Conivaptan: a step forward in the treatment of hyponatremia?

Hyponatremia is one of the most common electrolyte abnormalities linked to adverse outcomes and increased mortality in hospitalized patients. While the differential diagnosis for hyponatremia is diverse, most cases stem from arginine vasopressin (AVP) dysregulation, where hypoosmolality fails to suppress AVP synthesis and release. The physiological effects of AVP are currently known to depend on its interaction with any of 3 receptor subtypes V1A, V2, and V1B. Activation of V2 by AVP is the key in renal water regulation and maintenance of total body volume and plasma tonicity. Despite the long-recognized problem with excess AVP in euvolemic and hypervolemic hyponatremia, traditional therapeutic options have relied on nonspecific and potentially problematic strategies. More recently, a new class of drugs, introduced as “aquaretics,” has gained great attention among clinicians because of its ability to correct hyponatremia via direct competitive inhibition of AVP at V2 receptors to induce renal electrolyte-free water excretion. In this paper, we aim to review available clinical data on the only FDA-approved aquaretic, dual V1A/V2 receptor antagonist conivaptan, discuss its clinical indications, efficacy, safety profile, and comment on its clinical limitations

Abacavir methanol 2.5-solvate

The structure of abacavir (systematic name: {(1S,4R)-4-[2-amino-6-(cyclo­propyl­amino)-9H-purin-9-yl]cyclo­pent-2-en-1-yl}methanol), C14H18N6O·2.5CH3OH, consists of hydrogen-bonded ribbons which are further held together by additional hydrogen bonds involving the hydroxyl group and two N atoms on an adjacent purine. The asymmetric unit also contains 2.5 mol­ecules of methanol solvate which were grossly disordered and were excluded using SQUEEZE subroutine in PLATON [Spek, (2009 ▶). Acta Cryst. D65, 148–155]

Computational identification and experimental characterization of substrate binding determinants of nucleotide pyrophosphatase/phosphodiesterase 7

<p>Abstract</p> <p>Background</p> <p>Nucleotide pyrophosphatase/phosphodiesterase 7 (NPP7) is the only member of the mammalian NPP enzyme family that has been confirmed to act as a sphingomyelinase, hydrolyzing sphingomyelin (SM) to form phosphocholine and ceramide. NPP7 additionally hydrolyzes lysophosphatidylcholine (LPC), a substrate preference shared with the NPP2/autotaxin(ATX) and NPP6 mammalian family members. This study utilizes a synergistic combination of molecular modeling validated by experimental site-directed mutagenesis to explore the molecular basis for the unique ability of NPP7 to hydrolyze SM.</p> <p>Results</p> <p>The catalytic function of NPP7 against SM, LPC, platelet activating factor (PAF) and para-nitrophenylphosphorylcholine (pNPPC) is impaired in the F275A mutant relative to wild type NPP7, but different impacts are noted for mutations at other sites. These results are consistent with a previously described role of F275 to interact with the choline headgroup, where all substrates share a common functionality. The L107F mutation showed enhanced hydrolysis of LPC, PAF and pNPPC but reduced hydrolysis of SM. Modeling suggests this difference can be explained by the gain of cation-pi interactions with the choline headgroups of all four substrates, opposed by increased steric crowding against the sphingoid tail of SM. Modeling also revealed that the long and flexible hydrophobic tails of substrates exhibit considerable dynamic flexibility in the binding pocket, reducing the entropic penalty that might otherwise be incurred upon substrate binding.</p> <p>Conclusions</p> <p>Substrate recognition by NPP7 includes several important contributions, ranging from cation-pi interactions between F275 and the choline headgroup of all substrates, to tail-group binding pockets that accommodate the inherent flexibility of the lipid hydrophobic tails. Two contributions to the unique ability of NPP7 to hydrolyze SM were identified. First, the second hydrophobic tail of SM occupies a second hydrophobic binding pocket. Second, the leucine residue present at position 107 contrasts with a conserved phenylalanine in NPP enzymes that do not utilize SM as a substrate, consistent with the observed reduction in SM hydrolysis by the NPP7-L107F mutant.</p

All-optical multimode fibre photoacoustic endomicroscopy with scalable spatial resolution and field-of-view

An all-optical, forward-viewing, optical-resolution photoacoustic endomicroscopy probe was developed for guiding minimally invasive procedures. The probe comprises a multimode fibre for the delivery of excitation laser via wavefront shaping, and a fibre-optic ultrasound sensor based on a plane-concave microresonator at the tip of a single-mode fibre. High-resolution photoacoustic microscopy images of mouse red blood cells and mouse ear vasculature were acquired, and the high scalability of the probe in terms of field-of-view and spatial resolution was demonstrated. The ultrathin photoacoustic endomicroscopy probe promises to guide minimally invasive surgery by providing both molecular and microstructural information

Targeting integrin αvβ6 with gallium-68 tris (hydroxypyridinone) based PET probes

Expression of the cellular transmembrane receptor αvβ6 integrin is mostly restricted to malignant epithelial cells in a wide variety of carcinomas, including pancreatic and others derived from epithelial tissues. Thus, this protein is considered an attractive target for tumour imaging and therapy. Two different (68)Ga hexadentate tris (3,4-hydroxypyridinone) (THP) chelators were produced in this study and coupled to the αvβ6 integrin–selective peptide cyclo(FRGDLAFp(NMe)K) via NHS chemistry. Radiolabelling experiments confirmed a high radiochemical yield of the two PET probes. In addition, cellular binding studies showed high binding affinities in the nanomolar range. The two integrin αvβ6-peptide-THP synthesized and radiolabeled in this study will facilitate in vivo monitoring of transmembrane receptor αvβ6 integrin by using the advantage of THP chemistry for rapid, efficient and stable gallium chelation

(1E,3E,5E,7E)-4,4′-(Octa-1,3,5,7-tetra­ene-1,8-di­yl)dipyridine

The title compound, C18H16N2, crystallizes with one and a half independent mol­ecules in the asymmetric unit, with the half-mol­ecule being completed by crystallographic inversion symmetry. Both independent mol­ecules are almost planar, with the non-H atoms exhibiting r.m.s. deviations from the least-squares mol­ecular plane of 0.175 and 0.118 Å, respectively

Effects of salinity and alkalinity on growth and survival of all-male giant freshwater prawn (Macrobrachium rosenbergii De Man, 1879) juveniles

All-male giant freshwater prawns (AMGFPs) have been a popular crop cultivated in the Mekong Delta, Vietnam, due to their proven production efficiency compared to all-female or mixed-sex prawn cultures. However, the crucial water quality factors impacting AMGFP aquaculture efficiency have yet to be elaborately investigated. Two separate experiments were randomly arranged with three replicates to evaluate the effects of salinity or alkalinity on the growth and survival of AMGFP juveniles during the grow-out period. The results show that the prawn survival rate in the salinity range of 0–15‰ varied from 66.1 to 74.8％ and in a salinity range of 0–5‰ was relatively low compared to the range of 10-15‰; however, the difference was not significant among salinities after 90 days of culture (p > 0.05). All the prawn growth performance parameters significantly decreased with increasing salinities of 0, 5, 10, and 15‰ after 30, 60, and 90 days of culture (p 0.05), and both were significantly higher than those at salinities of 10 and 15‰ (p < 0.05) after 90 days of culture. In addition, the survival rate reached 82.5–84.4％ and did not significantly differ among alkalinities of 80, 100, 120, 140, and 160 mgCaCO3 L−1. However, the growth performance parameters and yield of AMGFPs at an alkalinity of 160 mg L−1 were significantly higher than those at lower alkalinities (80, 100, 120, and 140 mg CaCO3 L−1) after 90 days of culture. Therefore, it is recommended that a salinity range of 0–5‰ and alkalinity of 160 mgCaCO3 L−1 is optimal for the growth-out culture of AMGFP juveniles

Versatile Diphosphine Chelators for Radiolabeling Peptides with ^99mTc and ⁶⁴Cu

We have developed a diphosphine (DP) platform for radiolabeling peptides with 99mTc and 64Cu for molecular SPECT and PET imaging, respectively. Two diphosphines, 2,3-bis(diphenylphosphino)maleic anhydride (DP Ph) and 2,3-bis(di- p-tolylphosphino)maleic anhydride (DP Tol), were each reacted with a Prostate Specific Membrane Antigen-targeted dipeptide (PSMAt) to yield the bioconjugates DP Ph-PSMAt and DP Tol-PSMAt, as well as an integrin-targeted cyclic peptide, RGD, to yield the bioconjugates DP Ph-RGD and DP Tol-RGD. Each of these DP-PSMAt conjugates formed geometric cis/ trans-[MO 2(DP X-PSMAt) 2] + (M = 99mTc, 99gTc, natRe; X = Ph, Tol) complexes when reacted with [MO 2] + motifs. Furthermore, both DP Ph-PSMAt and DP Tol-PSMAt could be formulated into kits containing reducing agent and buffer components, enabling preparation of the new radiotracers cis/ trans-[ 99mTcO 2(DP Ph-PSMAt) 2] + and cis/ trans-[ 99mTcO 2(DP Tol-PSMAt) 2] + from aqueous 99mTcO 4 - in 81% and 88% radiochemical yield (RCY), respectively, in 5 min at 100 °C. The consistently higher RCYs observed for cis/ trans-[ 99mTcO 2(DP Tol-PSMAt) 2] + are attributed to the increased reactivity of DP Tol-PSMAt over DP Ph-PSMAt. Both cis/ trans-[ 99mTcO 2(DP Ph-PSMAt) 2] + and cis/ trans-[ 99mTcO 2(DP Tol-PSMAt) 2] + exhibited high metabolic stability, and in vivo SPECT imaging in healthy mice revealed that both new radiotracers cleared rapidly from circulation, via a renal pathway. These new diphosphine bioconjugates also furnished [ 64Cu(DP X-PSMAt) 2] + (X = Ph, Tol) complexes rapidly, in a high RCY (&gt;95%), under mild conditions. In summary, the new DP platform is versatile: it enables straightforward functionalization of targeting peptides with a diphosphine chelator, and the resulting bioconjugates can be simply radiolabeled with both the SPECT and PET radionuclides, 99mTc and 64Cu, in high RCYs. Furthermore, the DP platform is amenable to derivatization to either increase the chelator reactivity with metallic radioisotopes or, alternatively, modify the radiotracer hydrophilicity. Functionalized diphosphine chelators thus have the potential to provide access to new molecular radiotracers for receptor-targeted imaging. </p