Neuropsychopharmacology of Emerging Drugs of Abuse: meta- and para-Halogen-Ring-Substituted α-PVP ("flakka") Derivatives.

Changes in the molecular structure of synthetic cathinones has led to an increase in the number of novel emerging drugs in the illicit drug market at an unprecedented rate. Unfortunately, little is known about the neuropsychopharmacology of recently emerged halogen-substituted α-PVP derivatives. Thus, the aim of this study was to investigate the role of para- and meta-halogen (F-, Cl-, and Br-) substitutions on the in vitro, in silico, and in vivo effects of α-pyrrolidinopentiophenone (α-PVP) derivatives. HEK293 cells expressing the human dopamine or serotonin transporter (hDAT and hSERT) were used for the uptake inhibition and transporter affinity assays. Molecular docking was used to model the interaction mechanism against DAT. Swiss CD-1 mice were used for the horizontal locomotor activity, open field test, and conditioned place preference paradigm. All compounds demonstrated potent DA uptake inhibition and higher DAT selectivity than cocaine. Meta-substituted cathinones showed higher DAT/SERT ratios than their para- analogs, which correlates with an increased psychostimulant effect in vivo and with different meta- and para-in silico interactions at DAT. Moreover, all compounds induced rewarding and acute anxiogenic effects in mice. In conclusion, the present study demonstrates the role of meta- and para-halogen substitutions in the mechanism of action and provides the first evidence of the rewarding and anxiety-like properties of halogenated α-PVP derivatives.

Neutrophilic drug reactions.

Neutrophilic drug reactions are unique eruptions that can affect hospitalized patients and share a common pathophysiology with neutrophils as the key mediators of inflammation. They range in clinical presentation from papules and plaques to bullae and erosions to pustules. Although there is some overlap in presentation, each has distinguishing features that aid the clinician in differentiation from one another and from other drug hypersensitivity reactions. Much of the data on these reactions are from case reports and series or retrospective review studies. There are limited prospective observational studies dedicated to these adverse drug reactions. We review the more common and life-threatening neutrophilic drug reactions, their proposed mechanism of action, and their management.

Evaluation of xenon, light-emitting diode (LED) and halogen light toxicity on cultured retinal pigment epithelial cells.

OBJECTIVE: To compare the possible toxic effects of three light sources used in vitreoretinal endoillumination systems; halogen, xenon, and light-emitting diode (LED) on retinal pigment epithelium (RPE) cell cultures, after two different exposure times. MATERIAL AND METHODS: ARPE-19 human RPE cell cultures were exposed to halogen, xenon, and LED light sources at a distance of 1.5 cm for 30 and 60 min with equal lumen output levels. Cells in the control group were not exposed. RPE cell cultures were compared in terms of cell viability, DNA damage, apoptosis rate, and IL-1ß, IL-6, and TNF- α levels. RESULTS: The halogen light group showed significantly more DNA damage, higher TNF-α, IL-1ß, and IL-6 levels, and lower viable cell count at 30 min compared to the control group. The rates of early and late apoptosis were also significantly higher at 60 min. There were no statistically significant differences in any of the parameters between the xenon and LED light sources and the control group at 30 or 60 min. CONCLUSION: New generation lights, xenon, and LED, seem to be safe in terms of RPE cells. Halogen light may cause toxic effects on RPE cells when used for a long time with maximal power output.

Analysis of energy saving lamps for use by photosensitive individuals.

Due to European legislation, the British government has begun the phase out of incandescent bulbs, to be replaced by energy-saving alternatives. The alternatives that are available on the market are Compact Fluorescent Lamps (CFL), Energy-Efficient Halogens (EEH) and Light Emitting Diodes (LED). Whilst previous research has shown that CFLs emit UVC, UVB and UVA, there is conflicting data available on whether double enveloped CFLs are a safer alternative to single enveloped CFLs for individuals suffering from photosensitivity. The emission spectra of 106 single enveloped CFLs and 65 double enveloped CFLs were measured. There were 17 different models of single enveloped CFLs, including lamps from 6 different manufacturers (ranging from 8-20 W) and 9 models of double enveloped CFLs from 6 different manufacturers (7-15 W). In addition, the emission spectra of 53 LEDs and 56 EEHs were also analysed. The LEDs consisted of 8 different models, from 3 manufacturers, spanning between 2.5 and 12 W. There were 11 models of EEH from 6 different manufacturers with wattages ranging from 28-70 W. In order to reduce sample bias, some bulbs were provided by the lighting industry federation and others were purchased randomly from local retailers. The results validate previous research in that considerable variation exists in the UV emitted from CFLs. This variation in UV levels is true, not only within different makes and models but also, surprisingly, within a box of 8 seemingly identical bulbs supplied by a single manufacturer. It was concluded that double enveloped CFLs do reduce the levels of UVC and UVB and therefore are a safer alternative for photosensitive individuals. However, as some double enveloped CFLs and EEHs do emit UVA at levels that provoke a reaction in the skin of UVA sensitive individuals, newly emerging LEDs that have minimal UV levels may provide a safer alternative.

Comparison of composite curing parameters: effects of light source and curing mode on conversion, temperature rise and polymerization shrinkage.

This study analyzed the degree of conversion, temperature increase and polymerization shrinkage of two hybrid composite materials polymerized with a halogen lamp using three illumination modes and a photopolymerization device based on blue light emitting diodes. The degree of conversion of Tetric Ceram (TC) (Ivoclar Vivadent) and Filtek Z 250 (F) (3M/ESPE) was measured by Fourier transformation infrared spectroscopy at the surface and 2-mm depth; temperature rise was measured by digital multimeter, and linear polymerization shrinkage was measured during cure by digital laser interferometry. Composite samples were illuminated by quartz-tungsten-halogen curing unit (QTH) (Astralis 7, Ivoclar Vivadent) under the following modes: "high power" (HH) 40 seconds at 750 mW/cm2, "low power" (HL) 40 seconds at 400 mW/cm2 and "pulse/soft-start" (HP) increasing from 150 to 400 mW/cm2 during 15 seconds followed by 25 seconds pulsating between 400 and 750 mW/cm2 in 2-second intervals and by light emitting diodes (LED) (Lux-o-Max, Akeda Dental) with emitted intensity 10 seconds at 50 mW/cm2 and 30 seconds at 150 mW/cm2. A significantly higher temperature increase was obtained for both materials using the HH curing mode of halogen light compared to the HP and HL modes and the LED curing unit after 40 seconds. Significantly lower temperature values after 10-second illumination were obtained when LED was used compared to all halogen modes. For all curing modes, there was no significant difference in temperature rise between 20 and 40 seconds of illumination. Results for the degree of conversion measurements show that there is a significant difference in the case of illumination of resin composite samples with LED at the surface and 2 mm depth. For polymerization shrinkage, lower values after 40 seconds were obtained using LED compared to QTH.

Comparison of temperature changes in the pulp chamber induced by various light curing units, in vitro.

This study compared the temperature increase in a pulp chamber as a result of using various light-curing units during resin composite polymerization, and it determined the effect of remaining dentin thickness on temperature rise. A Class II occlusodistal cavity with a remaining dentin thickness of 2 mm was prepared in an extracted human mandibular molar. A 2-mm layer of fine hybrid resin composite was placed on the floor of the proximal box. A K-type thermocouple was inserted into pulp chambers filled with heat sink compound, and pulp chamber temperature rise (starting temperature: 37.0 +/- 0.1 degrees C) during polymerization of the composite was measured. The light-curing units tested included two halogen lights, Spectrum 800 and Elipar Trilight (Standard and Exponential mode); a light-emitting diode (LED, Elipar Freelight) and a plasma arc (Virtuoso, Xenon Power Arc). Irradiation time was 40 seconds for the halogen and LED lights and 3 seconds for the plasma arc light. Five measurements were carried out for every light-curing unit. The same experimental design was conducted after the cavity preparation was modified, leaving a 1-mm thick dentin layer. The Kruskal-Wallis and multiple comparison tests were used to evaluate the differences among the tested curing units. Mann Whitney-U tests were used to compare the mean temperature rise in each curing unit for different remaining dentin thicknesses. The increase in pulp chamber temperature ranged between 1.40-3.8 degrees C. The highest temperature rise was observed when using Elipar Trilight Standard mode, and the lowest temperature rise was observed with light emitting diode for both remaining dentin thicknesses. The only significant differences in temperature rise were observed between Elipar Trilight Standard mode and LED. No significant difference (p > 0.01) existed for the different modes of Elipar Trilight. A statistically significant higher temperature rise was observed within each curing unit at a depth of 1 mm compared to 2 mm. Although the tested light-curing units caused a temperature rise in the pulp chamber, none exceed the critical value of 5.5 degrees C.

Temperature rise during orthodontic bonding with various light-curing units--an in vitro study.

The purpose of this in vitro study was to investigate the temperature changes in the pulp chamber during bracket bonding using three different light sources. Bracket bonding was performed on one lower first premolar and one lower central incisor at two different distances (surface and 10 mm). The measurements were taken with a J-type thermocouple wire, placed in the pulp chamber and connected to a data logger. Analysis of variance revealed that pulp chamber temperature changes were influenced by the light source, the tooth type, and the distance from the tip of the light guide to the bracket surface. Halogen induced significantly higher intrapulpal temperature changes than light-emitting diode and Xenon Plasma Arc (PAC) (P = .000). The temperature increase was significantly higher when the light-guide tip was positioned at the surface of the teeth than at the 10-mm distance with all light-curing units (P = .000). All light-curing units produced higher intrapulpal temperature increase in the mandibular incisor than in the premolar. Power PAC produced significantly higher heat changes in the incisor than in the premolar. Orthodontic bonding with different light-curing units did not exceed the critical 5.5 degrees C value for pulpal health.

Influence of heat from light curing units and dental composite polymerization on cells in vitro.

OBJECTIVES: The aim of the present study was to test the hypothesis that the use of a light curing unit (LCU) with high light power would result in a higher temperature and therefore a statistically significant lower number of living human gingiva fibroblasts within a pulp chamber model than the use of a light emitting diode (LED) LCU. MATERIALS AND METHODS: The composites Admira, Grandio, Filtek Supreme and Filtek Z250 were polymerized with the LCUs Swiss Master Light, Optilux 501 and an LED LCU prototype in a mould on top of a pulp chamber model. The temperature was recorded within the pulp chamber with a thermocouple. The cytotoxicity of the polymerized samples was tested by using the MTT test. RESULTS: In general there was no considerable difference in the temperature increase within the pulp chamber model for the different LCUs and composites. There was no statistically significant difference in the cell number (p=0.3767) when the different LCUs were used. CONCLUSIONS: Using a high power halogen LCU for a short time or a standard halogen or LED LCU for a longer time did not result in a considerable difference in the temperature increase or the number of living cells within a pulp chamber model. This study indicates not only that the temperature may have an effect on the living cells, but also that cells may be negatively affected by the unpolymerized composite or light of the LCUs.

Photocontact dermatitis and chloracne: two major occupational and environmental skin diseases induced by different actions of halogenated chemicals.

Among occupational and environmental disorders, contact or photocontact dermatitis and an acneiform eruption are two major skin disorders. Photocontact dermatitis was historically caused by various halogenated salicylanilides, while the acne is induced by halogenated aromatic hydrocarbons and thus called chloracne. Therefore, it should be noted that halogenated chemical compounds are important causative agents in the occupational and environmental medicine. In photocontact dermatitis, photoconjugation of epidermal cells with a photohaptenic halogenated chemical is the initial step. Langerhans cells serve as antigen-presenting cells and T cells sensitized by photoantigen-bearing Langerhans cells induce this photosensitivity. On the other hand, in chloracne, halogeneted hydrocarbons render keratinocytes of the outer root sheath and sebaceous duct hyperplastic. The dilated infundibulum of most hair follicles is then filled with comedone that consist of many accumulated layers of keratinized cells and sebum. Therefore, halogenated chemicals exhibit different actions, i.e. the induction of an immunologic consequence and the modulation of keratinocyte biology. These two conditions also provide good experimental models for investigating dermatology.

Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model.

The use of many halogenated alkanes such as carbon tetrachloride (CCl4), chloroform (CHCl3) or iodoform (CHI3), has been banned or severely restricted because of their distinct toxicity. Yet CCl4 continues to provide an important service today as a model substance to elucidate the mechanisms of action of hepatotoxic effects such as fatty degeneration, fibrosis, hepatocellular death, and carcinogenicity. In a matter of dose,exposure time, presence of potentiating agents, or age of the affected organism, regeneration can take place and lead to full recovery from liver damage. CCl4 is activated by cytochrome (CYP)2E1, CYP2B1 or CYP2B2, and possibly CYP3A, to form the trichloromethyl radical, CCl3*. This radical can bind to cellular molecules (nucleic acid, protein, lipid), impairing crucial cellular processes such as lipid metabolism, with the potential outcome of fatty degeneration (steatosis). Adduct formation between CCl3* and DNA is thought to function as initiator of hepatic cancer. This radical can also react with oxygen to form the trichloromethylperoxy radical CCl3OO*, a highly reactive species. CCl3OO* initiates the chain reaction of lipid peroxidation, which attacks and destroys polyunsaturated fatty acids, in particular those associated with phospholipids. This affects the permeabilities of mitochondrial, endoplasmic reticulum, and plasma membranes, resulting in the loss of cellular calcium sequestration and homeostasis, which can contribute heavily to subsequent cell damage. Among the degradation products of fatty acids are reactive aldehydes, especially 4-hydroxynonenal, which bind easily to functional groups of proteins and inhibit important enzyme activities. CCl4 intoxication also leads to hypomethylation of cellular components; in the case of RNA the outcome is thought to be inhibition of protein synthesis, in the case of phospholipids it plays a role in the inhibition of lipoprotein secretion. None of these processes per se is considered the ultimate cause of CCl4-induced cell death; it is by cooperation that they achieve a fatal outcome, provided the toxicant acts in a high single dose, or over longer periods of time at low doses. At the molecular level CCl4 activates tumor necrosis factor (TNF)alpha, nitric oxide (NO), and transforming growth factors (TGF)-alpha and -beta in the cell, processes that appear to direct the cell primarily toward (self-)destruction or fibrosis. TNFalpha pushes toward apoptosis, whereas the TGFs appear to direct toward fibrosis. Interleukin (IL)-6, although induced by TNFalpha, has a clearly antiapoptotic effect, and IL-10 also counteracts TNFalpha action. Thus, both interleukins have the potential to initiate recovery of the CCl4-damaged hepatocyte. Several of the above-mentioned toxication processes can be specifically interrupted with the use of antioxidants and mitogens, respectively, by restoring cellular methylation, or by preserving calcium sequestration. Chemicals that induce cytochromes that metabolize CCl4, or delay tissue regeneration when co-administered with CCl4 will potentiate its toxicity thoroughly, while appropriate CYP450 inhibitors will alleviate much of the toxicity. Oxygen partial pressure can also direct the course of CCl4 hepatotoxicity. Pressures between 5 and 35 mmHg favor lipid peroxidation, whereas absence of oxygen, as well as a partial pressure above 100 mmHg, both prevent lipid peroxidation entirely. Consequently, the location of CCl4-induced damage mirrors the oxygen gradient across the liver lobule. Mixed halogenated methanes and ethanes, found as so-called disinfection byproducts at low concentration in drinking water, elicit symptoms of toxicity very similar to carbon tetrachloride, including carcinogenicity.

[Induced acne]. / Acnés induites.

Induced acne belongs to the clinical forms of acne. Some dermatoses present with acne-like patterns. They can be induced or perpetuated by non physiological factors. Among these factors, medicines must always be considered, taken either topically (dermocorticoids, sulfur, anti-acneic topics) or generally (androgens, oral corticoids, ACTH, anti-epileptics, anti-depressive drugs, anti-tuberculosis medications). Halogens (iodine, bromine) found in inhaled or orally taken pharmaceutical products, or associated with occupational contact, can also induce acne. Acne of exogenous origin has been described in some specific occupations, and are induced by exposure to chlorine, industrial oils, tar. Sun exposure, PUVA therapy and ionizing radiation are potentially acneigenous. Finally acne caused by cosmetics includes acne cosmetica, brilliantine and oily creams acne and detergent acne.

Differential effects of dihalogenated and trihalogenated acetates in the liver of B6C3F1 mice.

Haloacetates are produced in the chlorination of drinking water in the range 10--100 microg l(-1). As bromide concentrations increase, brominated haloacetates such as bromodichloroacetate (BDCA), bromochloroacetate (BCA) and dibromoacetate (DBA) appear at higher concentrations than the chlorinated haloacetates: dichloroacetate (DCA) or trichloroacetate (TCA). Both DCA and TCA differ in their hepatic effects; TCA produces peroxisome proliferation as measured by increases in cyanide-insensitive acyl CoA oxidase activity, whereas DCA increases glycogen concentrations. In order to determine whether the brominated haloacetates DBA, BCA and BDCA resemble DCA or TCA more closely, mice were administered DBA, BCA and BDCA in the drinking water at concentrations of 0.2--3 g l(-1). Both BCA and DBA caused liver glycogen accumulation to a similar degree as DCA (12 weeks). The accumulation of glycogen occurred in cells scattered throughout the acinus in a pattern very similar to that observed in control mice. In contrast, TCA and low concentrations of BDCA (0.3 g l(-1)) reduced liver glycogen content, especially in the central lobular region. The high concentration of BDCA (3 g l(-1)) produced a pattern of glycogen distribution similar to that in DCA-treated and control mice. This effect with a high concentration of BDCA may be attributable to the metabolism of BDCA to DCA. All dihaloacetates reduced serum insulin levels. Conversely, trihaloacetates had no significant effects on serum insulin levels. Dibromoacetate was the only brominated haloacetate that consistently increased acyl-CoA oxidase activity and rates of cell replication in the liver. These results further distinguish the effects of the dihaloacetates from those of peroxisome proliferators like TCA.

Anestesia intravenosa total en pacientes sometidos a cirugía

El presente estudio se realizó en el Hospital Escuela Oscar Danilo Rosales Argüello con el fin de disminuir los peligros a que estan expuestos el personal que labora en sala de operaciones, por la exposición de halogenados. Con el objetivo de disminuir los riesgos se utilizó unicamente, farmacos intravenosos, con solo la utilización de oxígeno, que se suministra por medio de ambú con un litro de oxígeno. Los farmacos principales son Fentanyl, Ketamina, Droperidol y Diazepán; por lo que se denominó a la técnica como Neuroleptoanalgesia o Ataranalgesia, las que se pueden utilizar en quirofanos donde no hayan máquinas de anestesia o esten en mal estado

Dermatosis ocupacionales / Occupational dermatoses

Las dermatosis ocupacionales constituyen un amplio grupo de enfermedades que se presentan con frecuencia en la práctica dermatológica. Este artículo expone las patologías relacionadas con los diferentes ámbitos de la actividad laboral, sus aspectos clínicos más relevantes y los mecanismos etiopatogénicos involucrados

Drinking water chlorination by-products and cancer.

This review discusses the relation between by-products of drinking water chlorination and cancer in the light of present toxicological and epidemiologic evidence. During the chlorination of drinking water, a complex mixture of by-products forms from chlorine and the organic and inorganic compounds present in raw water. The quality and quantity of such compounds depend on the specific nature of the organic material in raw waters, the inorganic material in raw water, pH, temperature, other water treatment practices, and the chlorine timing and dose added. Chlorination by-products are important mainly when surface water is used for drinking water as more organic compounds are present in surface waters than in ground waters. The gastrointestinal and urinary tract are the cancer sites that are most often associated with the use of chlorinated surface water or with the quantity of chlorination by-products in the water-supply network. Yet the microbial quality of drinking water should not be compromised by excessive caution over the potential long-term effects of disinfection by-products because the risk of illness and death resulting from exposure to pathogens in untreated drinking water may be several orders of magnitude greater than the cancer risks from chlorination by-products.

[Involvement of enhanced glutamate release in halogenated volatile anesthetic-induced excitation in mouse brain].

The present experiments aimed to elucidate the mechanisms of excitatory effects of volatile anesthetics. In ddN mice, enflurane (2% in air), sevoflurane (2%) or isoflurane (1.2%) induced opisthotonus. In ddY mice, a halogenated ethane, tetrachlorodifluoroethane (CCl2FCCl2F:DF-112, 2%) induced tonic-clonic convulsion. These CNS excitatory effects were suppressed by pretreatment with an N-methyl-D-aspartate antagonist, MK-801 (0.5mg.kg-1). Halogenated volatile anesthetics (enflurane, sevoflurane, isoflurane and halothane) increased glutamate release from synaptosomes of the mouse cerebral cortex at concentrations corresponding to those used clinically. The convulsive gas, DF-112, released glutamate more potently than the anesthetics. These data suggest the involvement of enhanced glutamate release in the mechanisms of excitatory effects of halogenated volatile anesthetics.