Pharmacokinetic and Pharmacodynamic Properties of a Micro-Dose Nasal Spray Formulation of Desmopressin (AV002) in Healthy Water-Loaded Subjects

Pharmaceutical Research - For some biological systems, there exist several models with somewhat different features and perspectives. We propose an evaluation method for NLME models by analyzing...     

Vascular Assessment in Patients With a Lower Limb Wound: A Correlational Study of Photoplethysmography and Laser Doppler Flowmetry Toe Pressure Techniques

Background:Vascular assessment of the lower limbs is essential in patients with diabetes. In the presence of noncompressible arteries, the ankle brachial index (ABI) can either be inconclusive or provide false-positive results. Toe pressure measurement has been suggested as an alternative as a noninvasive method for detecting peripheral arterial disease (PAD). Toe pressure measurement can be performed either by photoplethysmography (PPG) or by Laser Doppler flowmetry (LDF). The aim of this study was to determine correlations between the two techniques in order to promote the use of PPG in clinical practice.Methods:This was a prospective correlational study of 108 consecutive recruited adult patients, with and without diabetes, with at least one lower limb wound from a University-affiliated hospital wound care clinic. Toe pressure measurements were both performed with PPG and LDF devices.Results:Mean toe pressure values for PPG and LDF were, respectively, 83.7 (SD 35.4) and 79.5 (SD 32.0) mmHg (with a paired t-test 3.969, P < 0.01). In patients with at least one lower limb wound, a strong linear relation was found between PPG and LDF toe pressure techniques with a Pearson’s r correlation coefficient of 0.920 (P < 0.001).Conclusions:PPG and LDF toe pressure techniques are equivalent in patients with at least one lower limb wound, irrespective of the presence of diabetes. Therefore, in the presence of an ABI with inconclusive results, such as in a patient with noncompressible vessels, both toe pressure techniques can be used for assessing the vascular supply of the lower limb with a wound.     

Susceptibility of Escherichia coli to the amoxycillin–clavulanate combination: which recommendations should be used to provide relevant information to clinicians?

This study compared MIC distributions of amoxycillin-clavulanate obtained with NCCLS and French (Comite de l'Antibiogramme de la Societe Francaise de Microbiologie; CA-SFM) methodologies for Escherichia coli isolates from urine that were non-susceptible to amoxycillin-clavulanate by the disk diffusion method. With the NCCLS and CA-SFM methods, 74% and 13%, respectively, of these isolates were susceptible to amoxycillin-clavulanate. Therefore, the apparent relatively poor efficacy of amoxycillin-clavulanate against E. coli in French hospitals probably reflects a methodological difference rather than a localised resistance problem. This implies that amoxycillin-clavulanate could be used as an alternative to fluoroquinolones for treatment of E. coli urinary tract infections. Susceptibility tests for amoxycillin-clavulanate should be standardised worldwide.     

The effect of dichloroacetate and alanine on the metabolic recovery of perfused mouse liver after cold ischemia.

Pyruvate dehydrogenase has been thought to be involved in the improved recovery of livers, from fasted donors, reperfused with alanine after cold preservation. The aim of this work was to investigate the effect on perfused mouse liver of dichloroacetate, an activator of this enzyme. Livers from fed and fasted animals were perfused with oxygenated Krebs-Henseleit buffer for 30 min, then stored at 4 degrees C in University of Wisconsin solution for 48 h. Then reperfusion at 37 degrees C was performed with Krebs-Henseleit buffer containing 2 mM dichloroacetate for 1 h. (3-(13)C)Alanine (8 mM) was then added and perfusion was continued for a second hour. (31)P-NMR was used to measure nucleoside triphosphate recovery of the livers. At the end of reperfusion, (13)C-NMR spectra of perfusates were recorded. Dichloroacetate (DCA) was found to activate pyruvate dehydrogenase in all cases. However, it decreased the functional recovery of livers from both fed and fasted mice. In order to study the effect of alanine on this DCA deleterious effect, we reperfused the livers according to a modified protocol. The first hour of perfusion without alanine was omitted and the organs were reperfused directly for 1 h in the presence of 2 mM dichloroacetate and 8 mM (3-(13)C)alanine. In this protocol, the deleterious effect of DCA was completely suppressed for livers from fasted mice. These results led to the conclusion that the specific beneficial effect of alanine on livers from fasted livers persists in the presence of DCA and thus cannot be explained solely by the induction of a greater pyruvate dehydrogenase reaction rate.     

Targeting heterogeneous nuclear ribonucleoparticule A1 and A2 proteins by RNA interference promotes cell death in transformed but not in normal mouse cell lines

The heterogeneous nuclear ribonucleoparticule A1 and A2 proteins can bind to vertebrate single-stranded telomeric sequences. Moreover, changes in the levels of heterogeneous nuclear ribonucleoparticule A1 can influence telomere length in mouse and human cells. We have shown previously that the combined knockdown of A1 and A2 proteins in human transformed cells promotes apoptosis. In contrast, a similar reduction in A1 and A2 expression in normal mortal human cell lines does not induce cell death. Here, we show that a variety of mouse cell lines display a similar behavior on reduction of A1 and A2 protein levels using small interfering RNA. In addition, the expression of the mouse A1 cDNA protects human HeLa cells from apoptosis when human A1 and A2 proteins are targeted by RNA interference. Lastly, we show that knockdown of A1 and A2 expression also impairs the growth of a human transformed cell line that does not express telomerase. These results firmly establish A1 and A2 as proteins required for the viability of transformed murine and human cells, irrespective of the status of telomerase expression or the length of the double-stranded telomeric repeat.