Production, quality control, biodistribution assessment and preliminary dose evaluation of [177Lu]-tetra phenyl porphyrin complex as a possible therapeutic agent / Produção, controle de qualidade, avaliação de biodistribuição e avaliação da dose preliminar de [177Lu] -tetra complexo fenil porfirina como um possível agente terapêutico

Due to interesting therapeutic properties of ¹⁷⁷Lu and tumor avidity of tetraphenyl porphyrins (TPPs), ¹⁷⁷Lu-tetraphenyl porphyrin was developed as a possible therapeutic compound. ¹⁷⁷Lu of 2.6-3 GBq/mg specific activity was obtained by irradiation of natural Lu₂O₃sample with thermal neutron flux of 4 × 10¹³ n.cm^-2.s^-1. Tetraphenyl porphyrin was synthetized and labeled with ¹⁷⁷Lu. Radiochemical purity of the complex was studied using Instant thin layer chromatography (ITLC) method. Stability of the complex was checked in final formulation and human serum for 48 h. The biodistribution of the labeled compound in vital organs of wild-type rats was studied up to 7 d. The absorbed dose of each human organ was calculated by medical internal radiation dose (MIRD) method. A detailed comparative pharmacokinetic study was performed for ¹⁷⁷Lu cation and [¹⁷⁷Lu]-TPP. The complex was prepared with a radiochemical purity: >97±1% and specific activity: 970-1000 MBq/mmol. Biodistribution data and dosimetric results showed that all tissues receive approximately an insignificant absorbed dose due to rapid excretion of the complex through the urinary tract. [¹⁷⁷Lu]-TPP can be an interesting tumor targeting agent due to low liver uptake and very low absorbed dose of approximately 0.036 to the total body of human...

Devido às propriedades interessantes do ¹⁷⁷Lu e da avidez tumoral das tetrafenil porfirinas (TPP), desenvolveu-se a ¹⁷⁷Lu-tetrafenil porfirina como composto terapêutico potencial. ¹⁷⁷Lu de atividade específica de 2,6-3 GBq/mg foi obtido por irradiação de amostra de Lu₂O₃ com fluxo térmico de nêutrons de 4 × 10¹³ n.cm^-2.s^-1. Sintetizou-se a tetrafenil porfirina e marcou-se com ¹⁷⁷Lu. A pureza radioquímica do complexo foi estudada usando método de Cromatografia Instantânea de Camada Delgada ( ITLC). A estabilidade do complexo foi checada na formulação final e no ser humano por 48 h. A biodistribuição do composto marcado em órgãos vitais de ratos do tipo selvagem foi estudada por mais de 7 dias. A dose absorvida para cada órgão humano foi calculada pelo método da Dose Médica de Radiação Interna (MIRD). Estudo farmacocinético comparativo detalhado foi efetuado para o cátion ¹⁷⁷Lu e para o [¹⁷⁷Lu]-TPP. O complexo foi preparado com pureza radioquímica >97±1% e atividade específica de 970-1000 MBq/mmol. Os dados de biodistribuição e os resultados dosimétricos mostraram que todos os tecidos receberam uma dose absorvida aproximadamente insignificante devido à rápida excreção do complexo pelo trato urinário. O [¹⁷⁷Lu]-TPP pode ser um agente interessante de direcionamento do tumor devido à baixa captação pelo fígado e pela dose bem baixa absorvida, de, aproximadamente, 0,036 do corpo humano total...

Structural and Functional Outcomes in Chronic Central Serous Chorioretinopathy Treated with Photodynamic Therapy

PURPOSE: To study the retinal pigment epithelium (RPE) and retinal alterations in chronic central serous chorioretinopathy treated with photodynamic therapy, and its correlation with functional parameters such as best-corrected visual acuity (BCVA) and contrast sensitivity (CS). METHODS: Retrospective, noncomparative, consecutive evaluation by optical coherence tomography and its correlation with BCVA and CS in 31 eyes of 26 patients. RESULTS: In all affected patients, 88.5% were male with a mean age of 42.9 years. The right eye was involved in 64.5% of cases, bilateral in 19% and 73.9% were hyperopic (spherical refraction between 0 and +5.0 diopters). Of these cases, 51.5% had peri-RPE abnormalities, 17.3% hyperreflective substances at RPE, 19.4% RPE atrophy, 55.3% foveolar atrophy, 3.1% pigment epithelial detachment, 5.2% subretinal fluid persistence, 8.3% fibrin deposits, 68.4% photoreceptor inner and outer segment line interruption and 31.1% external limiting membrane interruption. CONCLUSIONS: Time evolution and number of outbreaks were related to the decrease in foveal and chorodial thickness and in those with worse BCVA and CS. RPE abnormalities and atrophy were related to the age of onset of symptoms. Photoreceptor elongation has been correlated with poor BCVA and inner and outer segment line destructuring and interruption with poor CS.

Combined Treatment of Photodynamic Therapy and Bevacizumab for Choroidal Neovascularization Secondary to Age-Related Macular Degeneration

PURPOSE: To evaluate the outcome of a combined photodynamic therapy and intravitreal injection of bevacizumab in choroidal neovascularization secondary to age-related macular degeneration. METHODS: Photodynamic therapy (PDT) was administered to 28 eyes followed by 3 consecutive bevacizumab injections. Patients were followed-up for more than 12 months. At baseline, 1, 3, 6, and 12 months post PDT, visual acuity (VA) and central macular thickness were measured using optical coherence tomography. RESULTS: The mean VA was significantly improved from logarithm of the minimal angle of resolution 0.86 at baseline to 0.69 at 1 month (p = 0.011), 0.63 at 3 months (p = 0.003), 0.64 at 6 months (p = 0.004) and 0.60 at 12 months (p < 0.001). Central macular thickness decreased significantly from 328.3 microm at baseline to 230.0 microm at 6 months and 229.9 microm at 1 year (p < 0.001). Reinjection mean number was 0.4 for 6 months and 0.8 for 12 months. By 1 year, retreatment was performed in 10 eyes (36%). CONCLUSIONS: PDT combined with three consecutive intraviteal bevacizumab injections was effective in improving VA and reducing central macular thickness.

Validação de metodologia para dosagem de porfirinas urinárias por cromatografia líquida de alta eficiência / Validation of a high performance liquid chromatography method for quantification of urinary porphyrins

Porfirinas são produtos originados da biossíntese do heme. As enzimas envolvidas neste processo podem ter sua atividade inibida por fatores genéticos, adquiridos ou uma combinação de ambos, acarretando um aumento sérico do substrato correspondente que será eliminado pela urina. Considerando-se a importância do diagnóstico precoce nas alterações da biossíntese do heme, o objetivo deste trabalho foi desenvolver um método de cromatografia líquida de alta eficiência (CLAE) com detecção por fluorescência, sensível o suficiente para identificar cinco frações de porfirinas urinárias: uroporfirina (8-carboxil porfirina), heptaporfirina (7-carboxil porfirina), hexaporfirina (6-carboxil porfirina), pentaporfirina (5-carboxil porfirina) e coproporfirina I e III (4- carboxil porfirinas). Métodos de extração por detecção espectrofotométrica não são sensíveis para este propósito. O cromatógrafo utilizado, da marca Shimadzu, é composto de duas bombas, injetor automático e detector de fluorescência (RF-535) com excitação de 400 nm e emissão de 620 nm. Foi utilizada uma coluna de fase reversa com um programa de gradiente linear. O método desenvolvido apresentou linearidade de 8,0 a 120,0 µg/L para as frações de interesse, demonstrando ser adequado na identificação e quantificação das porfirinas com diferentes grupos carboxílicos, importantes para o diagnóstico precoce e acompanhamento de porfirias.

Porphyrins are products that originate from the heme biosyntetic pathway. Enzymes that take part in this route can have their activity inhibited due to inherited/acquired or both factors resulting in increased serum heme precursor that will be eliminated in urine. Considering the importance of early detection of heme biosynthesis alterations, the purpose of this study was to establish a high pressure liquid chromatographic (HPLC) method with fluorescence detection, to detect five fractions of porphyrins: uroporphyrin (8-carboxyporphyrin), heptaporphyrin (7-carboxyporphyrin), hexaporphyrin (6-carboxyporphyrin), pentaporphyrin (5-carboxyporphyrin) and coproporphyrin I and III (4- carboxyporphyrin). Extraction methods with spectrophotometric detection are not sensitive enough for this purpose. The HPLC (Shimadzu Co., Kioto, Japan) was composed of two high-pressure pumps, auto-sampler and fluorescence detector (RF-535) with excitation at 400 nm and emission at 620 nm. The sample was eluted from a reversed-phase column with a linear gradient. The linearity of the method was from 8.0 to 120 µg/L for all fractions, proving its ablility to identify and quantify porphyrins with differents carboxylic groups for early diagnosis and follow-up of porphyrias.

Photodynamic therapy for AMD and non-AMD patients: one-year results in Thais.

OBJECTIVE: To evaluate the effect of photodynamic therapy (PDT) with verteporfin for age-related macular degeneration (AMD) and non-AMD in Thais, and compare with the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) and Verteporfin in Photodynamic Therapy (VIP) study. MATERIAL AND METHOD: The authors prospectively evaluated all data of 51 eyes of 51 patients who had undergone PDT and accomplished a 1-year follow up. The assessments were divided into two categories: group 1 included three subsets of AMD, and group 2 was non-AMD. The first group classified into three subgroups: group 1A: AMD with subfoveal choroidal neovascularization (CNV) and TAP/VIP compatible with recommendation guidelines characteristics, group 1B: AMD with subfoveal CNV and TAP/VIP incompatible, and group 1C: AMD with non-subfoveal CNV. The measurement outcomes comprised of the baseline characteristics, change in visual acuity, and number of treatments. RESULTS: Thirty-eight eyes had CNV-related AMD and 13 eyes were non-AMD. At the 12-month examination, the mean visual acuity change in group 1A, 1B, 1C had increased 0.19 (p = 0.077), 0.14 (p = 0.076), and 0.24 (p = 0.003), respectively. The number of treatments was 1.8 in group 1A, 2.3 in group 1B, and 1.5 in group 1C. CONCLUSION: PDT is beneficial to Thai patients with AMD at first year even if they were not compatible with TAP/VIP criteria.

Toxoplasmosis retinochoroiditis after photodynamic therapy and intravitreal triamcinolone for a supposed choroidal neovascularization: a case report

The purpose is to report a complication after photodynamic therapy (PDT) and intravitreal triamcinolone for a presumed choroidal neovascularization in age-related macular degeneration. Photodynamic therapy and intravitreal triamcinolone were used in an 84-year-old man with choroidal neovascularization in the left eye. Forty-five days after therapy, the patient returned with a severe necrotizing uveitis in the posterior pole and vitritis. Laboratory investigation disclosed a high anti-Toxoplasma IgG titer. Therapy with pyrimethamine, sulfadiazine and folinic acid resulted in total lesion healing although central vision was lost. Intravitreal triamcinolone may have had an influence on the exacerbation of retinochoroiditis in the posterior pole of the patient. Although rare, this complication may not be disregarded in the cases that require intraocular corticosteroids for treatment of several conditions, especially in patients who had previously suffered from toxoplasmosis infection.

O objetivo é relatar complicação após terapia fotodinâmica (PDT) e triancinolona intravítrea para presumida neovascularização de coróide em degeneração macular relacionada à idade. A terapia fotodinâmica e triancinolona intravítrea foram utilizados em paciente de 84 anos, do sexo masculino, com neovascularização de coróide no olho esquerdo. Quarenta e cinco dias após o tratamento, o paciente retornou com grave retinite necrosante do pólo posterior e vitreíte. Investigação laboratorial indicou alto título de IgG anti-Toxoplasma. Tratamento com pirimetamina, sulfadiazina e ácido folínico levaram à total cicatrização da lesão embora a visão central tenha sido comprometida. Conclui-se que a triancinolona intravítrea pode ter influenciado na exacerbação da retinocoroidite no pólo posterior do paciente. Embora rara, esta complicação não pode ser descartada nos casos que necessitem corticóide intra-ocular para tratamento de várias doenças, principalmente em pacientes que tenham tido surtos prévios de toxoplasmose ocular.

Combination therapy of intravitreal triamcinolone and photodynamic therapy with verteporfin for subfoveal choroidal neovascularization.

AIM: To evaluate the six months follow-up outcome of combined intravitreal triamcinolone acetonide (IVTA) and photodynamic therapy (PDT) for subfoveal choroidal neovascularization compared to PDT alone. STUDY DESIGN: Prospective interventional pilot study. MATERIALS AND METHODS: Patients with six months follow-up of IVTA following PDT (Group I, eight eyes) and PDT alone (Group II, eight eyes) were included. Four mg/ 0.1 ml of IVTA was injected 7-10 days following PDT. The patients were reevaluated every month for the first two months and every three months thereafter in both the groups. RESULTS: Group I: The mean age was 65.8+/-11.8 years (range: 47-79 years). Five patients were male. The total treatment sessions in six months were 11 (mean: 1.36). At six months, one eye had >or= 10 letters gain and three eyes had > 10 letters loss. Four eyes had stable vision. Two eyes (25%) developed increased intraocular pressure (>40 mmHg) during follow-up. Group II: The mean age was 58.7+/-11.7 years (range: 46-76 years). Five patients were male. The total treatment sessions in six months were 17 (mean: 2.13). At six months, six eyes had >or= 10 letters gain and none had > 10 letters loss. Two eyes had stable vision. CONCLUSION: The mean number of treatment sessions following combination therapy of IVTA (4 mg) and PDT appears relatively less (1.36 at six months) compared to PDT alone (mean: 2.13). (P =0.02).

Treatment of subfoveal choroidal neovascularization secondary to age related macular degeneration with single treatment of verteporfin photodynamic therapy: a safety and short-term outcome.

OBJECTIVE: To evaluate the short-term efficacy on visual outcome and safety of a single treatment of photodynamic therapy with verteporfin using the standard dosage regimen in patients with predominantly classic subfoveal choroidal neovascularization (CNV) from age related macular degeneration. DESIGN: Prospective, noncomparative, consecutive, interventional case series. SETTING: Department of Ophthalmology, Chulalongkorn University and Hospital, Bangkok, Thailand. PARTICIPANTS: Patients with subfoveal CNV caused by age related macular degeneration. METHOD: Standardized protocol refraction, visual acuity testing, complete ophthalmic examination, color photography, and fluorescein angiography were used to evaluate the effects of a single treatment of photodynamic therapy with verteporfin. Follow-up was planned through 3 months in all patients. RESULTS: A total of 39 eyes from 35 patients enrolled into the present study and have completed 3 months follow-up. The mean +/- SD logMAR BCVA at baseline was 0.76 +/- 0.48, equivalent to the Snellen BCVA of 20/114 (range, 20/40 to 20/1000). The mean +/- SD logMAR BCVA at the final 3-month visit was 0.55 +/- 0.37, which was a Snellen equivalent of 20/70 (range, 20/30 to 20/1000). The mean line of BCVA improvement was 2.1 lines. The improvement in BCVA at the 3-month follow-up was statistically significant (Wilcoxon signed-rank test, P = .043). No patient suffered moderate loss of vision or a loss of vision in 2 or more lines. None of the patients suffered severe visual threatening adverse events at the time of treatment and during the study period. CONCLUSIONS: The results of short-term visual outcome is encouraging; PDT is the least invasive treatment method currently available to achieve a stable or improved vision in AMD patients. PDT with verteporfin can lead to cessation of fluorescein leakage from CNV for up to 3 months, with stabilization or improvement of vision for 12 weeks. A randomized, controlled study in the near future would be beneficial to demonstrate the long-term results and efficacy in the treatment of CNV associated with AMD.