Radioiodinated Hypericin: Its Biodistribution, Necrosis Avidity and Therapeutic Efficacy are Influenced by Formulation

Purpose

To study whether formulation influences biodistribution, necrosis avidity and tumoricidal effects of the radioiodinated hypericin, a necrosis avid agent for a dual-targeting anticancer radiotherapy.

Methods

Iodine-123- and 131-labeled hypericin (¹²³I-Hyp and ¹³¹I-Hyp) were prepared with Iodogen as oxidant, and formulated in dimethyl sulfoxide (DMSO)/PEG400 (polyethylene glycol 400)/water (25/60/15, v/v/v) or DMSO/saline (20:80, v/v). The formulations with excessive Hyp were optically characterized. Biodistribution, necrosis avidity and tumoricidal effects were studied in rats (n?=?42) without and with reperfused liver infarction and implanted rhabdomyosarcomas (R1). To induce tumor necrosis, R1-rats were pre-treated with a vascular disrupting agent. Magnetic resonance imaging, tissue-gamma counting, autoradiography and histology were used.

Results

The two formulations differed significantly in fluorescence and precipitation. ¹²³I-Hyp/Hyp in DMSO/PEG400/water exhibited high uptake in necrosis but lower concentration in the lung, spleen and liver (p?<?0.01). Tumor volumes of 0.9?±?0.3 cm³ with high radioactivity (3.1?±?0.3% ID/g) were detected 6 days post-treatment. By contrast, ¹³¹I-Hyp/Hypin DMSO/saline showed low uptake in necrosis but high retention in the spleen and liver (p?<?0.01). Tumor volumes reached 2.6?±?0.7 cm³ with low tracer accumulation (0.1?±?0.04%ID/g).

Conclusions

The formulation of radioiodinated hypericin/hypericin appears crucial for its physical property, biodistribution, necrosis avidity and tumoricidal effects.     

Effects of ponesimod,a selective S1P1 receptor modulator,on the pharmacokinetics of a hormonal combination contraceptive

Purpose

To determine the effects of steady-state concentrations of the selective S1P₁ receptor modulator ponesimod on the pharmacokinetics (PK) of a single dose of a combined oral contraceptive, containing 1 mg norethisterone (NET) and 35 μg ethinyl estradiol (EE) and to investigate the effects on heart rate at different ponesimod doses within an up-titration regimen prior to co-administration of the contraceptive.

Methods

Twenty-two healthy women (age: 29-60 years) received twice a single oral dose of the combined oral contraceptive, alone or in combination with multiple doses of 40 mg ponesimod attained by an up-titration regimen. Heart rate (HR) effects were assessed on the first day of each up-titration level. PK parameters of NET and EE were determined by non-compartmental analysis.

Results

Geometric mean ratios (ponesimod and contraceptive / contraceptive alone) of C_max and AUC_0-24 of NET were 0.87 (90 % CI: 0.80, 0.94) and 0.84 (90 % CI: 0.76, 0.93), respectively. Geometric mean ratios of C_max and AUC_0-24 of EE were 0.94 (90 % CI: 0.86, 1.03) and 0.95 (90 % CI: 0.89, 1.01), respectively. The maximum mean HR reduction after the first dose of 10 mg ponesimod was 12.4 bpm (SD?±?6.2) at 2.5 h post-dose. On Day 4 (first dose of 20 mg) and Day 7 (first dose of 40 mg) the maximum mean HR reduction was 4.3 bpm (SD?±?5.7) and 1.4 (SD?±?6.4), respectively, at 2.5 h post-dose compared to baseline.

Conclusion

No clinically relevant PK interactions between ponesimod and the combined oral contraceptive were observed, therefore, efficacy of hormonal contraceptives is not expected to be affected by concomitant administration of ponesimod. The up-titration regimen showed that HR reductions are diminished upon repeated ponesimod administration.     

Clinical outcome of double crown-retained implant overdentures with zirconia primary crowns

PURPOSEThis retrospective study aims at the evaluation of implant-supported overdentures (IODs) supported by ceramo-galvanic double crowns (CGDCs: zirconia primary crowns + galvano-formed secondary crown).RESULTSOne of the 86 inserted implants failed during the healing period (cumulative survival rate (CSR) implants: 98.8%). During the prosthetic functional period (mean: 5.9 ± 2.2 years), 1 implant demonstrated an abutment fracture (CSR-abutments: 98.2%), and one case of peri-implantitis was detected. All IODs remained in function (CSR-denture: 100%). A total of 15 technical complications required interventions to maintain function (technical complication rate: 0.178 treatments/patients/year).CONCLUSIONConsidering the small sample size, the use of CGDCs for the attachment of IODs is possible without an increased risk of technical complications. However, for a final evaluation, results from a larger cohort are required.     

Computed tomography versus single-contrast arthrotomography in evaluation of the temporomandibular joint disc: A study of autopsy specimens

The lateral, central and medial parts of 15 right temporomandibular joint autopsy specimens were studied to compare the ability of computed tomography (CT) and single-contrast arthrotomography in diagnosing the disc position and configuration. The radiologic findings were compared with macroscopic findings in a blinded fashion. In the CT examination, the diagnostic accuracy was 40% in determining the disc position and 26.7% in determining the disc configuration. However, in many areas of the joints the disc was not possible to evaluate by CT. With arthrotomography the diagnostic accuracy in determining the disc position was 75.6% and the disc configuration 60%. The sensitivity of CT was 0.45 and of arthrotomography 0.95 for the diagnosis of the disc position. The specificity was 0.87 for CT and 0.76 for arthrotomography. From these results, we conclude that arthrotomography is a reliable aid to diagnosis of TMJ disc changes and that CT cannot replace it.     

Clinical association between chronic periodontitis and the leukocyte extravasation inhibitors developmental endothelial locus‐1 and pentraxin‐3

This clinical study aimed to determine whether periodontal disease is associated with expression of developmental endothelial locus‐1 (Del‐1) and pentraxin‐3 (PTX‐3), endogenous inhibitors of leukocyte extravasation in humans. Expression of DEL1, PTX3, interleukin‐17A (IL17A), and lymphocyte function‐associated antigen‐1 (LFA1) was determined, using RT‐PCR and melting curve analysis, in biopsies of gingival tissues from 95 patients: 42 with moderate periodontitis; 40 with severe periodontitis; and 13 healthy controls. Relative expression of DEL1 and PTX3 was statistically significantly weaker in patients with periodontitis than in the control subjects. On the contrary, both IL17A and LFA1 showed statistically significant stronger expression in patients with periodontitis than in healthy controls. Correlation analysis, performed using Spearman's test, showed that expression of DEL1 was statistically significantly linked to periodontitis (ρ = ?0.103) and to age (ρ = ?0.134), but not to the gender of the patient, and that expression of PTX3 was significantly correlated with periodontitis (ρ = ?0.354). Expression of neutrophil extravasation inhibitors DEL1 and PTX3 show significant, but weak, association with the clinical manifestation of chronic periodontitis.     

Analysis of the intraimplant microflora of two-piece dental implants

Objective

Information about the spectrum of microorganisms in the intraimplant cavities of two-piece dental implants is scarce. The purpose of this study was to assess the intraimplant microflora of two-piece dental implants by conventional biochemical testing, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and 16 s rDNA gene sequencing.

Materials and methods

Ten patients (six men and four women; average age?=?66.7 years; age range?=?58–78 years) received 35 two-piece titanium implants carrying ball attachments. Biofilm sampling was performed with sterile microbrushes, and nonadherent microbial samples were obtained by injection and reuptake of predefined volumes of NaCl solution. The samples were cultured and analyzed by conventional biochemical testing, MALDI-TOF MS, and 16 s rDNA gene sequencing.

Results

Of the 103 species detected, 27 and 33 were identified only in the biofilm and nonadherent microbial samples, respectively. Forty-three species were identified in both types of samples.

Conclusions

Two-piece dental implants harbored a broad spectrum of gram-positive and gram-negative aerobes and anaerobes, especially rods and cocci.

Clinical relevance

These findings confirm bacterial translocation from the oral cavity to intraimplant cavities. Microbiological methods as used in this study are necessary to reveal the complete vital microflora of intraimplant cavities.     

Case report: fusion of positron emission tomography (PET) and computed tomography (CT) images for image-guided endoscopic navigation in maxillofacial surgery: clinical application of a new technique.

INTRODUCTION: Surgery based on computed tomography (CT) data is becoming increasingly important in the head and neck region. The technique for hardware fusion between positron emission tomography (PET) and computed tomography (CT) has only been established commercially in the last 4 years. The advantages over CT alone are obvious. The surgeon is simultaneously provided with a map of anatomical as well as of functional (metabolic) details. The fused images offer improved localization of malignant lesions and improved targeting of biopsy, especially for small lesions. PURPOSE: A new technique for image-guided tumour localization for maxillofacial surgery based on PET/CT-image fusion is described. PATIENT AND METHOD: A 78-year-old woman was admitted to this department with a tumour of the skull base. Three dimensional fusion of computed CT with positron PET images on a commercially available navigation system is described. After patient-to-image registration, a high-resolution endoscope was calibrated intraoperatively. Image-guided biopsy specimens were taken under direct visual control. CONCLUSION: PET/CT-image fusion proved extremely helpful to navigate the endoscope to the target lesion and to identify the tumour.     

Antimicrobial efficacy of semiconductor laser irradiation on implant surfaces

PURPOSE: This study was conducted to investigate the antimicrobial effect of an 809-nm semiconductor laser on common dental implant surfaces. MATERIALS AND METHODS: Sandblasted and acid-etched (SA), plasma-sprayed (TPS), and hydroxyapatite-coated (HA) titanium disks were incubated with a suspension of S. sanguinis (ATCC 10556) and subsequently irradiated with a gallium-aluminum-arsenide (GaAlAs) laser using a 600-microm optical fiber with a power output of 0.5 to 2.5 W, corresponding to power densities of 176.9 to 884.6 W/cm2. Bacterial reduction was calculated by counting colony-forming units on blood agar plates. Cell numbers were compared to untreated control samples and to samples treated with chlorhexidine digluconate (CHX). Heat development during irradiation of the implants placed in bone blocks was visualized by means of shortwave thermography. RESULTS: In TPS and SA specimens, laser irradiation led to a significant bacterial reduction at all power settings. In an energy-dependent manner, the number of viable bacteria was reduced by 45.0% to 99.4% in TPS specimens and 57.6% to 99.9% in SA specimens. On HA-coated disks, a significant bacterial kill was achieved at 2.0 W (98.2%) and 2.5 W (99.3%) only (t test, P < .05). For specimens treated with CHX, the bacterial counts were reduced by 99.99% in TPS and HA-coated samples and by 99.89% in SA samples. DISCUSSION: The results of the study indicate that the 809-nm semiconductor laser is capable of decontaminating implant surfaces. Surface characteristics determine the necessary power density to achieve a sufficient bactericidal effect. The bactericidal effect, however, was lower than that achieved by a 1-minute treatment with 0.2% CHX. The rapid heat generation during laser irradiation requires special consideration of thermal damage to adjacent tissues. CONCLUSION: No obvious advantage of semiconductor laser treatment over conventional methods of disinfection could be detected in vitro.