Pharmacokinetics of single intravenous and oral doses of dolasetron mesylate in healthy elderly volunteers

Dolasetron mesylate (MDL 73,147EF, Anzemet; Hoechst Marion Roussel, Laval, Canada) is a 5-HT3 receptor antagonist undergoing clinical evaluation for use as an antiemetic agent. The pharmacokinetics of dolasetron and its reduced metabolite (MDL 74,156) were studied after administration of single intravenous and oral doses of dolasetron mesylate 2.4 mg/kg in 18 healthy elderly subjects. Expressed as the dolasetron base, this dose was 1.8 mg/kg. Dolasetron was rapidly metabolized to the reduced metabolite, which appeared in plasma within 10 minutes after intravenous or oral administration. The mean half-life (t1/2) of dolasetron was 0.24 hours after intravenous administration and 0.50 hours after oral administration. The pharmacokinetic parameters of the reduced metabolite were similar after intravenous and oral administration. The apparent absolute bioavailability of the reduced metabolite was 89%, and it had an elimination t1/2 of approximately 7 hours and an apparent volume of distribution (Vd beta) of 4.69 L/kg. Dolasetron was not detected in urine. Metabolites were excreted in urine almost completely within 24 hours of administration. The primary metabolite detected in urine was the (+)-enantiomer of the reduced metabolite, which accounted for 25.35% (+/- 7.79%) and 18.88% (+/- 7.65%) of the intravenous and oral doses, respectively. Hydroxylated metabolites accounted for 5% or less of the total dose via either route. The pharmacokinetics of the reduced metabolite after single intravenous or oral doses in elderly volunteers were consistent with pharmacokinetics observed in both young healthy men and cancer patients receiving high-dose cisplatin chemotherapy. Dosage adjustments of dolasetron mesylate on the basis of age do not appear to be necessary.     

Respiratory muscle work compromises leg blood flow during maximal exercise

We hypothesized that during exercise at maximal O2 consumption (VO2max), high demand for respiratory muscle blood flow (Q) would elicit locomotor muscle vasoconstriction and compromise limb Q. Seven male cyclists (VO2max 64 +/- 6 ml.kg-1.min-1) each completed 14 exercise bouts of 2.5-min duration at VO2max on a cycle ergometer during two testing sessions. Inspiratory muscle work was either 1) reduced via a proportional-assist ventilator, 2) increased via graded resistive loads, or 3) was not manipulated (control). Arterial (brachial) and venous (femoral) blood samples, arterial blood pressure, leg Q (Qlegs; thermodilution), esophageal pressure, and O2 consumption (VO2) were measured. Within each subject and across all subjects, at constant maximal work rate, significant correlations existed (r = 0.74-0.90; P < 0.05) between work of breathing (Wb) and Qlegs (inverse), leg vascular resistance (LVR), and leg VO2 (VO2legs; inverse), and between LVR and norepinephrine spillover. Mean arterial pressure did not change with changes in Wb nor did tidal volume or minute ventilation. For a +/-50% change from control in Wb, Qlegs changed 2 l/min or 11% of control, LVR changed 13% of control, and O2 extraction did not change; thus VO2legs changed 0.4 l/min or 10% of control. Total VO2max was unchanged with loading but fell 9.3% with unloading; thus VO2legs as a percentage of total VO2max was 81% in control, increased to 89% with respiratory muscle unloading, and decreased to 71% with respiratory muscle loading. We conclude that Wb normally incurred during maximal exercise causes vasoconstriction in locomotor muscles and compromises locomotor muscle perfusion and VO2.     

Sensitivity of frequency dependence of lung compliance in detecting uneven time constants

We have evaluated the sensitivity of frequency dependence (spon-1.5 Hz) of dynamic compliance (Cdyn) and pulmonary resistance (RL) by introducing two bronchial catheters in dog's lungs. We measured the differential bronchial pressure (Pbr) and defined the transfer ratio (H) as Pbr/Ppleural at points of zero mouth flow. Calculations predict H to be more sensitive compared to Cdyn or RL. We infused 0.5 and 2.0 ?g/(kg-min) histsnine to cause small airways constriction. With the larger dose, Cdyn, RL, and H all became frequency dependent with no change in RL(spon). With the smaller dose, H(spon) changed throughout the infusion , pnd, had different values from control at 30, 60, and 90breaths/min. However, Hwas frequency dependent in control suggesting that it is sensitive to interlobal anatomical differences. We conclude that the frequency Dependence of Cdyn is the most specific test for detecting small airways constriction.     

Control Sensor Linearization Using Artificial Neural Networks

Traditionally, the issues of cost, size, and weight of artificial neural network implementations have not been the primary concern of researchers. These issues are important in many applications such as those required in space travel, high-volume commercial products, or products with size limitations. In this paper, we discuss methods to improve the characteristics of control sensors using compact and low-cost circuitry. Our objective is to extend the linear region of operation of a nonlinear sensor using artificial neural networks. An analog circuit approach was investigated for high-speed applications and a microcontroller approach for low-speed applications. The methods are applied to the design of a discrete-component phase-locked loop. Both approaches resulted in doubling the sensor's linear range.     

Self-association of disulfide-dimerized melittin analogues

Two cysteine substitutions of bee venom melittin have been synthesized to investigate the effects of disulfide cross-linking on the self-association properties of the peptide in solution. K23C melittin (mltK23C) was designed to link nonpolar surfaces of the amphipathic melittin helix on the basis of the close juxtaposition of pairs of K23 side chains in the crystal of the native melittin tetramer. K23Q/Q25C melittin (mltQ25C) was designed to link the polar surfaces of the peptide such that self-association in membrane bound states might be stabilized. The mltK23C disulfide dimer, (mltK23C)2, is highly structured at low pH under conditions where native melittin, and the mltK23C monomer, are unstructured. High-resolution NMR, circular dichroism, and fluorescence spectroscopy established that (mltK23C)2 is a helical monomer (pseudodimer) with stable helical segments between residues 2-13 and 15-25. Although the symmetrical nature of the pseudodimer prevented high-resolution structure determination, analysis of calculated hydrogen bond lengths, chemical shifts, near-UV circular dichroism, and urea denaturation demonstrated similarities with alpha-helical coiled coils and with the structure of native melittin in methanol. Stopped flow fluorescence showed that (mltK23C)2 underwent pH- and divalent anion-linked dimerization to a melittin-like pseudotetramer, indicating that a pair of disulfide bonds could be accommodated in a structure similar to the native melittin crystal structure. Despite incorporation of two disulfide bonds into the melittin tetramer, the folding free energy (DeltaGw) of [(mltK23C)2]2 was similar to that for the native melittin tetramer under the condition used. Incorporation of a disulfide bond on the polar helix face in melittin did not stabilize helical structure in the absence of self-association. Instead, this molecule underwent pH- and divalent anion-linked self-association to an ill-defined aggregate which precipitated.     

Influence of three principles of pacing on the temporal organisation of work during cyclic assembly and disassembly tasks

A study was conducted to investigate the influence of different approaches to arranging the pace and temporal organisation of repetitive assembly and disassembly tasks on both average performance and its variability and to compare assembly and disassembly times derived with psychophysical methods to a more traditional methods-time measurement (MTM) approach. The conditions studied were a traditional assembly line arrangement, where assemblies were started at a pace of 110 MTM (repeated on two occasions), a batch condition, where subjects were required to complete 36 assemblies within the total amount of time allowed at 110, MTM and a psychophysical condition, where subjects were allowed to choose their pace (repeated on two occasions). Overall, the results suggest that the mean time spent working in each cycle (the 'on-time') remained fairly constant across conditions, while the idle 'off-time' in between on-times was shorter and of less varied duration in the more autonomous batch and psychophysical conditions. During the second psychophysical (self-paced) condition, subjects completed a significantly higher number of assemblies than during the 110 MTM line condition. The higher pace was achieved through reduction in mean off-times and the potential implications for musculoskeletal risk are discussed. STATEMENT OF RELEVANCE: Higher levels of autonomy over work pace, which intuitively would be beneficial from an ergonomics standpoint, actually led to subjects selecting to organise work such that off-times (idle times) were reduced. In contrast, active 'on' times were not affected much by autonomy. These results point to a reason that piecework would be associated with increased risk for musculoskeletal disorders.     

The effects of nitrogen additions to a cobalt-chromium surgical implant alloy

The determination of the feasibility of adding nitrogen to a cobalt-chromium implant alloy was undertaken with the ultimate goal of the work being the improvement of the static and fatigue properties of the alloy. Nitrogen additions were made using high-temperature heat treatments in a nitrogen-containing gas atmosphere. The effects of the nitrogen additions were characterized in this study using several techniques. The maximum solid solubility of nitrogen in the alloy at 1200° C (the heat-treatment temperature) was found to be approximately 0.35 wt % N. X-ray diffraction using nitrogen heat-treated powder samples indicated that the addition of nitrogen in solution resulted in a lattice dilation lying in the range of 0.0021 to 0.0035 nm per wt % N. Above the solubility limit, Cr₂N and Cr₂(CN) were present at the nitrogen heat-treatment temperatures in the form of large second-phase particles. Ageing of the alloy containing approximately 0.35 wt % N at 400° C resulted in the precipitation of CrN. A study of the nitrogen distribution suggested that the diffusion of nitrogen ms affected by the carbon content of the cobalt-base alloy.     

Apoptosis and necrosis: mechanisms of cell death induced by cyclosporine A in a renal proximal tubular cell line

BACKGROUND: The mechanisms of cyclosporine (CsA)-induced nephrotoxicity are not fully understood. While hemodynamic changes may be involved in vivo, there is also some evidence for tubular involvement. We previously showed direct toxicity of CsA in the LLC-PK1 renal tubular cell line. In the current study we examined mechanisms (apoptosis or necrosis) of cell death induced by CsA in the LLC-PK1 renal proximal tubular cell line. The possible role of the Fas (APO-1/CD95) antigen-Fas ligand system in the mediation of CsA-induced cell death was also investigated. METHODS: Cells were treated with CsA (0.42 nM to 83 microM) for 24 hours and alterations in DNA and protein synthesis and membrane integrity were examined. Flow cytometry was used to investigate: (i) alterations in the DNA content and cell cycle; (ii) the forward (FSC) and side (SSC) light scattering properties (indicators of cell size and granularity, respectively); (iii) the externalization of phosphatidylserine (PS) as a marker of early apoptosis using FITC-annexin V binding; and (iv) expression of the apoptotic Fas protein. DNA fragmentation in apoptotic cells was also determined by the TUNEL assay. RESULTS: CsA (all doses) caused a block in the G0/G1 phase of the cell cycle as indicated by a decrease in DNA synthesis and supported by an increase in the % of cells in the G0/G1 phase with concurrent decreases of those in the S and G2/M phases. The effect on protein synthesis appeared to be much less. Lower doses of CsA (4.2 nM) caused the appearance of a "sub-G0/G1" peak, indicative of reduced DNA content, on the DNA histogram that was paralleled by a reduction in cell size and an increased cell granularity and an increase in FITC-annexin V binding. DNA fragmentation was evident in these cells as assessed using the TUNEL assay. Higher doses of CsA increased cell size and decreased cell granularity and reduced membrane integrity. Expression of Fas, the cell surface molecule that stimulates apoptosis, was increased following low dose CsA exposure. CONCLUSIONS: These results indicate that CsA is directly toxic to LLC-PK1 cells with reduced DNA synthesis and cell cycle blockade. The mode of cell death, namely apoptosis or necrosis, is dose dependent. Fas may be an important mediator of CsA induced apoptosis in renal proximal tubular cells.     

Revisited: Comparison of two techniques to establish maximum acceptable forces of dynamic pushing for male industrial workers

The purpose of this experiment was to replicate a previous psychophysical experiment [Ciriello, V.M., McGorry, R.W., Martin, S.E., Bezverkny, I.B., 1999b. Maximum acceptable forces of dynamic pushing: comparison of two techniques. Ergonomics 42, 32–39] which investigated maximum acceptable initial and sustained forces while performing a 7.6 m pushing task at a frequency of 1 min⁻¹ on a magnetic particle brake treadmill versus pushing on a high-inertia pushcart. Fourteen male industrial workers performed both a 40-min treadmill pushing task and a 2-h pushcart task, with a unique water loading system, in the context of a larger experiment. During pushing, the subjects were asked to select a workload they could sustain for 8 h without “straining themselves or without becoming unusually tired, weakened, overheated or out of breath.” The results revealed that similar to the previous study maximum acceptable sustained forces of pushing determined on the high inertia cart were significantly higher (21%) than the forces determined from the magnetic particle brake treadmill. These results were countered by an 18% decrease in maximum acceptable forces for the criterion magnetic particle brake treadmill task, perhaps due to secular changes in the industrial population. Based on the present findings, it is concluded that the existing pushing data [Snook, S.H., Ciriello, V.M., 1991. The design of manual tasks: revised tables of maximum acceptable weights and forces. Ergonomics 34, 1197–1213] still provides an accurate estimate of maximal acceptable forces for this pushing distance and frequency.

Relevance to industry

Jobs are often redesigned to eliminate lifting and to include carts for transporting loads. Our database on maximum acceptable forces of pushing on a magnetic particle braked treadmill has been used as a tool to design manual handling tasks. This article links the existing database with actual cart pushing.     

Impact of police body armour and equipment on mobility

Body armour is used widely by law enforcement and other agencies but has received mixed reviews. This study examined the influence of stab resistant body armour (SRBA) and mandated accessories on physiological responses to, and the performance of, simulated mobility tasks. Fifty-two males (37 ± 9.2 yr, 180.7 ± 6.1 cm, 90.2 ± 11.6 kg, VO_2max 50 ± 8.5 ml kg⁻¹ min⁻¹, BMI 27.6 ± 3.1, mean ± SD) completed a running VO_2max test and task familiarisation. Two experimental sessions were completed (≥4 days in between) in a randomised counterbalanced order, one while wearing SRBA and appointments (loaded) and one without additional load (unloaded). During each session participants performed five mobility tasks: a balance task, an acceleration task that simulated exiting a vehicle, chin-ups, a grappling task, and a manoeuvrability task. A 5-min treadmill run (zero-incline at 13 km·h⁻¹, running start) was then completed. One min after the run the five mobility tasks were repeated.