAM epithelium and stroma into vascular lumina and accumulates predominantly in red blood cells. Accumulation of TPPS4 in immature erythrocytes persisted in higher levels in comparison with the primitive endothelium after day 2 of incubation. Laser/TPPS4-treated primitive red blood cells became sticking on the inner surfaces of tiny CAM capillaries and numerous "erythrocytic plugs" were quickly formed in irradiated CAM areas. Small erythrocytic clusters were also found after prolonged laser irradiation especially in superficial capillary network in CAM. Slight red blood cell disintegration, followed by blood leakages through vascular ruptures, was found after day 2 of further reincubation.
Allantois↗
Bilirubin ditaurate--a sensitive compound for examination of photosensitizers.
Bilirubin ditaurate (taurobilirubin) proved to be very suitable for estimation of efficiency of different photosensitizers and for determination of the activity of singlet oxygen. The degree of its bleaching was measured at 450 nm, the excitation light was over 600 nm. Halogen lamps were used as light sources. The decoloration of bilirubin ditaurate was related to the intensity of the light source in the presence of the photosensitizer meso-tetra (4-sulfonatophenyl)-porphine (TPPS4). From photosensitizers conventionally used in photodynamic therapy (photosan 3, TPPS4, and Zn and Al chelates of phthalocyanine) chloroaluminium phthalocyanine was most effective. From synthetic dyes of nonporphyrin type thiazine dyes were most active. The presumption is expressed that the efficiency of noncoherent light is comparable to the laser radiation when photosensitizers with large absorption band 600-700 nm are used for photodynamic therapy.
Bilirubin↗
Meso-tetra-(4-sulfonatophenyl)-porphine of low neurotoxicity.
The acute toxicity of specially purified meso-tetra-(4-sulfonatophenyl)-porphine (TPPS4) was measured in mice DBA/2 and Wistar rats after i.v. administration of the dye dissolved in saline solution. LD50 of our preparation was 352.5 mg/kg for mice and 574.9 mg/kg for rats. Motor nerve conduction velocity was measured in rats and rabbits in ether anesthesia N. ischiadicus and n. tibialis were stimulated by surface electrodes and M response was registered. No signs of neurotoxicity were found, even after application of 150 mg/kg b.w. of our TPPS4. Histologic evaluation was performed by routine method and standard electron microscopic procedure. Only minimal and sporadic axonal changes were found. The clinical application of low toxic TPPS4 was reconsidered.
Animals↗
Vascular pattern in the chorioallantoic membrane (CAM) after laser/photosensitive compound treatment. I. Macroscopic findings.
Laser light and photosensitive compound meso-tetra(4- sulfonatophenyl)porphine dodecahydrate tetra-sodium salt (TPPS4) activated by laser light were used for examining a regressive vascular effect with focal morphological differentiation of chick chorioallantoic membrane (CAM). After laser/TPPS4 treatment, arrest of blood flow in the irradiated area of CAM was observed in all cases, followed by massive aggregation of erythrocytes obstructing the vessel lumina. Similar effects were observed under much prolonged laser radiation in the area vasculosa. No extravasates were found. Those findings support the concept that the biological effect of low power laser/TPPS4 treatment causes changes in the relationship between red cells, blood plasma and embryonal endothelium during angiogenetic processes in growing embryonal vessels.
Allantois↗
[Trimethoprim in the therapy of symptomatic liver porphyria].
Administration of antimalaria drugs to patients with symptomatic hepatic porphyria (porphyria cutanea tarda) at the First Medical Clinic made it possible due to previous experimental studies, to influence the porphyrim metabolism of yeasts. The effect of trimetoprim was investigated in clinical work in 12 hitherto not treated patients with the manifest form of symptomatic hepatic porphyria. The group comprised 9 men, mean age 56.4 years, and 3 women mean age 43.6 years. During the two-year clinical study dermatological symptoms of the disease became milder or receded. Concurrently there was a significant regression of porphyrinuria. In the whole group porphyrinuria declined to 11% of the original values. The porphyrin content of hepatic tissue declined considerably after two years treatment. In the group as a whole to 40% of the original values. Trimetoprim is another drug which influences porphyrin metabolism. The authors did not detect any undesirable side-effects of trimetoprim treatment. The effect of trimetoprim on clinical and biochemical parameters of the disease is less marked than the effect of chloroquine. This new treatment can be used in patients resistant to chloroquine or in combination with other anti-malaria drugs.
Adult↗
[Interesting urinary findings in acute intermittent porphyria].
The authors describe an uncommon case of a patient with acute intermittent porphyria whose urine on standing, when exposed to light and air, turned dark and eventually black. The reason was increased excretion of porphobilin. The urine continued moreover increased amounts of Thormählen-positive substances, typical melanogens were not detected, however. The authors wish to draw attention to possible diagnostic errors which arise due to erroneous interpretation of laboratory results.
Adult↗
Hyperbaric oxygen and photodynamic therapy in tumour-bearing nude mice.
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Animals↗
Influence of hyperbaric oxygenation on bilirubin and ditaurobilirubin auto-oxidation and porphyrin-sensitized photo-oxidation.
Oxygen concentration controls the reaction rate of porphyrin-sensitized photo-oxidation under constant experimental conditions. The rate of bilirubin and ditaurobilirubin auto-oxidation and meso-tetra-(4-sulphonatophenyl) porphine-sensitized photo-oxidation in aqueous solution increases by about 3.5 times in 0.5 MPa of oxygen. Use of hyperbaric oxygenation in the photodynamic therapy of tumours and in the phototherapy of jaundice is proposed.
Bilirubin↗
[Photodynamic therapy of human tumor xenotransplants in athymic nu/nu mice].
The effect of phototherapy on the growth of two human tumors, i.e. carcinoma of the rectum I and III, was studied. The tumors were xenotransplated into athymic nu/nu mice. Meso-tetra-(para-sulfophenyl)-porphin, TPPS4, was used as photosensitizer. Incorporation studies showed the optimal dose for phototherapy to be 10 mg/kg TPPS4 and the time interval 72 hours. Under these experimental conditions (helium-neon laser, 632, 8, 300 J/cm2) one of six tumors was cured in the group with carcinoma of the rectum I, and that both after IV and IT administration of the photosensitizer. The other five experimental animals exhibited only partial responses to phototherapy. In the group with carcinoma of the rectum III, five out of six tumors were cured by IT administration of TPPS4 under the same experimental conditions. In one mouse there was only partial response to phototherapy. After IV administration of TPPS4, however, not a single tumor was cured and the response to phototherapy was only partial in all the six experimental animals.
Animals↗
[Experimental study of the action of antimalarial agents with respect to therapy in porphyria. Combined effect of chloroquine and pyrimethamine].
On an experimental model created from semiaerobically cultivated yeast cells of Caccharomyces cerevisiae (RIMB-75) the authors tested the effect of antimalarics used or tested for treatment of symptomatic liver porphyria. Chloroquine and pyrimethamine inhibited the synthesis of porphyrins, whereby pyrimethamine was more effective. Chloroquine released moreover intracellular porphyrins, contrary to pyrimethamine, which caused their intracellular cumulation. An equimolar combination of the two preparations preserved the inhibitory action of pyrimethamine, and the intracellular porphyrin content was reduced. Based on experimental results the suggested combination of chloroquine and pyrimethamine was successfully tested in clinical work.
Chloroquine↗