Photodynamic therapy: tumor volume limitation and tumor response for murine fibrosarcoma

The clonogenic survival rates and tumor growths following photodynamic therapy (PDT) were studied as a function of tumor volume for RIF-1 using C3H mice as an animal model. The clonogenic survival rates showed a saturation level approaching a 99.8% survival rate for large volumes (above 1,900 mm3), possibly indicating poor light utilization of 630 nm because of the limited tissue penetration and/or tumor hypoxia. With a small tumor volume [less than 150 mm3], the survival rate (less than 0.3%) showed an exponential increase with volume. The survival rates (less than 0.03%) corresponding to a volume lower than 50 mm3 gave complete tumor eradication. On the other hand, partial response and recurrence were noticed with volumes larger than 90 mm3, which had more than approximately 0.1% survival rates. After PDT, all tumors responded with immediate swelling and skin discoloration, followed by necrosis, tumor delay, and regrowth. Regrowth rate and tumor cell doubling time were slower than the control growths and decreased further following superficial irradiation with a second interstitial illumination. The regrowth rates were slow for small initial tumor volumes and fast for large initial tumor volumes. Also, the delay period was longer for the small initial tumor volumes in comparison to a shorter period for the medium tumor volumes and very low probability of delay for the large volumes.     

Development of an alternative light source to lasers for photodynamic therapy: 2. Comparative in vivo tumour response characteristics

The performance of a low cost, table-top/portable light source was tested against an argon ion pumped dye laser for in vivo photodynamic therapy (PDT). The prototype delivers up to 1 W via a 4 mm flexible lightguide within a 30 nm bandwidth centred at any wavelength from 300 nm to 1200 nm at fluence rates of up to 8 W cm^–2. An in situ bioassay using regrowth delay of tumour T50/80 was used to quantify the relative efficacy of the prototype with a laser. The tumours were sensitized with haematoporphyrin derivative (HpD) and externally irradiated. There was no significant difference in the response of the tumour to treatment between the two light sources (p = 0.69). Mean growth delays ranged from 2 days (light dose 10 J cm^–2) to 20 days (light dose 100 J cm^–2). The estimate for the difference in means (laser minus prototype growth delay) was only 0.66 days and was not statistically significant. This in vivo study demonstrates that the prototype is equivalent to a laser in PDT effect. The device has low capital/running cost, is simple to use and is one of the most powerful, spectrally efficient non-laser PDT sources available.     

Attempt of photodynamic therapy on esophageal varices

Small vessels gradually reappear within the esophageal wall after endoscopic injection sclerotherapy or endoscopic variceal ligation, which causes late recurrent bleeding. Additional ligation or a small amount of sclerotherapy of these thin and serpentine vessels is sometimes difficult to perform, and stenosis of the esophagus sometimes occurs after a small amount of sclerotherapy. In this study we attempted endoscopic photodynamic therapy on newly visible vessels and evaluated its ability to prevent recurrent bleeding. Fourteen patients with newly visible vessels within the esophageal wall were enrolled. All patients had esophageal varices secondary to hepatitis B and had their varices eliminated through endoscopic sclerotherapy before neovascularization. Seven patients received photodynamic therapy, and seven patients served as the control group. In the photodynamic therapy group, intravenous injection of 5 mg/kg of hematoporphyrin monomethyl ether was given and immediately followed by endoscopic irradiation of the newly visible vessels by copper vapor laser for 40 min with a power density of 150 mW/cm². Endoscopic examination was performed 3 months later to evaluate the therapeutic effect. The duration of non-bleeding was compared between the two groups. The number of newly visible vessels was found to have decreased after photodynamic therapy when compared with the control group (P < 0.001). Kaplan–Meier analyses demonstrated a longer period of non-bleeding in the photodynamic therapy group. The recurrent bleeding rate in the photodynamic therapy (PDT) group was lower than that in the control group (P = 0.027). One patient in the photodynamic therapy group suffered from facial dermatitis from shining direct light. Endoscopic photodynamic therapy seemed to be effective in the elimination of esophageal newly visible vessels and the prevention of recurrent bleeding.     

Effects of combination of melatonin and laser irradiation on ovarian cancer cells and endothelial lineage viability

The main goal of anti-cancer therapeutic approaches is to induce apoptosis in tumor masses but not in the normal tissues. Nevertheless, the combination of photodynamic irradiation with complementary oncostatic agents contributes to better therapeutic performance. Here, we applied two different cell lines; SKOV3 ovarian carcinoma cells and HUVECs umbilical cord cells as in vitro models to pinpoint whether pharmacological concentration of melatonin in combination with photodynamic therapy induces cell cytotoxicity. The cells were separately treated with various concentrations of melatonin (0 to 10 mM) and photodynamic irradiation alone or in combination. Cells were preliminary exposed to increasing concentrations of melatonin for 24 h and subsequently underwent laser irradiation for 60 s with an output power of 80 mW in continuous mode at 675 nm wavelength and a total light dose of 13.22 J/cm². Cell viability, apoptosis/necrosis rates, and reactive oxygen species levels as well as heat shock protein 70 expression were monitored after single and combined treatments. A statistical analysis was performed by applying one-way analysis of variance (ANOVA) and post hoc Tukey’s test. Combination treatment of both cell lines caused a marked increase in apoptosis/necrosis rate, reactive oxygen species generation, and heat shock protein 70 expression compared to incubation of the cells with each agent alone (p?<?0.05). SKOV3 cancer cells expressed higher level of heat shock protein 70 under experimental procedure as compared to HUVECs (p?<?0.05). Our results introduce melatonin as a potent stimulus for enhancing the efficacy of laser on induction of apoptosis in tumor cells.     

Hemodynamics of erection: current pharmacological findings

Over twenty drugs were injected into the corpora cavernosa. Pharmacologically these drugs come under seven therapeutic categories. Two types of pharmacodynamics explain the mode of action of these agents on the erectile tissues. The discovery of these drugs can be added to the array of investigations and actions normally used to study and remedy the problems of organic impotence, as well as a new test which may provide a therapeutic base for vascular rehabilitation and, in some cases, a substrate for a pharmacological prosthesis.     

The Well-being Model: A New Drug Interaction Model for Positive and Negative Effects

Background: Drugs are routinely combined in anesthesia and pain management to obtain an enhancement of the desired effects. However, a parallel enhancement of the undesired effects might take place as well, resulting in a limited therapeutic usefulness. Therefore, when addressing the question of optimal drug combinations, side effects must be taken into account.

Methods: By extension of a previously published interaction model, the authors propose a method to study drug interactions considering also their side effects. A general outcome parameter identified as patient's well-being is defined by superposition of positive and negative effects. Well-being response surfaces are computed and analyzed for varying drugs pharmacodynamics and interaction types. In particular, the existence of multiple maxima and of optimal drug combinations is investigated for the combination of two drugs.

Results: Both drug pharmacodynamics and interaction type affect the well-being surface and the deriving optimal combinations. The effect of the interaction parameters can be explained in terms of synergy and antagonism and remains unchanged for varying pharmacodynamics. For all simulations performed for the combination of two drugs, the presence of more than one maximum was never observed.     

Photodynamic therapy of C3H tumours in mice: Effect of drug/light dose fractionation and misonidazole

C3H mammary carcinomas transplanted to the feet of mice were treated with haematoporphyrin derivative (HPD) or Photofrin II(PII) and laser light at 630 nm. While fluence rates lower than 100 mW cm⁻² gave minimal hyperthermic effects, a slight but significant growth delay was observed in unsensitized tumours exposed to a fluence rate of 150 mW cm⁻² which induced tumour temperatures in the range 40–50°C. Different modes of fractionation of the light fluence and of the HPD dose were tested but were found to give poorer rather than better results than the application of a single light exposure 24 h after intraperitoneal injection of HPD. Different PII doses were applied together with different light fluences, keeping the product of the drug dose and light fluence constant. In the dose range 6.25–50 mg/kg body weight the resulting effect on tumours was constant, allowing for a slight effect of hyperthermia at the highest light fluences, and possibly a photodegradation of PII. Misonidazole given before photodynamic treatment (PDT) slightly reduced the effect of PDT on the tumour growth. When given after PDT, however, misonidazole improved the therapeutic results significantly.     

Ex vivo optical properties of human colon tissue

Using a spectrophotometer equipped with an internal integrating sphere, the absorption (μa) and the reduced scattering (μs′) coefficients of ex vivo human colon tissues were evaluated from reflectance and transmittance measurements. μa and μs′ varied from 47.7 to 1.0 cm^?1 and from 14.2 to 6.2 cm^?1, respectively, on passing from 300 nm to 800 nm. These results can be used to estimate the optical penetration depths when photodynamic therapy or light-induced fluorescence procedures are used.     

Development of cylindrical diffusing fibres suitable for interstitial photodynamic therapy

The development of suitable optical fibres, especially cylindrical diffusing fibres, has enabled the application of photodynamic therapy (PDT) in hollow organs such as the bronchus, oesophagus or the bladder. Although cylindrical diffusing fibres are commercially available, these are expensive and therefore many pre-clinical investigations are performed with institutionally-made fibres. We describe the production process of a plastic cylindrical diffusing fibre with good light distribution qualities and very low costs. To identify the permitted tolerances on fibre parameters, fibres with varying light distribution patterns were tested in an in vivo tumour model for growth delay after PDT. No significant difference in growth delay was found between these fibres using an energy of 100J cm⁻¹ at 24h after injection with Photofrin. These results indicate that by cheap, simple means, fibres can be made which are suitable for interstitial PDT and that small differences in light distribution patterns do not affect the in vivo response.     

肝外胆管细胞癌治疗现状及进展

近年来,肝外胆管细胞癌的发病有增加的趋势。目前仍以手术治疗为主要的治疗手段。针对已失去根治机会的病例,有效的胆汁引流、放化疗、光动力疗法是延缓肿瘤生长速度,提高患者生活质量,延长患者生存期的关键。     

Photodynamic therapy in the treatment of chronic periodontitis: a systematic review and meta-analysis

This meta-analysis was conducted to investigate the efficacy and safety of antimicrobial photodynamic therapy used alone or adjunctive to scaling root planing in patients with chronic periodontitis. The meta-analysis was conducted according to the QUOROM statement and recommendations of the Cochrane Collaboration. An extensive literature search was performed on seven databases, followed by a manual search. Weighted mean differences and 95% confidence intervals were calculated for clinical attachment level, probing depth and gingival recession. The I² test was used for inter-study heterogeneity; visual asymmetry inspection of the funnel plot, Egger’s regression test and the trim-and-fill method were used to investigate publication bias. At 3 months, significant differences in clinical attachment level (p?=?0.006) and probing depth reduction (p?=?0.02) were observed for scaling root planing with antimicrobial photodynamic therapy, while no significant differences were retrieved for antimicrobial photodynamic therapy used alone; at 6 months no significant differences were observed for any investigated outcome. Neither heterogeneity nor publication bias was detected. The use of antimicrobial photodynamic therapy adjunctive to conventional treatment provides short-term benefits, but microbiological outcomes are contradictory. There is no evidence of effectiveness for the use of antimicrobial photodynamic therapy as alternative to scaling root planing. Long-term randomized controlled clinical trials reporting data on microbiological changes and costs are needed to support the long-term efficacy of adjunctive antimicrobial photodynamic therapy and the reliability of antimicrobial photodynamic therapy as alternative treatment to scaling root planing.     

The Effect of Different Spot Sizes on the Efficacy of Hair Removal Using a Long-Pulsed Diode Laser

BACKGROUND: In the last years several lasers have proven their efficacy for hair removal. However, little is known about the efficacy of varying the spot size with those lasers. OBJECTIVE: To evaluate the long-term efficacy of hair removal using a diode laser with different spot sizes. METHODS: A long-pulsed diode laser (2 x 60 msec) was used. The spot size was 8 mm, 12 mm, or 14 mm. Twenty consenting volunteers were treated three times at regular intervals of 3 weeks. The ratio of the number of hairs in the treated area to an adjacent area left untreated (control) was referred to as regrowth. RESULTS: One month after laser treatment, regrowth was 23% (8 mm), 12% (12 mm), and 13% (14 mm). After 3 months regrowth was 67% (8 mm), 54% (12 mm), and 55% (14 mm). Fifteen months after treatment 4 of 16 volunteers had a regrowth rate of less than 25%. CONCLUSION: The results provide evidence for an effective and long-lasting growth delay of hairs using the long-pulsed diode laser. The use of large spot sizes improved the growth delay of hairs measured 1 month after treatment.     

Effect of multidrug-resistant P-glycoprotein gene expression on chloroaluminum tetrasulfonate phthalocyanine concentration

The effect of multidrug-resistant P-glycoprotein gene expression (MDR1) in 3T3 cells on cellular concentrations and cytotoxicity induced by the photodynamic agent chloroaluminum tetrasulfonate phthalocyanine (AISPc) was evaluated. 3T3 cells transfected with a retroviral vector expressing human MDR1 cDNA were resistant to colchicine. Resistant cells incubated with daunomycin accumulated only 40–50% of the quantity of daunomycin accumulated in control cells. Resistant cells incubated with daunomycin in the presence of verapamil had intracellular daunomycin concentrations approximately equal to control cells without verapamil. When these MDR1 3T3 cells were incubated with AISPc, cellular concentrations of AISPc did not differ between cells resistant to colchicine and those that were not. Similarly, there was little difference in cytotoxicity demonstrated by ⁵¹Cromium release in the two cell lines exposed to AISPc and light (675 nm; 6 J/cm²). This study suggests photodynamic therapy using AISPc may be a useful treatment modality for tumors in which the MDR1 P-glycoprotein confers resistance to cancer chemotherapeutics. © 1993 Wiley-Liss, Inc.     

Konservative Therapie der Gonarthrose

Osteoarthritis of the knee is a degenerative joint disease with progressive degradation of articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking and joint effusion depending on the stage of the disease. In an effort to delay major surgery, patients with knee osteoarthritis are offered a variety of nonsurgical modalities, such as weight loss, exercise, physiotherapy, bracing, orthoses, nonsteroidal anti-inflammatory drugs (NSAIDs) and intra-articular viscosupplementation or corticosteroid injection. In general, the goals of these therapeutic options are to decrease pain and improve function. Some of these modalities may also have a disease-modifying effect by altering the mechanical environment of the knee. Chondroprotective substances, such as lucosamine, chondroitin sulphate and hyaluronic acid are safe and provide short-term symptomatic relief while the therapeutic effects remain uncertain.     

Treatment of Canine Osseous Tumors with Photodynamic Therapy: A Pilot Study

Photodynamic therapy uses nonthermal coherent light delivered via fiber optic cable to locally activate a photosensitive chemotherapeutic agent that ablates tumor tissue. Owing to the limitations of light penetration, it is unknown whether photodynamic therapy can treat large osseous tumors. We determined whether photodynamic therapy can induce necrosis in large osseous tumors, and if so, to quantify the volume of treated tissue. In a pilot study we treated seven dogs with spontaneous osteosarcomas of the distal radius. Tumors were imaged with MRI before and 48 hours after treatment, and the volumes of hypointense regions were compared. The treated limbs were amputated immediately after imaging at 48 hours and sectioned corresponding to the MR axial images. We identified tumor necrosis histologically; the regions of necrosis corresponded anatomically to hypointense tissue on MRI. The mean volume of necrotic tissue seen on MRI after photodynamic therapy was 21,305 mm³ compared with a pretreatment volume of 6108 mm³. These pilot data suggest photodynamic therapy penetrates relatively large canine osseous tumors and may be a useful adjunct for treatment of bone tumors. One or more authors (SB) have received funding from Canadian Institutes of Health Research and QLT Inc, Vancouver, Canada, to complete this research project. Each author certifies that his or her institution has approved the animal protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.     

Evaluation of synergistic effects of sulforaphene with photodynamic therapy in human cervical cancer cell line

Sulforaphene from cruciferous vegetable has shown to modulate various signaling pathways of apoptosis. But it has not yet been studied extensively for the cervical cancer treatment. Previous studies show the promising role of photodynamic therapy for cervical cancer. Here, we confirm that sulforaphene can synergistically enhance the efficacy of photodynamic therapy. Human cervical cancer cells HeLa were treated with a very low dose of sulforaphene (2.0 μg/ml) and photodynamic therapy with radachlorin (0.5 μg/ml) at a fluence of 27 J/cm² (30 milliwatts/cm², λmax?～?670?±?3 nm). The combination treatment showed a synergistic effect to induce apoptosis. The mitochondrial apoptotic pathway was activated via caspase 3 and caspase 9. On the other hand, caspase 12 and C/EBP homologous protein (CHOP) were expressed that indicated endoplasmic reticulum stress. This combination treatment also activated death receptor pathway via activation of caspase 8 and inhibited cell proliferation via down-regulation of EGFR. Thus, several apoptotic pathways were simultaneously activated in this combination treatment which results in a synergistic efficacy of sulforaphene with photodynamic therapy. Therefore, this study could be useful in the improvement of therapies for human cervical and other types of cancers.     

Therapeutic drug monitoring in patients with chronic renal failure: evaluation of the Abbott TDx drug assay system

Immunoassay techniques have been widely used for therapeutic drug monitoring, but lack of antibody specificity can lead to measurement of erroneous drug concentrations due to cross-reactivity with other drugs, metabolites, or endogenous substances, particularly in patients with excretory organ compromise such as renal dysfunction. The Abbott TDx system, a popular automated immunoassay method for therapeutic drug monitoring, was used to measure apparent serum concentrations of carbamazepine, digoxin, gentamicin, lidocaine, phenobarbital, phenytoin, quinidine, valproic acid, and vancomycin in patients with renal failure who were not receiving these drugs. Endogenous substances and other concomitantly administered drugs did not lead to spuriously elevated drug levels, and a previous report of cross-reactive digoxin-like substances was not confirmed. Pooled plasma samples from the patients were spiked with digoxin or phenytoin, each at two concentrations, and the samples were assayed for the drug concentration using the TDx system. No falsely elevated values were found. This work suggests that the TDx system may be better suited for the measurement of these drugs in patients with renal failure than some other immunoassay methods.     

The well-being model: a new drug interaction model for positive and negative effects

BACKGROUND: Drugs are routinely combined in anesthesia and pain management to obtain an enhancement of the desired effects. However, a parallel enhancement of the undesired effects might take place as well, resulting in a limited therapeutic usefulness. Therefore, when addressing the question of optimal drug combinations, side effects must be taken into account. METHODS: By extension of a previously published interaction model, the authors propose a method to study drug interactions considering also their side effects. A general outcome parameter identified as patient's well-being is defined by superposition of positive and negative effects. Well-being response surfaces are computed and analyzed for varying drugs pharmacodynamics and interaction types. In particular, the existence of multiple maxima and of optimal drug combinations is investigated for the combination of two drugs. RESULTS: Both drug pharmacodynamics and interaction type affect the well-being surface and the deriving optimal combinations. The effect of the interaction parameters can be explained in terms of synergy and antagonism and remains unchanged for varying pharmacodynamics. For all simulations performed for the combination of two drugs, the presence of more than one maximum was never observed. CONCLUSIONS: The model is consistent with clinical knowledge and supports previously published experimental results on optimal drug combinations. This new framework improves understanding of the characteristics of drug combinations used in clinical practice and can be used in clinical research to identify optimal drug dosing.