Hypoxia and standing balance.

PURPOSE: Standing balance control is important for everyday function and often goes unnoticed until impairments appear. Presently, more than 200 million people live at altitudes > 2500 m above sea level, and many others work at or travel to these elevations. Thus, it is important to understand how hypoxia alters balance owing to implications for occupations and travelers. Herein, the influence of normobaric and hypobaric hypoxia on standing balance control is reviewed and summarized. As postural control relies on the integration of sensorimotor signals, the potential hypoxic-sensitive neurophysiological factors that contribute to balance impairments are also reviewed. Specifically, we examine how hypoxia impairs visual, vestibular, and proprioceptive cues, and their integration within subcortical or cortical areas. METHODS: This systematic review included a literature search conducted via multiple databases with keywords related to postural balance, hypoxia, and altitude. Articles (n = 13) were included if they met distinct criteria. RESULTS: Compared to normoxia, normobaric hypoxia worsened parameters of standing balance by 2-10% and up to 83 and 240% in hypobaric hypoxia (high-altitude and lab-based, respectively). Although balance was only disrupted during normobaric hypoxia at FIO2 < ~ 0.15, impairments consistently occurred during hypobaric hypoxia at altitudes > 1524 m (~ FIO2 < 0.18). CONCLUSION: Hypoxia, especially hypobaric, impairs standing balance. The mechanisms underpinning postural decrements likely involve alterations to processing and integration of sensorimotor signals within subcortical or cortical structures involving visual, vestibular, and proprioceptive pathways and subsequent motor commands that direct postural adjustments. Future studies are required to determine the sensorimotor factors that may influence balance control in hypoxia.

Influence of microsomal concentration on apparent intrinsic clearance: implications for scaling in vitro data.

The influence of microsomal concentration on unbound fraction (fu(mic)), half-life (t(1/2)), apparent intrinsic clearance (CL(int,app)) and apparent Michaelis-Menten constant (K(m,app)) was examined for two compounds, one representative of high nonspecific binding to microsomes (compound A) and one representative of low (compound B). Kinetic parameters were estimated for the two probe compounds at two human microsomal protein concentrations (0.46 and 2.3 mg/ml) and cytochrome P450 concentrations (0.20 and 1.0 microM), representing a 5-fold difference in microsomal concentration. For compound A, fu(mic) and CL(int,app) were inversely proportional to microsomal concentration. Conversely, the K(m,app) of compound A was proportional to microsomal concentration and the half-life was unchanged. For compound B, half-life was inversely proportional to microsomal concentration. In this case, fu(mic), CL(int,app), and K(m,app) were not proportionally influenced. The experimental observations were entirely consistent with that predicted by a mathematical relationship between microsomal concentration, fu(mic), t(1/2), CL(int,app), and K(m,app). These results demonstrate that when nonspecific binding is extensive, CL(int,app) is dependent on the arbitrary choice of microsomal concentration included in the incubation.

Preclinical pharmacology of CP-424,391, an orally active pyrazolinone-piperidine [correction of pyrazolidinone-piperidine] growth hormone secretagogue.

Growth hormone secretagogues (GHSs) represent attractive therapeutic alternatives to recombinant growth hormone (GH), given their ability to amplify pulsatile hormone secretion in a relatively physiologic manner. CP-424,391 (391) is a novel, orally active pyrazolinone-piperidine [corrected] GHS. In rat pituitary cell cultures, 391 stimulated GH release with an EC50 = 3 nM. The addition of 391 to rat pituitary cells activated intracellular calcium signaling but did not elevate intracellular cyclic adenosine monophosphate (cAMP). 391 also modulated the effects of GH-releasing hormone and somatostatin on pituitary cell GH-release and intracellular signaling. In nonpituitary cell lines, the ability of 391 to stimulate intracellular signaling was dependent on the expression of recombinant human GHS receptor. Acute administration of 391 to anesthetized rats or to conscious dogs induced pulsatile release of G H in a dose-dependent manner. Plasma insulin-like growth factor-I (IGF-I) was elevated progressively over a 5-d course of daily oral dosing in dogs. Chronic oral administration of 391 augmented body weight gain in rats and dogs. Thus, the peptidomimetic GHS 391 has potential utility for the treatment of clinical conditions that could benefit from systemic augmentation of GH and IGF-I levels.

First-pass metabolism and biliary recirculation of droloxifene in the female Sprague-Dawley rat.

1. Utilizing a validated ultrasensitive hplc assay (lower limit of quantitation 25 pg/ml), we characterized the disposition profile of droloxifene in the female Sprague-Dawley rat following intravenous, oral and intraportal administration. 2. The site and extent of first-pass metabolism and the extent of enterohepatic recirculation were investigated. 3. Our findings suggest that the intestine is neither a metabolic nor an absorptive barrier to the bioavailability of droloxifene in the female Sprague-Dawley rat and that first-pass hepatic extraction is approximately 70-80% following an oral dose of 1 mg/kg. 4. Employment of a modified linked-rat model revealed that droloxifene is subject to enterohepatic recirculation (approximately 5%) in the rat.

Sensitive method for the quantitation of droloxifene in plasma and serum by high-performance liquid chromatography employing fluorimetric detection.

A simple and highly sensitive reversed-phase fluorimetric HPLC method for the quantitation of droloxifene from rat, monkey, and human plasma as well as human serum is described. This assay employs solid-phase extraction and has a dynamic range of 25 to 10,000 pg/ml. Sample extraction (efficiencies > 86%) was accomplished using a benzenesulfonic acid (SCX) column with water and methanol rinses. Droloxifene and internal standard were eluted with 1 ml of 3.5% (v/v) ammonium hydroxide (30%) in methanol. Samples were quantitated using post-column UV-photochemical cyclization coupled with fluorimetric detection with excitation and emission wavelengths of 260 nm and 375 nm, respectively. Relative ease of sample extraction and short run times allow for the analysis of approximately 100 samples per day.