Acetohydroxamic acid salts: mild, simple and effective degradation reagents to counter Novichok nerve agents.

Novichoks is the latest known class of organophosphorus nerve agents to be developed. These highly lethal persistent agents, which exert their toxicity mainly through dermal exposure, pose new major challenges in mitigating their effect, mainly in respect to decontamination and medical countermeasures. Herein we report on the effective degradation of Novichok agents (A-230, A-232 and A-234) by hydroxamic acid salts.

Highly sensitive chemiluminescence sensors for the detection and differentiation of chemical warfare agents.

Highly sensitive chemiluminescence-based probes that effectively detect and differentiate between the extremely toxic real G- and V-type organophosphorus chemical warfare agents (OPCWAs) are presented. This straightforward approach does not require any instrumentation or light source; hence, it appears ideal for the future development of field colorimetric detectors.

"Catch-up" therapy: combining antidotal treatment with dermal application of AHA following percutaneous VX poisoning in the domestic swine.

Low-volatility organophosphorus chemical warfare agents (OP CWAs) are cholinesterase inhibitors which easily absorb into the skin, leading to the formation of a dermal depot from which they slowly enter the bloodstream. This leads to sustained cholinergic hyperstimulation, which if untreated may lead to death. However, current available countermeasures are not adequate to neutralize the agent residing in the dermal depot.

Software-Assisted Automated Detection and Identification of "Unknown" Analogues: Implementation on V-Type Nerve Agents.

V-type nerve agents are among the most toxic organophosphorus chemical warfare agents, and they are under strict regulation and supervision by the OPCW (Organization for the Prohibition of Chemical Weapons). The V-type class of materials refers to a potentially large number of analogues and isomers. In order to expose instances of unfulfillment of the OPCW treaty, it is essential to have the ability to detect and identify "unknown" analogues of this family, even in the absence of an analytical standard.

Towards catch-up therapy: evaluation of nucleophilic active pharmaceutical ingredients for the treatment of percutaneous VX poisoning, in-vial and in-vitro studies.

Dermal exposure to low volatility organophosphorus chemical warfare agents (OP CWA) poses a great risk to the exposed person. Due to their lipophilic nature, these compounds rapidly absorb into the skin, leading to the formation of a "dermal reservoir" from which they slowly enter the bloodstream causing prolonged intoxication. Traditionally, strategies to counter the toxicity of such substances consist of chemical decontamination/physical removal of the residual agent from the skin surface (preferably as soon as possible following the exposure) and administration of antidotes in the case of intoxication signs.

Animal Models for In Vivo Lactation Studies: Anatomy, Physiology and Milk Compositions in the Most Used Non-Clinical Species: A Contribution from the ConcePTION Project.

The present review aims to summarize the main features of mammary gland anatomy, and the physiology of lactation and colostrum/milk in the most commonly used animal species for regulatory toxicity. The final goal is the selection of a preferred animal species to be enrolled in studies investigating the potential transfer of drugs and exogenous molecules through milk, within the Innovative Medicines Initiative (IMI) funded project ConcePTION. Reference data regarding humans were also collected and analyzed in order to highlight critical similarities and differences with the studied species.

Selective detection of chemical warfare agents VX and Sarin by the short wavelength inner filter technique (SWIFT).

A novel SWIFT-based strategy for fluorimetric detection of practical amounts (minimal effective dose or lower) of chemical warfare agents is reported. This strategy employs readily available reagents and allows distinguishing between the V and G agents, as well as their discrimination from potential interferents.

CFH, a Functional Group-Dependent Hydrogen-Bond Donor: Is It a More or Less Lipophilic Bioisostere of OH, SH, and CH?

The effects of the CFH moiety on H-bond (HB) acidity and lipophilicity of various compounds, when attached directly to an aromatic ring or to other functions like alkyls, ethers/thioethers, or electron-withdrawing groups, are discussed. It was found that the CFH group acts as a HB donor with a strong dependence on the attached functional group ( A = 0.035-0.

Physicochemical, biological, functional and toxicological characterization of the European follow-on glatiramer acetate product as compared with Copaxone.

For more than 20 years, Copaxone (glatiramer acetate, Teva), a non-biological complex drug, has been a safe and effective treatment option for multiple sclerosis. In 2016, a follow-on glatiramer acetate product (FOGA, Synthon) was approved in the EU. Traditional bulk-based methods and high-resolution assays were employed to evaluate the physicochemical, functional, and bio-recognition attributes, as well as the in vivo toxicity profile of the active substances in Copaxone and Synthon EU FOGA lots.

Synthesis, Characterization, and Reactivity of Thermally Stable Anhydrous Quaternary Ammonium Fluorides.

The synthesis and properties of a new class of anhydrous quaternary ammonium fluorides, based on the rigid skeleton azabicyclo[2.2.2]octane, is described.

Safety and PK/PD correlation of TV-1106, a recombinant fused human albumin-growth hormone, following repeat dose administration to monkeys.

Purpose: TV-1106 is a recombinant human albumin genetically fused to growth hormone which is intended to reduce the frequency of injections for GH therapy users. We report the safety, tolerability, pharmacokinetics and pharmacodynamics of repeated subcutaneous injections of TV-1106 in Cynomolgus monkeys.

Method: Cynomolgus monkeys received four weekly subcutaneous injections of 0, 5, 10 or 20mg/kg TV-1106 and were monitored for safety signals throughout the study.

Synthesis of γ-hydroxypropyl P-chirogenic (±)-phosphorus oxide derivatives by regioselective ring-opening of oxaphospholane 2-oxide precursors.

The synthesis of P-chirogenic (±)-phosphine oxides and phosphinates via selective nucleophilic ring opening of the corresponding oxaphospholanes is described. Two representative substrates: the phosphonate 2-ethoxy-1,2-oxaphospholane 2-oxide and the phosphinate 2-phenyl-1,2-oxaphospholane 2-oxide were reacted with various Grignard reagents to produce a single alkyl/aryl product. These products may possess further functionalities in addition to the phosphorus center such as the γ-hydroxypropyl group which results from the ring opening and π-donor moieties such as aryl, allyl, propargyl and allene which originates from the Grignard reagent.

Component mobility by a minute quantity of the appropriate solvent as a principal motif in the acceleration of solid-supported reactions.

The effects solvents have on fluoride-promoted heterogeneous hydrolysis and alcoholysis of various organo-phosphorus (OP) compounds on the surface of KF/Al2O3 are described. Solid-state magic angle spinning NMR analyses and SEM microscopy have shown that not only is the identity of the solvent important in these reactions but also its quantity. That is, minimal solvent amounts are favored and much more effective in such solid-supported reactions (and maybe generally) than those featuring solvent-free or excess solvent (>50 wt %) conditions.

Role of the P-F bond in fluoride-promoted aqueous VX hydrolysis: an experimental and theoretical study.

Following our ongoing studies on the reactivity of the fluoride ion toward organophosphorus compounds, we established that the extremely toxic and environmentally persistent chemical warfare agent VX (O-ethyl S-2-(diisopropylamino)ethyl methylphosphonothioate) is exclusively and rapidly degraded to the nontoxic product EMPA (ethyl methylphosphonic acid) even in dilute aqueous solutions of fluoride. The unique role of the P-F bond formation in the reaction mechanism was explored using both experimental and computational mechanistic studies. In most cases, the "G-analogue" (O-ethyl methylphosphonofluoridate, Et-G) was observed as an intermediate.

The mechanism of nucleophilic displacements at phosphorus in chloro-substituted methylphosphonate esters: P-O vs P-C bond cleavage: a DFT study.

Potential energy surfaces for the nucleophilic displacements at phosphorus in dimethyl methyl-, chloromethyl-, dichloromethyl-, and trichloromethylphosphonates have been computed at the B3LYP/6-31+G* level of theory, using IEF-PCM to account for the solvent effect. The results reveal that sequential addition of chlorine substituents on the methyl phosphonates increases the stability of transition states and intermediates which facilitate P-C bond cleavage. Thus, while nonsubstituted dimethyl methylphosphonate and dimethyl chloromethylphosphonate may undergo exclusive P-O bond cleavage, the trichlorinated analogue exclusively undergoes P-C bond dissociation.

Selective site controlled nucleophilic attacks in 5-membered ring phosphate esters: unusual C-O vs. common P-O bond cleavage.

Clean endocyclic C-O bond cleavage has been achieved in the reactions of 5-membered phosphate triesters with various nucleophiles.

A general method for preparation of metal carbenes via solution- and polymer-based approaches.

A new general, synthetically simple, and safe method for the preparation of metal carbene complexes, which is based on diphenyl sulfonium salts as carbenoid precursors, has been developed, and its scope and applications were studied. In general, deprotonation of a sulfonium salt with a base results in a sulfur ylide, which, in turn, reacts with an appropriate metal precursor to give the corresponding metal carbene complex. Thus, starting from benzyldiphenylsulfonium salt, the complexes (PCX)Rh=CHPh (X = P, N) were prepared in quantitative yield.

Localization of the gene for congenital dyserythropoietic anemia type I to a <1-cM interval on chromosome 15q15.1-15.3.

Congenital dyserythropoietic anemias (CDA) are a rare group of red-blood-cell disorders of unknown etiology that are characterized by ineffective erythropoiesis, pathognomonic cytopathology of the nucleated red blood cells in the bone marrow, and secondary hemochromatosis. In CDA type I, bone-marrow electron microscopy reveals characteristic findings in erythroid precursors, including spongy heterochromatin and enlarged nuclear pores. Since the genetic basis of CDA type I is not evident, we used homozygosity and linkage mapping to localize the genetic defect responsible for CDA type I in 25 Bedouins from four large consanguineous families.

Hexabromotricyclobutabenzene and hexabromohexaradialene: their nickel-mediated one-pot syntheses and crystal structure.

The reaction of hexakis(dibromomethyl)benzene with [(Bu3 P)2 -Ni(COD)] (COD = 1,5-cyclooctadiene) in DMF at 65-70°C yielded a mixture of the title compounds. The mixture was separated by column chromatography to yield hexabromotricyclobutabenzene (3 a) and hexabromohexaradialene (4) in 24 and 16% yields, respectively. (1) H and (13) C NMR spectroscopy suggest that 3 is obtained as the syn-all-trans isomer 3 a, and the symmetric anti-all-trans isomer 3 b is not obtained at all.

Serum B-N-acetyl hexosaminidase levels in rats with experimental acute pancreatitis, small-bowel ischemia, and small-bowel obstruction.

B-N-acetyl hexosaminidase (B-NAH), a lysosomal hydrolase, was measured in the blood of rats with induced acute pancreatitis, massive small-bowel ischemia, and small-bowel closed-loop obstruction. B-NAH was not significantly elevated within 24 h after induction of the above conditions. This suggests that B-NAH is not an acute phase reactant in a severe acute abdominal catastrophe, such as those mentioned above.