Structure-activity relationship studies of CNS agents. Part 29. N-Methylpiperazino-substituted derivatives of quinazoline, phthalazine and quinoline as novel α1, 5-HT1A and 5-HT2A receptor ligands

New N-methylpiperazino-substituted quinazolines 8 and 9, phthalazine 13, and quinoline 19 have been synthesized. The receptor binding profiles (α₁, 5-HT_1A, 5-HT_2A) of these compounds and their analogs (7–22) have been determined. It has been demonstrated that orientation of a local dipole moment of the heteroaromatic ring system affects both the α₁ and 5-HT_2A affinity of the investigated class of ligands. Distortion of the coplanar unfused heteroaromatic ring system results in a decreased 5-HT_2A affinity. 4-(4-Methylpiperazino)-2-(2-thienyl)quinoline 18 is the most active and selective α₁ ligand (K_i = 4.9 nM) with a much lower affinity for 5-HT_1A (K_i = 3420 nM) and 5-HT_2A (K_i = 211 nM) receptors.     

Biological evaluation of intervertebral disc cells in different formulations of gellan gum‐based hydrogels

Gellan gum (GG)‐based hydrogels are advantageous in tissue engineering not only due to their ability to retain large quantities of water and provide a similar environment to that of natural extracellular matrix (ECM), but also because they can gelify in situ in seconds. Their mechanical properties can be fine‐tuned to mimic natural tissues such as the nucleus pulposus (NP). This study produced different formulations of GG hydrogels by mixing varying amounts of methacrylated (GG‐MA) and high‐acyl gellan gums (HA‐GG) for applications as acellular and cellular NP substitutes. The hydrogels were physicochemically characterized by dynamic mechanical analysis. Degradation and swelling abilities were assessed by soaking in a phosphate buffered saline solution for up to 170 h. Results showed that as HA‐GG content increased, the modulus of the hydrogels decreased. Moreover, increases in HA‐GG content induced greater weight loss in the GG‐MA/HA‐GG formulation compared to GG‐MA hydrogel. Potential cytotoxicity of the hydrogel was assessed by culturing rabbit NP cells up to 7 days. An MTS assay was performed by seeding rabbit NP cells onto the surface of 3D hydrogel disc formulations. Viability of rabbit NP cells encapsulated within the different hydrogel formulations was also evaluated by Calcein‐AM and ATP assays. Results showed that tunable GG‐MA/HA‐GG hydrogels were non‐cytotoxic and supported viability of rabbit NP cells. Copyright © 2012 John Wiley & Sons, Ltd.     

Surface shield: device to reduce personnel radiation exposure

A simple device is described that can reduce personnel exposure from scatter radiation by up to 75%. The device consists of an oblong piece of shielding (0.75-mm lead equivalent) that is taped to the side of the patient during percutaneous renal stone removal and other interventional procedures. Contrary to other shields and barriers, this does not interfere with access to the patient. Scatter exposure data from phantom studies are presented and the rationale for surface shielding discussed.     

Renal tubular transport of morphine, morphine-6-glucuronide, and morphine-3-glucuronide in the isolated perfused rat kidney.

The isolated perfused rat kidney was used to examine the renal handling of morphine and its inactive metabolite morphine-3-glucuronide (M3G), and active metabolite morphine-6-glucuronide (M6G). The kidneys were perfused with Krebs-Henseleit buffer (pH 7.4) containing albumin, glucose, and amino acids, and drug concentrations were measured by high performance liquid chromatography. There was no conversion of morphine to the glucuronides or deconjugation of M3G or M6G. At an initial morphine concentration of 100 ng/ml, the unbound renal clearance to glomerular filtration rate ratio (CLur/GFR) was 5.5 +/- 3.2 (mean +/- SD), indicating that net tubular secretion of morphine occurred. In the presence of M3G (2000 ng/ml) and M6G (500 ng/ml) this Clur/GFR ratio was elevated to 17.3 +/- 4.8 (p less than .001), which implicates an interaction between these compounds at an active reabsorption transport system. The CLur/GFR ratio for M3G at 2000 ng/ml was 0.90 +/- 0.04, indicating the possibility of a small component of tubular reabsorption, and this ratio was not significantly altered in the presence of morphine and M6G. M6G was reabsorbed, probably actively, to a greater extent than M3G, with an initial CLur/GFR ratio of 0.67 +/- 0.04, which was not affected when morphine and M3G were coadministered. These data demonstrate an unusual phenomenon in that the glucuronide metabolites, which are larger and less lipophilic than the parent drug morphine, undergo net tubular reabsorption. The renal handling of morphine is a complex combination of glomerular filtration, active tubular secretion, and possibly active reabsorption.     

Prognosis of patients with acute renal failure requiring dialysis: results of a multicenter study

Despite several decades of clinical experience, the mortality rate for patients with acute renal failure (ARF) requiring dialysis remains high, and the evaluation of the patients prognosis has been difficult. To date, the Acute Physiology and Chronic Health Evaluation II (APACHE II) scoring system has been used more frequently for prediction in studies of ARF than any other scoring system, but has not been prospectively validated in controlled multicenter studies of this entity. In a multicenter, prospective, controlled trial evaluating the use of biocompatible hemodialysis membranes (BCMs) in patients with ARF, we evaluated the extent to which the APACHE II scoring system, based on the physiological variables in the 24 hours before the onset of dialysis and the presence or absence of oliguria, is predictive of outcome. Analysis of survival and recovery of renal function for the 153 patients treated in this study show that APACHE II scores are predictive both of survival and recovery of renal function, whether analyzed separately by type of dialysis membrane used (BCM or bioincompatible [BICM]) or for both groups combined (all P < 0.01). There was no evidence of a significant center effect or interaction of APACHE II score with dialysis membrane in our study. After adjusting for the APACHE II score, there was a positive effect of the BCM on both probability of survival (P < 0.05) and recovery of renal function (P < 0.01). In patients dialyzed with BCMs, oliguria at onset of dialysis had an adverse effect on both survival and recovery of renal function (both P < 0.01). Receiver operator curves (ROCs) using APACHE II score and the use of BCMs in nonoliguric patients yielded a statistically significant improvement versus the use of APACHE II score alone in the area under the curve (AUC) for survival (0.747 to 0.801; P < 0.05) and recovery of renal function (0.712 to 0.775; P < 0.05). We conclude that the use of the APACHE II score determined at the time of initiation of dialysis for patients with ARF is a statistically significant predictor of patient survival and recovery of renal function. The use of the APACHE II score measured at the time of dialysis initiation, especially when modified by the presence or absence of oliguria, should help in predicting outcome when evaluating interventions for patients with ARF.     

The effects of cadmium on the self-administration of ethanol and an isocaloric/isohedonic equivalent

During a period of baseline fluid intake recording, adult male rats were presented with a three-bottle, two-fluid choice test that offered either a 10% ethanol solution (v/v) and tap water as alternatives, or a sucrose/quinine solution and tap water as alternatives. The sucrose/quinine solution was equivalent to the ethanol solution both in terms of calories and palatability. After intakes stabilized, half of the animals from each test condition were placed on a diet containing 100 ppm cadmium and the remaining half of the animals were placed on a standard laboratory diet. After 60 days of exposure to their respective diets, all animals were presented their earlier test solutions, both in a nonchoice and choice format. The results from the choice test indicated that although cadmium treatment did not produce a clear preference for ethanol over water, cadmium exposure was associated with a significant increase in ethanol consumption. Moreover, the self-administration of the isocaloric/isohedonic equivalent (sucrose/quinine solution) was unaffected by cadmium contamination. These data are discussed in terms of their implications for both nutritional and sensory-impairment accounts of metal-related changes in the volitional intake of ethanol.     

In vitro and in vivo selectin-blocking activities of sulfated lipids and sulfated sialyl compounds

There is accumulating evidence that sulfated lipids, sulfated oligosaccharides and other sulfated compounds are reactive with selectins in a manner that interferes with selectin interactions with their natural ligands. In the report we describe the ability of sulfated lipids (sulfatides and gangliosides) and multimeric forms of sulfated sialic acid to block binding of P- and E-selectin-Ig to neutrophils. The in vivo ability of these compounds to block lung injury in rats following i.v. infusion of purified cobra venom factor (CVF), which induces injury that is L- and P-selectin dependent, was also determined as well as effects on recruitment of neutrophils, as measured by lung myeloperoxidase. There was a significant correlation between the ability of sulfated lipids and sialyl compounds to interfere in vitro with P-selectin-Ig binding to neutrophils and to protect against P-selectin-dependent acute lung injury induced by CVF. The biological effects of these sulfated compounds were also associated with diminished accumulation of neutrophils. The protective effects of these compounds may be linked to their ability to interfere with P- selectin binding to counter-receptors on neutrophils.