Gold Nanoparticles in Glioma Theranostics.

Despite many endeavors to treat malignant gliomas in the last decades, the median survival of patients has not significantly improved. The infiltrative nature of high-grade gliomas and the impermeability of the blood-brain barrier to the most therapeutic agents remain major hurdles, impeding an efficacious treatment. Theranostic platforms bridging diagnosis and therapeutic modalities aim to surmount the current limitations in diagnosis and therapy of glioma. Gold nanoparticles (AuNPs) due to their biocompatibility and tunable optical properties have widely been utilized for an assortment of theranostic purposes. In this Review, applications of AuNPs as imaging probes, drug/gene delivery systems, radiosensitizers, photothermal transducers, and multimodal theranostic agents in malignant gliomas are discussed. This Review also aims to provide a perspective on cancer theranostic applications of AuNPs in future clinical trials.

In Vivo Reflectance Confocal Microscopy of Gold Microparticles Deposited in the Skin. A Case Report on Cutaneous Chrysiasis.

Cutaneous chrysiasis is gold deposition in the dermis, described after parenteral administration of gold salts or after topical exposure to gold-containing materials. Gold microparticles (GMPs) have versatile therapeutic effects and are increasingly used in medicine. This case report describes the development of a blue-gray macule following the facial application of GMPs and laser treatment of acne vulgaris. Dermoscopy showed a nonspecific homogenous blue-gray pattern, gradually fading over an 8-month-period. Reflectance confocal microscopy (RCM) detected hyperreflective, subcellular particles in the papillary dermis, localized around hair follicles, eccrine glands, and inside macrophages. Histopathological evaluation, darkfield illumination with hyperspectral imaging, and neutron activation analysis confirmed the presence of GMPs in the dermis. RCM allowed non-invasive fast visualization of aggregates of hyperreflective particles in the dermis and can potentially be used for monitoring localized cutaneous chrysiasis and other metal deposition conditions over time. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Radio-sensitization efficacy of gold nanoparticles in inhalational nanomedicine and the adverse effect of nano-detachment due to coating inactivation.

Gold nanoparticles (GNPs) are an emerging area of interest in radiation therapy due to their unique radio-sensitizing properties. In the literature, the enhancing capability of GNPs is usually quantified using the metric dose enhancement ratio (DER). Traditionally, the focus of the vast majority of studies has always been on intravenous administration of GNPs. However, recent work showed the potential of using GNP inhalation, rather than intravenous injection, to enhance the dose to the lung. Yet, some of these studies are employing simplistic analytical methods to calculate DER and, thus far, there are no detailed computations of the enhancement profiles therein. Moreover, the coating on the GNP surface can be adversely affected by the large gradient of the radiation dose in the immediate vicinity of GNPs, leading to the rupture of ligands and detachment of GNPs from the surface of the membrane, and hence the loss of its efficacy. In this study, a next-generation deterministic code was used to resolve the DER profile at the interface between the septum, air, and surface of GNPs when they are attached and detached. The results show that the large values of DER in conjunction with the developed hot spots are very effective in lung treatment; on the other hand, coating rupture can lead to significant reduction in DER that may reach 64%. Thus, GNPs can be beneficial in inhalational medicine to treat lung cancer, provided that more comprehensive studies on the characteristics of the coating are addressed to maximize the radio-therapeutic benefit of GNPs.

[Lichenoid drug reactions]. / Lichenoide Arzneimittelreaktionen.

Lichenoid drug reactions are rare compared to typical morbilliform drug exanthema or urticaria. They are associated with specific drugs or drug families like gold, antimalarial drugs, ß­blockers and angiotensin-converting-enzyme inhibitors. Recent observations included associations with novel drugs such as biologics (e. g. tumour necrosis factor antagonists) and immune checkpoint inhibitors (anti-programme cell death protein 1 antibodies). Lichenoid drug reactions most often resemble lichen planus mainly in areas of ultraviolet-light exposed skin, but also mucosal lichen planus and even bullous lesions may occur.

Organ-specific distribution of gold nanoparticles by their surface functionalization.

The behavior and fate of intravenously (i.v.) injected nanoparticles (NPs) can be controlled by several physicochemical factors including size, shape and surface charge. To evaluate the role of surface charge on distribution of NPs, we used neutral-charged 15-nm-sized polyethylene glycol-coated gold nanoparticles (AuNP(PEG)) as a core NP and carboxyl or amine groups were conjugated to AuNP(PEG) to generate negative (AuNP(COOH)) or positive AuNP (AuNP(NH2)), respectively. Each type of AuNP was i.v. injected into mice (1 mg kg(-1)) and the concentration of Au was measured in different organs at 30 min, 4, 24 h, 7, 14 days, 1, 3 and 6 months post-injection. The organ distribution also showed the higher deposition rate depending on their functional groups: AuNP(PEG) for mesenteric lymph node, kidney, brain and testis; AuNP(COOH) for liver; AuNP(NH2) for spleen, lung and heart. The blood circulation time and the major excretion route were different depending on their functional groups. In conclusion, functional groups conjugated on the surface of AuNPs produce differences in blood kinetics, organ distribution and elimination pattern which can be important information for directing NPs to specific organs or improving the kinetic properties.

[Allergies to dental materials and effectiveness of treatment in the north-eastern region of Hungary]. / Fogászati anyagokkal szemben kialakuló allergiás megbetegedések és ellátásuk hatékonyságának vizsgálata az észak-alföldi régióban.

The recognition and treatment of allergy is a great challenge for all fields of medicine. The high prevalence of allergic reactions to dental materials and the related financial burden of their treatment make investigation of this disease very important. Our investigation was carried out on patients assigned to our outpatient department for dental allergy test between 1996 and 1998. We determined the distribution of gender and age among the allergic patients in the examined population. We also studied the prevalence of allergic reactions to different dental allergens and the distribution of dental allergens. In a follow-up study we determined the proportion of those patients, who were retreated in conformity with the results of epicutan tests and we followed up the positive effects of these treatments. We have found that dental allergy occurred five times more frequently in women (84%) than in men (16%) and the most affected age group was between 20 to 39 and 40-49 years (31%). Seventy-five percent of the patients suffered from a combination of metal and polymer allergy. The most frequent metal allergen was TEGDMA (triethylene glycol dimethacrylate) (49.7%). The suggested treatment plan was carried out in 63% of the allergic patients. The applied treatment was successful in 48% of these cases. We experienced that 48% of these patients got rid of their earlier signs and symptoms.

Crisiasis corneal. Depósitos corneales de sales de oro en paciente con artritis reumatoide. Análisis con microscopía confocal / Corneal chrysiasis. Gold salt deposits in the cornea in a patient with rheumatoid arthritis. An analysis with confocal microscopy

Caso clínico: Mujer de 60 años de edad con artritis reumatoide de veinte años de evolución, en tratamiento con sales de oro (SO) intramusculares mensuales en los últimos 7 años. Refería visión de halos y presentaba una agudeza visual de 0,6 en ambos ojos (AO) y en la lámpara de hendidura destacaban depósitos en el estroma central de AO de material granulado dorado disperso y sin reacción inflamatoria. Se realizó estudio con microscopía confocal. Discusión: Los depósitos de SO son dosis-dependientes y reversibles aunque de forma muy lenta. En este trabajo se presenta por primera vez la evidencia de los depósitos de SO en todas las capas de la córnea, de predominio en el estroma y endotelio corneales (AU)

Case report: A 60-year-old woman with rheumatoid arthritis of 20 years onset, on treatment with monthly intramuscular gold salts (GS) for the last 7 years. She complained of suffering from halo vision, and the examination showed a visual acuity of 0.6 in both eyes (BE). The slit lamp showed some deposits in the stroma with scattered golden granulated, without any further inflammatory reaction. Discussion: GS deposits are dose-dependent and reversible, although very slowly. In this article, we introduce, for the first time, evidence of deposits of GS in all layers of the cornea, predominantly in the corneal stroma and in the endothelium (AU)

Gold(III)-dithiocarbamato anticancer agents: activity, toxicology and histopathological studies in rodents.

Gold(III)-dithiocarbamato complexes have recently gained increasing attention as potential anticancer agents because of their strong tumor cell growth--inhibitory effects, generally achieved by exploiting non-cisplatin-like mechanisms of action. The rationale of our research work is to combine the antitumor properties of the gold(III) metal center with the potential chemoprotective function of coordinated dithiocarbamates in order to reduce toxic side effects (in particular nephrotoxicity) induced by clinically established platinum-based drugs. In this context, [Au(III) Br(2) (ESDT)] (AUL12) was proved to exert promising and outstanding antitumor activity in vitro and to overcome both acquired and intrinsic resistance showed by some types of tumors toward cisplatin. As a subsequent extension of our previous work, we here report on detailed in vivo studies in rodents, including antitumor activity toward three transplantable murine tumor models, toxicity, nephrotoxicity and histopathological investigations. Remarkably, the gold(III) complex AUL12 stands out for higher anticancer activity than cisplatin toward all the murine tumor models examined, inducing up to 80% inhibition of tumor growth. In addition, it shows low acute toxicity levels (lethal dose, LD(50) = 30 mg kg(-1) ) and reduced nephrotoxicity. Altogether, these results confirm the reliability of our drug design strategy and support the validation of this gold(III)-dithiocarbamato derivative as a suitable candidate for clinical trials.

Contact allergy to gold as a model for clinical-experimental research.

The high frequency of contact allergy to gold in patients with dermatitis was established after exhaustive skin testing, determining the right test agent, the best concentration, and repeated test readings. Metallic gold in contact with skin is slowly ionized, permitting absorption and haptenisation. Contact allergy to gold is statistically correlated to the presence of dental gold. But in many case reports it has also been attributed to wearing gold jewellery, albeit not statistically demonstrated. Epicutaneous testing with gold salts increases the blood gold level, and by intramuscular injection systemic contact dermatitis is provoked in an allergic individual. In coronary heart disease, gold-coated intravascular stents have been shown to be correlated to contact allergy and even to an increased risk of restenosis. Gold is far from inert.

Diagnosis and management of oral lichenoid reactions.

Lichen planus is one of the most common mucocutaneous conditions seen in dental practice. A variety of other conditions known as lichenoid reactions can simulate lichen planus either clinically or histologically. This paper will discuss the more common lichenoid reactions seen in clinical practice and review the diagnosis and management of these conditions.

The history of gold therapy for tuberculosis.

This is a historical study of the popularization of a medical therapy contrary to pertinent experimental findings. Presumably this circumstance reflects the desperation about tuberculosis: highly prevalent, highly fatal, and lacking any etiologically directed therapy. Gold compounds were introduced, based initially on the reputation of Robert Koch, who had found gold cyanide effective against M. tuberculosis in cultures, but not in experimentally infected animals. Treatment of pulmonary tuberculosis with these compounds was popularized, particularly by Danish physicians, in the mid-1920s, despite consistently negative experimental results, based on Paul Ehrlich's theories of antimicrobial drug effects. Difficulties in the design of interpretable clinical studies were soon recognized but also generally ignored, thus permitting data to be interpreted as favorable to antituberculous gold therapy. Eventually toxicity was considered to outweigh the alleged therapeutic benefit of all gold compounds. This resulted in their discard shortly before the introduction of streptomycin therapy.

Preclinical tolerance and pharmacokinetic assessment of MU-Gold, a novel chemotherapeutic agent, in laboratory dogs.

MU-Gold, tetrakis (trishydroxymethyl) phosphine gold(I) chloride, a novel gold compound, has cytotoxic effects against human androgen-dependent and -independent prostatic, gastric, and colonic carcinoma in cell culture and against malignant lymphoma in rodent models. A pilot study was conducted to evaluate the tolerance and pharmacokinetic properties of MU-Gold in normal dogs in anticipation of clinical trials in cancer-bearing dogs. MU-Gold (10 mg/kg) was administered by i.v. injection to three purpose-bred dogs. Serum was collected from all dogs for measurement of gold levels via atomic absorption spectrometry. In addition, complete blood counts and biochemical profiles were monitored for Dogs 2 and 3 every 7 days for 30 days. A two-compartment i.v. bolus model with first-order kinetics, mean elimination half-life of approximately 40 hours, and mean volume of distribution of 0.6 L/kg was established. Serum gold concentrations ranging from 10 to 50 mcg/ml were sustained for 2 to 3 days with no clinically significant toxicities observed. Based on in vitro results in earlier studies and preliminary pharmacokinetic data collected in the present study, Phase I clinical trials should be conducted to define the optimal dosage, dose-limiting toxicities, and other characteristics of MU-Gold that will be used to design Phase II clinical trials.

Gold allergy in Japan.

In Japan, gold dermatitis due to ear piercing increased in the early 1990s, but has subsequently become rare. To evaluate this clinical finding and to determine the frequency of gold allergy in Japan, we analysed the results of patch testing with 0.2% gold chloride from 1990 to 2001. 653 patients were tested from March 1990 to December 2001. 55 patients showed a positive reaction to gold (8.4%). Significantly more women (10.2%) than men (0.8%) reacted (P < 0.005), but there was no significant difference between positive rates from 1990 to 1995 (9.2%) and from 1996 to 2001 (7.2%). Our data suggest that patients with gold allergy did not decrease in number, despite a decreased number of patients showing clinically overt gold dermatitis. Thus, gold allergy has changed from being clinically overt to becoming occult in Japan.

Reversible pancreatitis, hepatitis, and peripheral polyneuropathy associated with parenteral gold therapy.

A 63-year-old man with seronegative rheumatoid arthritis developed acute pancreatitis, severe hepatitis, and sensorimotor polyneuropathy after receiving 150 mg of intramuscular aurothioglucose (gold). Positive lymphocyte transformation test to gold indicated a cell mediated hypersensitivity to the drug, while multiple investigations ruled out other underlying causes for his illness. After cessation of gold therapy a complete recovery occurred.

In vitro lymphocyte reactivity to gold compounds in the diagnosis of contact hypersensitivity.

The use of the lymphocyte transformation test (LTT) in the diagnosis of contact hypersensitivity to gold was studied in 8 patients who had positive patch tests to gold salts, and in 8 control subjects who were negative to such patch tests. Gold sodium thiosulfate and gold chloride were added to cultures of lymphocytes, which were labeled by 3H-thymidine after 96 h. The lymphocyte stimulation index was calculated as the beta-counts in stimulated cultures divided by those in control cultures. The index was statistically significantly higher for the patient group (p=0.005-0.04) than for the control group. Levels of interferon-gamma (IFN-gamma) were determined for the supernatants of the lymphocyte cultures. An index IFN-gamma, which is defined as the level of IFN-gamma in stimulated cultures divided by that in control cultures, was statistically significantly higher for the patient group (p=0.01-0.006). The LTT stimulation index showed specificity and sensitivity between 67 and 80%, the respective values for Index IFN-gamma being between 73 and 100% when the patch test was used as a reference method. Evaluation of lymphocyte reactivity might be of future interest in the diagnosis of allergic reactions to gold if the sensitivity and specificity can be improved.