Biomedical subjects

Dean M Robinson

Publications and source records attributed to Dean M Robinson.

24 records · Page 2Linked to original sources

PubMed2005

Darbepoetin alfa: its use in anemia associated with chronic kidney disease.

Darbepoetin alfa (Aranesp), Nespo) is an amino acid substituted analog of human erythropoietin (EPO) that promotes erythrocyte survival, proliferation, and differentiation. Approved in Europe and the US for the treatment of anemia associated with chronic kidney disease (CKD), it is characterized by delayed clearance and a more prolonged elimination half-life than recombinant human erythropoietin (rhEPO; epoetin alfa and beta), permitting an extended interval between doses. Darbepoetin alfa is generally well tolerated, and clinical trials of 20-52 weeks' duration have demonstrated the efficacy of subcutaneous and intravenous administration at 1- or 2-week intervals in the initial treatment of anemia associated with CKD both in dialysis patients and in patients not yet on dialysis. Trials of up to 52 weeks' duration demonstrated that in the majority of patients with CKD, treatment with darbepoetin alfa at up to 4-week intervals maintained hemoglobin (Hb) levels established by prior erythropoietic treatment, while in patients undergoing dialysis, intravenous or subcutaneous darbepoetin alfa administered at 1- or 2-week intervals was noninferior to rhEPO administered once, twice, or three times per week in maintaining established Hb levels.

Anemia↗

PubMed2005

Fondaparinux sodium: a review of its use in the treatment of acute venous thromboembolism.

Fondaparinux sodium (fondaparinux) is a synthetic sulfated pentasaccharide anticoagulant developed from the antithrombin binding moiety of heparin. Through the activation of antithrombin it inhibits Factor Xa, the activation of thrombin, and the subsequent coagulation cascade. Fondaparinux is approved in Europe and the US for the treatment of acute venous thromboembolism (VTE), including both deep vein thrombosis (DVT) and pulmonary embolism (PE), when used in conjunction with warfarin. In phase III clinical trials, subcutaneous fondaparinux was noninferior to subcutaneous enoxaparin or intravenous unfractionated heparin (UFH) in the prevention of recurrent symptomatic VTE in patients with acute DVT and PE, respectively, and equally well tolerated. It thus provides a valuable alternative to UFH and low-molecular weight heparins in the treatment of acute VTE, particularly in the outpatient setting.

Acute Disease↗

PubMed2004

Noradrenergic modulation of XII motoneuron inspiratory activity does not involve alpha2-receptor inhibition of the Ih current or presynaptic glutamate release.

Norepinephrine has powerful and diverse modulatory effects on hypoglossal (XII) motoneuron activity, which is important in maintaining airway patency. The objective was to test two hypotheses that alpha2-adrenoceptor-mediated, presynaptic inhibition of glutamatergic inspiratory drive (Selvaratnam SR, Parkis MA, and Funk GD. Brain Res 805: 104-115, 1998) and postsynaptic inhibition of the hyperpolarization-activated inward current (Ih) (Parkis MA and Berger AJ. Brain Res 769: 108-118, 1997) modulate XII inspiratory activity. Nerve and whole cell recordings were applied to rhythmic medullary slice preparations from neonatal rats (postnatal days 0-4) to monitor XII inspiratory burst amplitude and motoneuron properties. Application of an alpha2-receptor agonist (clonidine, 1 mM) to the XII nucleus reduced inspiratory burst amplitude to 71 +/- 3% of control but had no effect on inspiratory synaptic currents. It also reduced the Ih current by approximately 40%, but an Ih current blocker (ZD7288), at concentrations that blocked approximately 80% of Ih, had no effect on inspiratory burst amplitude. The clonidine inhibition was unaffected by the GABAA antagonist (+)bicuculline but attenuated by the alpha2-antagonist rauwolscine and the imidazoline 1 (I1) antagonist efaroxan. The I1 agonist rilmenidine, but not the alpha2-agonist UK14304, inhibited XII output. Clonidine also reduced action potential amplitude or impaired repetitive firing. Although a contribution from alpha2, and in particular I1, receptors remains possible, results demonstrate that 1) noradrenergic modulation of XII inspiratory activity is unlikely to involve alpha2-receptor-mediated presynaptic inhibition of glutamate release or modulation of Ih; 2) inhibition of repetitive firing is a major factor underlying the inhibition of XII output by clonidine; and 3) Ih is present in neonatal XII motoneurons but does not contribute to shaping their inspiratory activity.

Action Potentials↗

PubMed2003

Oscillations in endogenous inputs to neurons affect excitability and signal processing.

Synchrony and oscillations in neuronal firing play important roles in information processing in the mammalian brain. Here, we evaluate their role in controlling neuronal output in a well defined motor behavior, breathing, using an in vitro preparation from neonatal rat that generates respiratory-related motor output. In this preparation, phrenic motoneurons (PMNs) receive endogenous rhythmic inspiratory currents with prominent oscillations in the 20-50 Hz range. We recorded these inspiratory currents in individual PMNs and used them as test inputs for the same motoneuron (MN) during the normally silent expiratory periods. The impact of the oscillations on MN output was evaluated by filtering the currents before injection. Responses to unfiltered inspiratory currents were indistinguishable from voltage changes during spontaneous inspiratory periods. More than 90% of action potentials occurred within milliseconds [-2 to +4] of the oscillation peaks. The timing of action potentials was highly reproducible in response to unfiltered currents. Attenuation of the oscillations by low-pass filtering (<50 Hz) decreased the precision in action potential timing and significantly reduced the number of action potentials by approximately 35%. The adrenergic agonist phenylephrine increased instantaneous firing frequency in responses evoked by square-wave or low-pass filtered inspiratory currents but had no effect on firing frequency evoked by unfiltered currents. We conclude that oscillations control the precise timing of action potentials, help to maximize synaptic drive efficiency, and constrain MN firing frequencies to those optimal for muscle contraction.

Action Potentials↗

PubMed2002

Prenatal nicotine exposure increases apnoea and reduces nicotinic potentiation of hypoglossal inspiratory output in mice.

We examined the effects of in utero nicotine exposure on postnatal development of breathing pattern and ventilatory responses to hypoxia (7.4 % O2) using whole-body plethysmography in mice at postnatal day 0 (P0), P3, P9, P19 and P42. Nicotine delayed early postnatal changes in breathing pattern. During normoxia, control and nicotine-exposed P0 mice exhibited a high frequency of apnoea (f(A)) which declined by P3 in control animals (from 6.7 +/- 0.7 to 2.2 +/- 0.7 min(-1)) but persisted in P3 nicotine-exposed animals (5.4 +/- 1.3 min(-1)). Hypoxia induced a rapid and sustained reduction in f(A) except in P0 nicotine-exposed animals where it fell initially and then increased throughout the hypoxic period. During recovery, f(A) increased above control levels in both groups at P0. By P3 this increase was reduced in control but persisted in nicotine-exposed animals. To examine the origin of differences in respiratory behaviour, we compared the activity of hypoglossal (XII) nerves and motoneurons in medullary slice preparations. The frequency and variability of the respiratory rhythm and the envelope of inspiratory activity in XII nerves and motoneurons were indistinguishable between control and nicotine-exposed animals. Activation of postsynaptic nicotine receptors caused an inward current in XII motoneurons that potentiated XII nerve burst amplitude by 25 +/- 5 % in control but only 14 +/- 3 % in nicotine-exposed animals. Increased apnoea following nicotine exposure does not appear to reflect changes in basal activity of rhythm or pattern-generating networks, but may result, in part, from reduced nicotinic modulation of XII motoneurons.

Animals↗

PubMed2002

Effect of creatine manipulation on fast-twitch skeletal muscle of the mouse.

1. The effect of short-term, reversible alteration of muscle total creatine content (Crtot) on force development was sought in fast-twitch extensor digitorum longus (EDL) muscles of female mice. 2. Three in vivo interventions were investigated: 1% creatine-supplementation, treatment with the creatine-uptake inhibitor beta-guanidino propionic acid (beta-GPA; 1%) or beta-GPA treatment followed by creatine supplementation for 5 days. 3. The Crtot of isolated muscles, determined using reverse-phase high-performance liquid chromatography, was 133 +/- 38 mmol/kg dry in 11 EDL control muscles and was not significantly affected by dietary creatine-supplementation (152 +/- 25 mmol/kg dry; n = 8). Significant creatine depletion was observed in the beta-GPA-fed group (65 +/- 6 mmol/kg dry; n = 9) and this was reversed by 5 days of creatine supplementation (133 +/- 21 mmol/kg dry; n = 10). 4. Creatine depletion did not affect maximum tetanic stress. However, when muscle creatine was restored by creatine supplementation, a substantial increase in tetanic stress was observed. Significant correlations were observed between Crtot and maximum tetanic stress (r = 0.56) and relaxation rate (r = 0.43). The enhancement of force was not due to effects of creatine on muscle fibre type because neither mechanical tests of fibre characteristics nor the fibre types of the muscles were affected. 5. We conclude that, in muscles that contain large numbers of fast-twitch fibres, maximum tetanic stress is determined, in part, by muscle creatine stores.

Animals↗