Pharmacokinetics of ciprofloxacin in ICU patients on continuous veno-venous haemodiafiltration

Objectives: To investigate the pharmacokinetics of intravenous ciprofloxacin 200 mg every 8 h in critically ill patients on continuous veno-venous haemodiafiltration (CVVHDF), one form of continuous renal replacement therapy (CRRT). Design and setting: Open, prospective clinical study in a multidisciplinary, intensive care unit in a university-affiliated tertiary referral hospital. Patients: Sis critically ill patients with acute renal failure on CVVHDF. Interventions: Timed blood and ultrafiltrate samples were collected to allow pharmacokinetics and clearances to be calculated of initial and subsequent doses of 200 mg intravenous ciprofloxacin. CVVHD was performed with 1 l/h of dialysate and 2 l/h of predilution filtration solution, producing 3 lih of dialysis effluent. The blood was pumped at 200 ml/min using a Gambro BMM-10 blood pump through a Hospal AN69HF haemofilter,. Measurements and results: Ten pharmacokinetic profiles were measured. The CVVHDF displayed a urea clearance of 42 +/- 3 ml/min, and removed ciprofloxacin with a clearance of 37 +/- 7 ml/min. This rate was 2-2.5 greater than previously published for ciprofloxacin in other forms of CRRT. On average the CVVHDF was responsible for clearing a fifth of all ciprofloxacin eliminated (21 +/- 10%). The total body clearance of ciprofloxacin was 12.2 +/- 4.3 l/h. The trough concentration following the initial dose was 0.7 +/- 0.3 mg/l. The area under the plasma concentration time curves over a 24-h period ranged from 21 to 55 mg .h l(-1). Conclusions: Intravenous ciprofloxacin 600 mg/day in critically ill patients using this form of CRRT produced adequate plasma levels for many resistant microbes found in intensive care units.

Effect of drug concentration on adsorption of levofloxacin by polyacrylonitrile haemofilters

We studied an in vitro model of continuous venovenous haemofiltration to determine levofloxacin adsorption by polyacrylonitrile (PAN) filters. Four doses of levofloxacin (5, 25, 50 and 100 mg) were used, resulting in circulating concentrations of levofloxacin at 120 min of 3.56 +/- 0.14, 15.84 +/- 2.08, 31.42 +/- 1.95 and 58.23 +/- 1.10 mg/L, respectively. Adsorption at 2 h was 0.65 +/- 0.17, 5.99 +/- 2.49, 12.30 +/- 2.34 and 30.13 +/- 1.32 mg, respectively (P < 0.001). From 2 h to 4 h, increasing the blood pump rate and the ultrafiltration rate had no effect on adsorption. When the concentration was decreased from 3.55 +/- 0.13 mg/L at 4 h to 2.16 +/- 0.11 mg/L at 5 h by addition of lactated Ringer's solution, adsorption decreased from 0.67 +/- 0.16 mg to 0.21 +/- 0.25 mg (P < 0.05). These data show that adsorption of levofloxacin by PAN haemofilters is concentration dependent and reversible in vitro and suggest that adsorption by haemofilters is unlikely to affect levofloxacin pharmacokinetics significantly in vivo. (c) 2006 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Blood pressure and heart rate during tonic immobility in the black tipped reef shark, Carcharhinus melanoptera

Tonic immobility was induced in black tipped reef sharks (Carcharhinus melanoptera) and heart rate and ventral aortic blood pressure recorded. Without branchial irrigation, tonic immobility was correlated with a significant depression in blood pressure and heart rate irrespective of the sharks being in air or in water. Tonic immobility with branchial irrigation resulted in a significant increase in blood pressure in sharks in air, but not in water. Heart rate was unchanged when the gills were irrigated. Intra-arterial injections of atropine abolished the bradycardia and blood pressure rise associated with tonic immobility. We conclude that, during tonic immobility, sharks are able to receive afferent information from the ventilatory system and make appropriate responses via the vagus nerve.

Methemoglobin Reduction in Crocodile Blood: Are High Levels of MetHb Typical of Healthy Reptiles?

In 82 wild-caught Crocodylus porosus, levels of NADH-MetHb reductase and GSH seem adequate to maintain hemoglobin in its reduced functional state. Studies of C. porosus erythrocytes in vitro show reduction of metHb in the presence of lactate, glucose and plasma, but not pyruvate. These findings, together with recent data which show low metHb in a variety of reptiles, cast doubt on the accepted view that high levels of MetHb are typical of healthy reptiles. One explanation for the sharp contrast between earlier and more recent data could be technical. We found low metHb in Crocodylus johnstoni, Chelodina longicollis and Sphenomorphus quoyi. However, high and variable values reminiscent of many of the earlier data were obtained by omitting final centrifugation prior to spectrophotometry. Interestingly, this step is not part of the standard clinical method but is necessary in analyses of blood with nucleated red cells. These observations suggest that high metHb may not be typical of reptiles after all.

Peptidergic control of gastrointestinal blood flow in the estuarine crocodile, Crocodylus porosus

Peptidergic mechanisms influencing the resistance of the gastrointestinal vascular bed of the estuarine crocodile, Crocodylus porosus, were investigated. The gut was perfused in situ via the mesenteric and the celiac arteries, and the effects of different neuropeptides were tested using bolus injections. Effects on vascular resistance were recorded as changes in inflow pressures. Peptides found in sensory neurons [substance P, neurokinin A, and calcitonin gene-related peptide (CGRP)] all caused significant relaxation of the celiac vascular bed, as did vasoactive intestinal polypeptide (VIP), another well-known vasodilator. Except for VIP, the peptides also induced transitory gut contractions. Somatostatin and neuropeptide Y (NPY), which coexist in adrenergic neurons of the C. porosus, induced vasoconstriction in the celiac vascular bed without affecting the gut motility. Galanin caused vasoconstriction and occasionally activated the gut wall. To elucidate direct effects on individual vessels, the different peptides were tested on isolated ring preparations of the mesenteric and celiac arteries. Only CGRP and VIP relaxed the epinephrine-precontracted celiac artery, whereas the effects on the mesenteric artery were variable. Somatostatin and NPY did not affect the resting tonus of these vessels, but somatostatin potentiated the epinephrine-induced contraction of the celiac artery. Immunohistochemistry revealed the existence and localization of the above-mentioned peptides in nerve fibers innervating vessels of different sizes in the gut region. These data support the hypothesis of an important role for neuropeptides in the control of the vascular bed of the gastrointestinal tract in C. porosus.

Relationships between blood pressure and heart rate in the saltwater crocodile Crocodylus porosus

The cardiac limb of the baroreflex loop was studied in the saltwater crocodile Crocodylus porosus, The classical pharmacological methodology using phenylephrine and sodium nitroprusside was used to trigger blood pressure changes, and the resulting alterations in heart rate were analysed quantitatively using a logistic function. Interindividual differences in resting heart rates and blood pressures were observed, but all seven animals displayed clear baroreflex responses. Atropine and sotalol greatly attenuated the response. A maximal baroreflex gain of 7.2 beats min(-1) kPa(-1) was found at a mean aortic pressure of 6.1 kPa, indicating the active role of the baroreflex in a wide pressure range encompassing hypotensive and hypertensive states. At the lowest mean aortic pressures (5.0 kPa), the synergistic role of the pulmonary-to-systemic shunt in buffering the blood pressure drop also contributes to blood pressure regulation, Pulse pressure showed a better correlation,vith heart rate and also a higher gain than mean aortic, systolic or diastolic pressures, and this is taken as an indicator of the existence of a differential control element working simultaneously with a linear proportional element.

Heart rate, blood lactate and kinematic data of elite colts (under-19) rugby union players during competition

Physiological and kinematic data were collected from elite under-19 rugby union players to provide a greater understanding of the physical demands of rugby union. Heart rate, blood lactate and time-motion analysis data were collected from 24 players (mean +/- s((x) over bar): body mass 88.7 +/- 9.9 kg, height 185 +/- 7 cm, age 18.4 +/- 0.5 years) during six competitive premiership fixtures. Six players were chosen at random from each of four groups: props and locks, back row forwards, inside backs, outside backs. Heart rate records were classified based on percent time spent in four zones (>95%, 85-95%, 75-84%, <75% HRmax). Blood lactate concentration was measured periodically throughout each match, with movements being classified as standing, walking, jogging, cruising, sprinting, utility, rucking/mauling and scrummaging. The heart rate data indicated that props and locks (58.4%) and back row forwards (56.2%) spent significantly more time in high exertion (85-95% HRmax) than inside backs (40.5%) and outside backs (33.9%) (P < 0.001). Inside backs (36.5%) and outside backs (38.5%) spent significantly more time in moderate exertion (75-84% HRmax) than props and locks (22.6%) and back row forwards (19.8%) (P < 0.05). Outside backs (20.1%) spent significantly more time in low exertion (< 75% HRmax) than props and locks (5.8%) and back row forwards (5.6%) (P < 0.05). Mean blood lactate concentration did not differ significantly between groups (range: 4.67 mmol.l(-1) for outside backs to 7.22 mmol.l(-1) for back row forwards; P < 0.05). The motion analysis data indicated that outside backs (5750 m) covered a significantly greater total distance than either props and locks or back row forwards (4400 and 4080 m, respectively; P < 0.05). Inside backs and outside backs covered significantly greater distances walking (1740 and 1780 m, respectively; P < 0.001), in utility movements (417 and 475 m, respectively; P < 0.001) and sprinting (208 and 340 m, respectively; P < 0.001) than either props and locks or back row forwards (walking: 1000 and 991 m; utility movements: 106 and 154 m; sprinting: 72 and 94 m, respectively). Outside backs covered a significantly greater distance sprinting than inside backs (208 and 340 m, respectively; P < 0.001). Forwards maintained a higher level of exertion than backs, due to more constant motion and a large involvement in static high-intensity activities. A mean blood lactate concentration of 4.8-7.2 mmol.l(-1) indicated a need for 'lactate tolerance' training to improve hydrogen ion buffering and facilitate removal following high-intensity efforts. Furthermore, the large distances (4.2-5.6 km) covered during, and intermittent nature of, match-play indicated a need for sound aerobic conditioning in all groups (particularly backs) to minimize fatigue and facilitate recovery between high-intensity efforts.

Hypoxia stimulates cerebral blood flow in the estuarine crocodile (Crocodylus porosus)

The effect of N-2 respiration on cerebral blood flow (CBF) velocity on the dorsal surface of cerebellum was examined in the estuarine crocodile, Crocodylus porosus, using epi-illumination microscopy. Twelve minutes of N-2 respiration resulted in a 126% increase in CBF velocity. N-2 respiration had no effect on blood pressure, indicating an underlying cerebral vasodilation. In addition, heart rate increased significantly. Systemic injections of aminophylline and the NO synthase (NOS) inhibitor nitro-L-arginine (L-NA) did not affect the hypoxia induced increase in CBF. We conclude that C. porosus responds to hypoxia with adenosine and nitric oxide (NO) independent cerebral vasodilation, and that this is likely to be a mechanism protecting the brain from energy deficiency during prolonged dives. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.

Targeting local tissues by transdermal application: Understanding drug physicochemical properties that best exploit protein binding and blood flow effects

The targeting of topically applied drug molecules into tissues below a site of application requires an understanding of the complex interrelationships between the drug, its formulation, the barrier properties of the skin, and the physiological processes occurring below the skin that are responsible for drug clearance from the site, tissue, and/or systemic distribution and eventual elimination. There is still a certain amount of controversy over the ability of topically applied drugs to penetrate into deeper tissues by diffusion or whether this occurs by redistribution in the systemic circulation. The major focus of our work in this area has been in determining how changes in drug structure and physicochemical properties, such as protein binding and lipophilicity, affect drug clearance into the local dermal microcirculation and lymphatics, as well as subsequent distribution into deeper tissues below an application site. The present study outlines our recent thinking on the drug molecule optimal physical attributes, in terms of plasma and tissue partitioning behaviour, that offer the greatest potential for deep tissue targeting. Drug Dev. Res. 46:309-315, 1999. (C) 1999 Wiley-Liss, Inc.

The plasma membrane calcium pump, its role and regulation: New complexities and possibilities

Significant progress has been achieved in elucidating the role of the plasma membrane Ca2+-ATPase in cellular Ca2+ homeostasis and physiology since the enzyme was first purified and physiology since the enzyme was first purified and cloned a number of years ago. The simple notion that the PM Ca2+-ATPase controls resting levels of [Ca2+](CYT) has been challenged by the complexity arising from the finding of four major isoforms and splice variants of the Ca2+ pump, and the finding that these are differentially localized in various organs and subcellular regions. Furthermore, the isoforms exhibit differential sensitivities to Ca2+, calmodulin, ATP, and kinase-mediated phosphorylation. The latter pathways of regulation can give rise to activation or inhibition of the Ca2+ pump activity, depending on the kinase and the particular Ca2+ pump isoform. Significant progress is being made in elucidating subtle and more profound roles of the PM Ca2+-ATPase in the control of cellular function. Further understanding of these roles awaits new studies in both transfected cells and intact organelles, a process that will be greatly aided by the development of new and selective Ca2+ pump inhibitors. (C) 1999 Elsevier Science Inc.

Administration of growth hormone or IGF-I to pregnant rats on a reduced diet throughout pregnancy does not prevent fetal intrauterine growth retardation and elevated blood pressure in adult offspring

Increasing evidence from human epidemiological studies suggests that poor growth before birth is associated with postnatal growth retardation and the development of cardiovascular disease in adulthood. We have shown previously that nutritional deprivation in the pregnant rat leads to intrauterine growth retardation (IUGR), postnatal growth failure, changes in the endocrine parameters of the somatotrophic axis, and to increased blood pressure in later life. In the present study, we investigated whether administration of insulin-like growth factor-I (IGF-I) or bovine growth hormone (GH) during pregnancy could prevent IUGR and/or alter long-term outcome. Dams h-om day 1 of pregnancy throughout gestation received a diet of nd libitum available food or a restricted dietary intake of 30% of ad libitum fed dams. From day 10 of gestation, dams were treated for 10 days with three times daily subcutaneous injections of saline (100 mu l), IGF-I (2 mu g/g body weight) or GH (2 mu g/g body weight). Maternal weight gain was significantly increased (P

An outbreak of blood disease of banana in Irian Jaya, Indonesia

Blood disease of banana is substantiated by using the polymerase chain reaction for the first time from Irian Jaya, Indonesia.

Blood vessels from bone marrow

Lengths of silastic tubing were inserted into the peritoneal cavity of rats or rabbits. By two weeks the free-floating implants had become covered by a capsule consisting of several layers of macrophage-derived myofibroblasts and collagen matrix overlaid by a single layer of mesothelial cells. The tubing was removed from the harvested implant and the tissue everted. This now resembled an artery with an inner lining of mesothelial cells (the intima), a media of myofibroblasts, and an outer collagenous adventitia. The tube of living tissue was grafted by end-to-end anastomoses into the transected carotid artery or abdominal aorta of the same animal in which the tissue had been grown, where it remained parent for four months and developed structures resembling elastic lamellae, The myofibroblasts developed a high volume fraction of myofilaments and became responsive to contractile and relaxing agents similar to smooth muscle cells of the adjacent artery wall.