Pharmacological profile of natural and synthetic compounds with rigid adamantane-based scaffolds as potential agents for the treatment of neurodegenerative diseases.

This review is dedicated to the comparative analysis of structure-activity relationships for more than 75 natural and synthetic derivatives of adamantane. Some of these compounds, such as amantadine and memantine, are currently used to treat dementia, Alzheimer's and Parkinson's diseases and other neurodegenerative diseases. The data presented show that the pharmacological potential of 1-fluoro- and 1-phosphonic acid adamantane derivatives against Alzheimer's and Parkinson's diseases and other neurodegenerative diseases exceeds those of well-known amantadine and memantine. The information presented in this review highlights the promising directions of studies for biochemists, pharmacologists, medicinal chemists, physiologists, and neurologists, as well as to the pharmaceutical industry.

Prostate-Specific Membrane Antigen-Targeted Radiohalogenated PET and Therapeutic Agents for Prostate Cancer.

Radiohalogenated agents are often the first line of pursuit in the development of new radiopharmaceuticals-whether antibodies, peptides, or small molecules-because of their ease of synthesis, lack of substantial steric perturbation of the original affinity agent (in some cases, providing enhanced affinity), and capacity to be transformed into therapeutics (in some cases, with a mere switch of an isotope). They often provide proof of a principle before optimization for pharmacokinetics or generation of radiometallated agents, when the latter are necessary. In particular, 18F has been well integrated into normal clinical work flow in the form of 18F-FDG for oncologic imaging, with reliable daily production and distribution to sites for immediate use, without the need for on-site preparation. Here we discuss radiohalogenated versions of imaging and therapeutic agents targeting the prostate-specific membrane antigen (PSMA); these were among the first such agents to be synthesized and used clinically. PSMA is highly expressed on prostate cancer epithelial cells and is currently being extensively investigated around the world as a target for imaging and therapy of prostate cancer. Additionally, the presence of PSMA on nonprostate tumor neovasculature has opened the possibility of PSMA-targeted molecules as generalizable cancer imaging and therapy agents. We focus on 18F-labeled agents for PET, as they begin to redefine-along with the corresponding 68Ga-labeled agents discussed elsewhere in this supplement to The Journal of Nuclear Medicine-the management of prostate cancer across a variety of clinical contexts.

Los Halógenos, ¿materia mineral farmacéutica? / Halogens: pharmaceutics mineral materia?

En 1906 se otorga el Premio Nobel de Química a Henri Moissan, primer farmacéuticoy primer francés en recibir tal distinción. Era el broche de oro de un largocapítulo en el que a través de más de cien años, Scheele (1774), Courtois (1813),Balard (1823) y Moissan (1886), todos ellos farmacéuticos, aíslan el cloro, iodo,bromo y flúor, respectivamente. Por esta razón se plantea el título del trabajo enclave de interrogante. La elucidación de su naturaleza demolió la teoría de laacidez de Lavoisier, y el descubrimiento del bromo contribuyó a aportar luz sobrela sistematización de los elementos químicos. Se aportan detalles de la vida de losdescubridores y, de la concesión del Premio Nobel a Moissan, que realizó la proezade domar a la bestia salvaje de los elementos químicos

In 1906 Henri Moissan was the first French person and first pharmacist to beawarded the Nobel Prize in Chemistry. It was the end of a large and gold chapterin which through more than a century, Scheele (1774), Courtois (1813), Balard(1823) and Moissan (1886), all of them pharmacists, isolated chlorine, iodine, bromine and fluorine, respectively. That is the reason why the title figures as aquestion. The elucidation of the halogen’s nature demolished the Lavoisier’s aciditytheory. Some aspects of the life of the discoverers are given. Moissan was able toisolate and study fluorine, that savage beast among the elements

Effect of incremental filling technique on adhesion of light-cured resin composite to cavity floor.

The purpose of this study was to evaluate the effect of various incremental filling techniques on adhesion between composite and cavity floor using light-cured resin composite. Black ABS resin and hybrid resin composite were used as mold materials--instead of dentin--for the preparation of cavities, and standardized to 5x5x5 mm. Each cavity was then treated with a bonding system (Clearfil SE bond). Resin composite (Clearfil Photo Core) was placed on the bonding resin using different incremental filling techniques or in bulk and irradiated for a total of 80 seconds using a halogen light unit. Specimens were subjected to the micro-tensile bond test at a crosshead speed of 1 mm/min. Data were analyzed by two-way ANOVA. The results indicated that an incremental filling technique was more effective in improving adhesion to the cavity floor than a bulk filling technique.

Radiohalogens for imaging and therapy.

Radiohalogens play a very important role in radiopharmaceuticals used for medical imaging (now referred to as molecular imaging) and therapy applications. Development of new radiopharmaceuticals that have radiohalogens incorporated requires an understanding of parameters that are unique to chemistry involving these radionuclides. Those parameters include requirement for production and purification of the halogen radionuclides, as well as development of reaction conditions for use with high specific activity short-lived radionuclides. In this tutorial review, several radiohalogens, their radiolabeling chemistry and their application to medical imaging and therapy are discussed.

DOTA-D-Tyr(1)-octreotate: a somatostatin analogue for labeling with metal and halogen radionuclides for cancer imaging and therapy.

The goal of this study was to evaluate a somatostatin receptor ligand, DOTA-D-Tyr(1)-octreotate (DOTA-DY1-TATE), that has the chelator 1,4,7,10-tetraazacyclotetradecane-N,N',N'',N'"-tetraacetic acid (DOTA) attached to the D-Tyr(1) residue, allowing radiolabeling with both radiohalogens and radiometals. A potential advantage of having a chelator attached to the Tyr(1) residue is that halogen radiolabels may residualize or remain trapped in tumor cells rather than clear from the tumor. DOTA-DY1-TATE was synthesized by solid-phase methods and radiolabeled with (61)Cu, (64)Cu, and (125)I in high radiochemical purity and specific activity. A competitive binding assay demonstrated that (nat)Cu-DOTA-DY1-TATE and DOTA-(nat)I-DY1-TATE had comparable affinity to (nat)In-DTPA-OC in AR42J rat pancreatic tumor cells membranes. (61)Cu-DOTA-DY1-TATE had a dissociation constant (K(d)) of 176.4 pM and a receptor concentration (B(max)) of 244.4 fmol/mg. A tumor uptake of 1.515 %ID/g was determined for (64)Cu-DOTA-DY1-TATE and 0.814 %ID/g for DOTA-(125)I-DY1-TATE in AR42J tumor bearing Lewis rats at 1 h postinjection. DOTA-(125)I-DY1-TATE remained in the tumor at a higher concentration out to 4 h postinjection, suggesting that the iodine may have residualized in the tumor cells. MicroPET imaging of (64)Cu-DOTA-DY1-TATE in AR42J tumor bearing rats and SCID mice at 2 h postinjection showed significant uptake and good contrast in the thigh tumors in the rat model and in the neck and thigh tumors of the mouse. This study demonstrates that DOTA-DY1-TATE is a somatostatin analogue that can be labeled with both metal and halogen radionuclides, and its (64)Cu- and (125)I-radiolabeled compounds showed somatostatin receptor-mediated uptake in normal and tumor tissues.

(Z)-1,4-diamino-2-butene as a vector of boron, fluorine, or iodine for cancer therapy and imaging: synthesis and biological evaluation.

Polyamine vectors are attractive for tumor targeting. We envisaged (Z)-1,4-diamino-2-butene (Z-DAB), an unsaturated analogue of putrescine as vector of (10)B, (18)F and (131)I for boron neutron capture therapy (BNCT), and tumor imaging by positron emission tomography or scintigraphy respectively. In the present work, the synthesis and characterization of new derivatives of Z-DAB were reported. Z-DAB was actively transported in cells via the polyamine transport system and converted into the spermidine analogue.(E)-2-iodo-1,4-diamino-2-butene (E-I-DAB) was not taken up by the polyamine transport system and may not be suitable for tumor imaging. In contrast, (Z)-2-[4-(5,5-dimethyl-dioxaborinan-2-yl)phenyl]methyl-1,4-diamino-2-butene (Z-4-Bbz-DAB) was a substrate of the transport system and allowed significant boron accumulation in 3LL cells. Its potential in BNCT will be evaluated.

Improvement of poult performance following Bordetella avium challenge by administration of a novel oxy-halogen formulation.

The ability of a novel oxy-halogen formulation (OHF) to alter the development of bordetellosis (turkey coryza) in large white turkey poults was assessed. Bordetella avium (BA)-infected (1-day-of-age) and noninfected control poults received 0, 0.008%, or 0.016% of an OHF continuously in the drinking water. At 4, 7, 10, 14, and 17 days of age, reisolation of BA from infected poults was attempted. Infected poults receiving 0.016% OHF exhibited significantly lower cumulative BA reisolation rates (90%) when compared with infected poults receiving 0 (96.7%) or 0.008% OHF (100%). At 7, 14, and 17 days of age, infected poults in the OHF-treated groups were significantly heavier than those BA-challenged poults receiving control water. Feed utilization was significantly improved from hatch to 7 days of age in BA-infected poults receiving OHF when compared with infected poults receiving control water. Clinical symptoms were severe only in untreated, infected poults and were mild or absent in all others. Damage to the tracheal epithelium, as measured by scanning electron microscopy, paralleled the clinical signs. Tracheal epithelial damage was virtually eliminated by OHF administration in infected poults. These results suggest that OHF treatment ameliorates many of the symptoms frequently associated with bordetellosis in young turkeys.

Actualización en hipertemia maligna / Actualization in malignant hyperthemia

Se presenta una revisión de una entidad nosológica poco frecuente pero de alta letalidad haciendo énfasis el los hallazgos recientes en los métodos diagnósticos, fisopatología, bases genéticas y manejo terapeútico

[The search for new antiparasitic agents. 9. The anthelmintic activity of halogen-containing sulfonamidobenzamides]. / Izyskanie novykh protivoparazitarnykh sredstv. 9. Protivogel'mintnaia aktivnost' galoidsoderzhashchikh sul'fonamidobenzamidov.

The results of preclinical trials of 28 new compounds of haloid-containing sulfamidobenzamides with low toxicity are presented. The trials on a hymenolepiasis model showed that effectiveness of N-(2,5-dichlorophenyl)-2/(3-nitro-4-chlorophenyl) sulfonylamino/-5-bromobenzamide was similar to that of the well-known drug niclosamide. In the trials on an opisthorchiasis model, 2 compounds were shown to be highly effective, and on a trichocephaliasis model 5 compounds showed a high activity.

Pyrimidinones. 1. 2-Amino-5-halo-6-aryl-4(3H)-pyrimidinones. Interferon-inducing antiviral agents.

Interferon induction and antiviral activity was discovered with 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone. An analogue study incorporating a series of 2-amino-5-substituted-6-arylpyrimidinones revealed that the most potent interferon inducers were mono- and difluorophenyl analogues. These same analogues were also potent antiviral agents against Semliki Forest virus and herpes simplex type 1. In addition the monomethoxyphenyl analogues were potent antiviral agents but weak interferon inducers. Relatively modest structural changes led to dramatic changes in bioactivity. There was a relatively poor correlation between levels of circulating interferons induced and systemic antiviral activity.

5-(Haloalkyl)-2'-deoxyuridines: a novel type of potent antiviral nucleoside analogue.

Syntheses of 5-(2-haloethyl)-2'-deoxyuridines, 5-(3-chloropropyl)-2'-deoxyuridines, and 5-(2-chloroethyl)-2'-deoxycytidine are described. The antiviral activities of these compounds were determined in cell culture against herpes simplex virus types 1 and 2. All compounds were shown to possess significant and selective antiviral activity. The most potent derivative, 5-(2-chloroethyl)-2'-deoxyuridine (CEDU), inhibited HSV-1 at concentrations below 0.1 microgram/mL. It exerted measurable inhibitory effects on cell proliferation only at concentrations higher than 100 micrograms/mL. In vivo CEDU reduced the mortality rate of HSV-1-infected mice at concentrations lower than 5 mg/kg per day when given intraperitoneally and orally. Thus, it proved to be more effective in this in vivo model than the reference compounds (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and 9-[(2-hydroxyethoxy)methyl]guanine (ACV).

Antimalarial phenanthrene amino alcohols. 3. Halogen-containing 9-phenanthrenemethanols.

A series of new 9-phenanthrene amino alcohols has been prepared in which each compound bears from one to five halogen or halogen-containing moieties. A number of these compounds are extremely active against Plasmodium berghei in the mouse. Some structural requirements for optimal efficacy are considered.