Microtubule-associated protein tau in development, degeneration and protection of neurons

As a principal neuronal microtubule-associated protein, tau has been recognized to play major roles in promoting microtubule assembly and stabilizing the microtubules and to maintain the normal morphology of the neurons. Recent studies suggest that tau, upon alternative mRNA splicing and multiple posttranslational modifications, may participate in the regulations of intracellular signal transduction, development and viability of the neurons. Furthermore, tau gene mutations, aberrant mRNA splicing and abnormal posttranslational modifications, such as hyperphosphorylation, have also been found in a number of neurodegenerative disorders, collectively known as tauopathies. Therefore, changes in expression of the tau gene, alternative splicing of its mRNA and its posttranslational modification can modulate the normal architecture and functions of neurons as well as in a situation of tauopathies, such as Alzheimer's disease. The primary aim of this review is to summarize the latest developments and perspectives in our understanding about the roles of tau, especially hyperphosphorylation, in the development, degeneration and protection of neurons.     

Phase I clinical trial and pharmacokinetic evaluation of NK911, a micelle-encapsulated doxorubicin

NK911 is a novel supramolecular nanocarrier designed for the enhanced delivery of doxorubicin (DXR) and is one of the successful polymer micelle systems to exhibit an efficient accumulation in solid tumours in mice. The purpose of this study was to define the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of NK911 and to evaluate its pharmacokinetic profile in man. NK911 was given intravenously to patients with solid tumours every 3 weeks using an infusion pump at a rate of 10 mg DXR equivalent min(-1). The starting dose was 6 mg DXR equivalent m(-2), and the dose was escalated according to the accelerated titration method. A total of 23 patients participated in this study. Neutropenia was the predominant haematological toxicity, and grade 3 or 4 neutropenia was observed at doses of 50 and 67 mg m(-2). Common nonhaematological toxicities were mild alopecia, stomatitis, and anorexia. In the dose identification part of the study, DLTs were observed at a dose of 67 mg m(-2) (grade 4 neutropenia lasting more than 5 days). Thus, this dosage level was determined to be the MTD. Infusion-related reactions were not observed in any cases. The C(5 min) and area under the concentration curve parameters of NK911 exhibited dose-dependent characteristics. Among the 23 patients, a partial response was obtained in one patient with metastatic pancreatic cancer. NK911 was well tolerated and produced only moderate nausea and vomiting at myelosuppressive dosages. The recommended phase II dose was determined to be 50 mg m(-2) every 3 weeks.     

The influence of molecular structure on the affinity and efficacy of some β-adrenoceptor agonists

Summary The affinity and efficacy of a number of sympathomimetic amines structurally related to prenalterol and the selective 911n8n1518p20p6/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">₁-adrenoceptor agonist RO 363 were determined using a combination of radioligand binding and organ bath techniques. Affinity of the molecules (pK _D) was calculated from their ability to displace the radioligand [¹²⁵I]iodocyanopindolol ([¹²⁵I]CYP) from 911n8n1518p20p6/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenoceptor sites in left atrial (911n8n1518p20p6/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">₁) and uterine (911n8n1518p20p6/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">₂) membrane homogenates. These pK _D values were used to calculate efficacy from the positive inotropic and uterine relaxant responses elicited by the drugs in organ bath experiments. The drugs studied were either arylethanolamines i.e., (–)-isoprenaline (ISO), p-hydroxyisoprenaline (pOH-ISO), compounds XIV and XVI or aryloxypropanolamine-derivatives, i.e., oxymethylene-isoprenaline (OM-ISO), prenalterol and Compound XI which possessed ap-phenol or catechol ring and an isopropyl or a homoveratryl amine substituent. Only ISO, OM-ISO, pOH-ISO and Compound XVI were active as agonists in both tissue preparations. These drugs were partial agonists which exhibited a wide range of pD₂ values and did not display any marked selectivity for either 911n8n1518p20p6/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenoceptor subtype. Compound XI and prenalterol were inactive as agonists and together with the partial agonists behaved as competitive antagonists to ISO in the two preparations. All drugs tested displaced [¹²⁵I]CYP from 911n8n1518p20p6/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenoceptor sites, however, there was also a wide range of potency amongst the drugs.Analysis of the structure-affinity and structure-efficacy relationships indicated that removal of the 3-hydroxyl group from the catechol ring reduces both affinity and efficacy without altering the selectivity of the drug for either 911n8n1518p20p6/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenoceptor subtype. While aryloxypropanolamine derivatives have generally higher affinities than arylethanol-amines, especially at 911n8n1518p20p6/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenoceptor sites, their efficacies are generally reduced at both 911n8n1518p20p6/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenoceptors. The presence of a homoveratryl group in aryloxypropanolamines enhances slightly the affinity for 911n8n1518p20p6/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">₁- and reduces affinity for 911n8n1518p20p6/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">₂-adrenoceptors. With this amine group, efficacy is markedly reduced at 911n8n1518p20p6/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">₂- as opposed to 911n8n1518p20p6/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">₂-adrenoceptor sites.Thus for prenalterol, the small degree of cardioselectivity can be attributed to the oxymethylene group whilst its lack of agonist activity (i.e., efficacy) reflects a combined action of this group and the absence of the 3-hydroxyl group on the phenyl ring. In RO363 it can be deduced that the oxymethylene group, together with the homoveratryl substituent are responsible for the observed selective affinity of the drug for 911n8n1518p20p6/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">₁- as opposed to 911n8n1518p20p6/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">₂-adrenoceptors.     

Pharmaceutical and Biomedical Differences between Micellar Doxorubicin (NK911) and Liposomal Doxorubicin (Doxil)

The stability and biological behavior of an in vitro system of doxorubicin (DXR) entrapped in NK911, polymer micelles, was examined and compared with those of DXR entrapped in Doxil, polyethylene-glycol-conjugated liposomes. The fluorescence of DXR inside micelles or liposomes in an aqueous solution is known to be strongly quenched by the outer shells of the micellar or liposomal formation. Thus, by measuring the fluorescence intensity of DXR released from NK911 or Doxil, we could determine the stability of the micellar or liposomal DXR formation. Furthermore, NK911 was found to be less stable than Doxil in saline solution. In drug distribution experiments using an in vitro solid tumor model, when spheroids formed from two human colonic cancer lines, HT-29 and WiDr, and a human stomach cancer line, MKN28, were exposed to NK911, DXR was distributed throughout the spheroids, including their center. On the other hand, when the spheroids were exposed to Doxil, DXR was distributed only to the surface of the spheroids. It has been suggested that Doxil can deliver DXR to a solid tumor more efficiently than NK911 via the EPR (enhanced permeability and retention) effect, because Doxil may be more stable in plasma than NK911. On the other hand, DXR packed in NK911 may be distributed by diffusion to cancer cells distant from the tumor vessel, because NK911 can leak out of the tumor vessel and may be able to release free DXR more easily than Doxil. It has been suggested that drug carrier systems such as liposomes and micelles should be selected appropriately bearing in mind the characteristics of the tumor vasculature and the tumor interstitium.     

Ventilator use by emergency medical services during 911 calls in the United States

Background

Emergency and transport ventilators use in the prehospital field is not well described. This study examines trends of ventilator use by EMS agencies during 911 calls in the United States and identifies factors associated with this use.

Access to Care and Health Outcomes Among Women Veterans Using Veterans Administration Health Care: Association With Food Insufficiency

Background

Food insecurity has been associated with worse health outcomes in the civilian population. Male veterans of the Gulf Wars have been shown to have a higher prevalence of food insecurity than similarly situated civilians. Women veterans have more risk factors for food insecurity, relative to male veterans, yet little is known about the prevalence of food insecurity in this cohort.