bluuebunny/crossref_metadata_2025 huggingface dataset:
Hip flexion and lumbar puncture: a radiological study
Authors: Fisher A. , Lupu L. , Gurevitz B. , Brill S. , Margolin E. , Hertzanu Y.
Published: March 2003

When lumbar puncture is performed in the sitting position, the patient's thighs are usually at an angle of approximately 90° to the trunk, whereas in the lateral position, hip flexion is employed by flexing the patient's knees to the chest. We measured the presumed but hitherto unquantified widening of lumbar interspinous spaces resulting from hip flexion. Lumbar spine lateral radiographs were taken in volunteers in the sitting position with and without hip flexion, and interspinous space width was measured and compared. Mean lumbar interspinous space width at L2−3, L3−4 and L4−5 increased by 7%, 11% and 21%, respectively, with the hips flexed. Hip flexion in the sitting position will anatomically optimise lumbar interspinous space width for needle passage, and statistically significant increases in space width have been demonstrated increasing progressively from L2−3 to L4−5.
Phaeochromocytoma: an unusual cause of hypertension in pregnancy
Authors: Bullough A. S. , Karadia S. , Watters M.
Published: March 2003

A primiparous, full‐term, 28‐year‐old woman underwent an emergency lower segment Caesarean section under epidural anaesthesia for failure to progress in the first stage. Despite an uneventful pregnancy and delivery, she developed a hypertensive crisis in the postoperative period complicated by acute pulmonary oedema requiring ventilation for 48 h in the intensive care unit. Intravenous magnesium sulphate infusions and hydralazine boluses were used to control the blood pressure, which was associated with clonus, hyperreflexia, tachycardia and profuse sweating. The patient made a good recovery. Later measurement of urinary catecholamines in the recovery phase showed greatly elevated levels of norepinephrine, dopamine and vanillyl mandelic acid. Further investigations included a normal abdominal computed tomography scan and a I‐123 meta‐iodo‐benzyl‐guanidine scintigraphy scan which revealed a 3‐ to 4‐cm irregular tumour located at the level of the lower pole of the right kidney and further liver hot spots. Intravenous magnesium sulphate infusion proved successful in controlling hypertension caused by a phaeochromocytoma in the postpartum period.
Patient‐controlled analgesia and intra‐operative suggestion
Authors: Dawson P. R. , Van Hamel C. , Wilkinson D. , Warwick P. , O'Connor M.
Published: March 2003

In a double‐blind randomised study, we investigated the influence of positive intra‐operative suggestions, presented to anaesthetised patients undergoing total abdominal hysterectomy, on postoperative pain, nausea and vomiting. One hundred and forty patients were randomly allocated to listen to one of four tapes containing either white noise or positive suggestions. The positive suggestions related to pain, postoperative nausea and vomiting, or both. We found that the positive intra‐operative suggestions had no beneficial effects in reducing postoperative pain or nausea scores, nor was the consumption of morphine or anti‐emetics reduced.
Retention of airborne latex particles by a bacterial and viral filter used in anaesthesia
Authors: Barbara J. , Chabane M. H. , Leynadier F. , Girard F.
Published: March 2003

We have developed a series of laboratory tests to evaluate the efficiency of a heat and moisture exchanger filter (Pall™ BB25) in retaining latex particles in order to protect allergic patients during anaesthesia. Latex particles were nebulised with cornstarch as a support and collected for assay in a flask, with or without the filter integrated into the experimental circuit. With the Pall BB25 filter in the circuit, no natural latex proteins were detected by measurement of either total protein or antigenic latex proteins. The Pall BB25 filter may represent a useful means of preventing inhalation of latex particles during anaesthesia in susceptible patients.
Snow, Empson and the Barkers of Bath
Authors: Zuck D.
Published: March 2003

The identity of the artist who painted the well‐known portrait of John Snow has been established. It has been discovered that the painting was exhibited at the Royal Academy of Arts, London in 1847.
Tracheal gas insufflation
Authors: Dingley J. , Findlay G. P. , Foëx B. A. , Little R. A. , King R. , Smithies M. N.
Published: March 2003

Tracheal gas insufflation is a technique in which gas is injected intratracheally during positive pressure ventilation. The fresh gas rinses expired gas from the tracheal tube and anatomical dead space, aiding carbon dioxide elimination. This reduces ventilatory volume and pressure, helping to reduce ventilator‐induced lung damage. Complications of tracheal gas insufflation include interference with ventilator function, tracheal damage and barotrauma. Expiratory washout is a variation of tracheal gas insufflation. We designed and constructed an original expiratory washout system and evaluated its safety and performance in lung and animal models. We found that expiratory limb and tracheal tube occlusion tests caused the device to disable itself at acceptable intratracheal pressures. We also demonstrated up to 31% reduction in tidal volume compared with conventional ventilation, supporting the possibility of using this device clinically to lessen volutrauma. We concluded that aspects of this design might alleviate many of the safety concerns of using tracheal gas insufflation.
Comparison of the effects of intravenous alfentanil and esmolol on the cardiovascular response to double‐lumen endobronchial intubation
Authors: Maguire A. , Thompson J. P. , Guest C. , Sadler P. J. , Strupish J. W. , West K. J.
Published: March 2003

We compared the effect of alfentanil 10 µg.kg−1 and esmolol 1.5 mg.kg−1 on the cardiovascular responses to laryngoscopy and double‐lumen endobronchial intubation in two groups of 20 ASA 2–3 patients undergoing pulmonary surgery, in a randomised double‐blind study. Arterial pressure and heart rate decreased after induction of anaesthesia and increased after intubation in both groups (p < 0.05) but remained at or below baseline values, and changes were comparable in both groups. Plasma catecholamine concentrations decreased after induction of anaesthesia in both groups (p < 0.05). Epinephrine concentrations increased in the esmolol group after intubation (p < 0.05) but remained below baseline in the alfentanil group (p < 0.05). Norepinephrine concentrations increased significantly in both groups after intubation but were higher in the esmolol group (p < 0.05). Although both esmolol 1.5 mg.kg−1 and alfentanil 10 µg.kg−1 similarly attenuated the arterial pressure and heart rate response to endobronchial intubation, plasma catecholamine concentrations increased in the esmolol group to values greater than previously reported after tracheal intubation.
Sequential organ scoring as a measure of effectiveness of care in the high‐dependency unit
Authors: De Silva R. J. , Anderson A. , Tempest H. , Ridley S.
Published: March 2003

High‐dependency units are of benefit to patients and to the associated intensive care unit. However, the effectiveness of high‐dependency care has not been quantified. We studied 100 consecutive patients whose high‐dependency unit admission was longer than 48 h. The Logistic Organ Dysfunction System was used to assess organ dysfunction on a daily basis in these patients. The median Logistic Organ Dysfunction System score on admission was 3. The mean duration of stay was 4.3 days, and the median Logistic Organ Dysfunction System score on day 4 was 1. Sixty‐six per cent of patients had a lower Logistic Organ Dysfunction System score at discharge. In the remaining patients, the commonest reason for no change or a higher Logistic Organ Dysfunction System score was renal dysfunction. High‐dependency care is effective in the majority of patients in terms of improved physiological status and most patients were discharged with minor physiological dysfunction. This level of physiological dysfunction could be applied as a discharge threshold. Poorer patient outcome is associated with increased age and a longer stay on the unit. This poor outcome was commonly due to renal system dysfunction, and invariably followed surgery.
Bilateral hypoglossal nerve injury following the use of the laryngeal mask airway
Authors: Stewart A. , Lindsay W. A.
Published: March 2003

A healthy 54‐year‐old man undergoing elective knee arthroscopy developed bilateral hypoglossal nerve palsy, lasting 6 weeks following the use of a laryngeal mask airway. He suffered impairment of speech and difficulty in swallowing, the latter resulting in almost 7 kg loss of weight within 2 weeks of surgery. We discuss the possible aetiology of the injury and review the literature describing injuries to the hypoglossal nerve.
Assessment of diaphragm function after stellate ganglion block using magnetic stimulation
Authors: Sawyer R. J. , Turnbull D. , Richmond M. N. , Hamnegard C. H. , Mills G. H.
Published: March 2003

Stellate ganglion block is a procedure frequently used for the management of patients with chronic sympathetically mediated pain affecting the arm, neck or head. We studied the effect of stellate ganglion block on ipsilateral phrenic nerve function, and hence diaphragmatic strength, in 11 adult patients with chronic sympathetically mediated pain. Pre‐ and post‐block forced vital capacity (FVC) measurements were recorded using a pneumotachograph and a Magstim nerve stimulator was used to generate pre‐ and post‐block twitch mouth pressures (PTWM). This device can be used to stimulate the phrenic nerves and hence the diaphragm. The resulting change in airway pressure was measured at the mouth and has previously been shown to reflect diaphragm strength. There was no statistically significant difference in FVC or PTWM pre‐ or post stellate ganglion block. In conclusion, a stellate ganglion block has no adverse effect on ipsilateral phrenic nerve function or diaphragm strength in healthy adult patients.
The influence of timing and route of administration of intravenous ketorolac on analgesia after hand surgery
Authors: Ashworth H. L. , Ong C. , Seed P. T. , Venn P. J.
Published: March 2003

Summary A double‐blind clinical trial was conducted on 47 patients scheduled for hand surgery under general anaesthesia to determine whether ketorolac given as part of an intravenous regional anaesthesia technique could provide better postoperative analgesia than ketorolac given intravenously either before or after surgery. Patients were randomly allocated to one of three groups to receive ketorolac 20 mg: intravenously in the non‐operative arm before surgery (systemic presurgery group); intravenously to the operative arm after tourniquet inflation (regional presurgery group); intravenously in the non‐operative arm after surgery (systemic postsurgery group). Postoperative pain scores were similar in the systemic presurgery and regional presurgery groups. The mean visual analogue summary pain score during the 24 h after surgery was 12.2 mm higher in the systemic postsurgery group than in the systemic presurgery group (95% CI: 0.8–23.7 mm, p = 0.037). There were no clinically important differences in mean postoperative visual analogue pain scores between the three study groups. There were no statistical differences in the mean postoperative morphine requirements between the three study groups. There is no benefit, in terms of improved postoperative analgesia, in giving ketorolac as an intravenous regional anaesthetic compared with systemic administration before surgery. The administration of ketorolac after surgery, rather then before, is not supported.
A comparison between midazolam co‐induction and propofol predosing for the induction of anaesthesia in the elderly
Authors: Jones N. A. , Elliott S. , Knight J.
Published: March 2003

Summary In a prospective, double‐blind, randomised, placebo‐controlled trial, we have compared the effects of midazolam co‐induction with propofol predosing on the induction dose requirements of propofol in elderly patients. We enrolled 60 patients aged > 70 years, attending for urological surgery. The patients were allocated randomly to one of three groups, to receive either midazolam 0.02 mg.kg−1, propofol 0.25 mg.kg−1, or normal saline 2 ml (placebo) 2 min prior to induction of anaesthesia using propofol 1% infusion at 300 ml.h−1. The propofol dose requirements for induction were recorded for two end‐points (loss of verbal contact and insertion of an oropharyngeal airway). Cardiovascular parameters were recorded at 1‐min intervals for each patient until induction was complete. The midazolam group showed a significant reduction in propofol dose requirements for induction (p = 0.05) compared to the placebo group. The propofol group did not show a significant dose reduction compared to placebo. There were no demonstrable differences in terms of improved cardiovascular stability between groups. We conclude that propofol predosing does not significantly reduce the induction dose of propofol required in the elderly, and there were no cardiovascular benefits to either midazolam co‐induction or propofol predosing in the elderly.
Facial fractures and submental tracheal intubation
Authors: Amin M. , Dill‐Russell P. , Manisali M. , Lee R. , Sinton I.
Published: March 2003

Submental tracheal intubation is a simple, quick and effective alternative to oral and nasal tracheal intubation or tracheostomy in the surgical management of selected patients with craniomaxillofacial injuries. It has a low morbidity and it does not impede the surgical field, allowing for temporary maxillo‐mandibular fixation (jaw wiring) intra‐operatively, and nasal assessment, manipulation and bone grafting, either simultaneously or as an independent procedure. We report 12 cases utilizing this technique in this retrospective study, this includes 11 patients with mid‐facial fractures and associated base of skull fractures, and one patient who underwent an elective Le Fort III advancement. The techniques and indications for submental tracheal intubation are described.
The effect of single use laryngoscopy equipment on illumination for tracheal intubation*
Authors: Anderson K. J. , Bhandal N.
Published: March 2003

Summary We measured the illumination generated by all 30 Macintosh size 3 laryngoscopes in our department with a lux‐meter and a standardised laryngoscope holding tube. We found a large range in illumination generated (65–3130 lx). We then measured the effect on the illumination for each laryngoscope by covering the blade with a cover (LaryGard). In every case, the illumination was reduced by the LaryGard, the mean (SD) reduction was 67 (19)%. When we compared the illumination generated by a disposable laryngoscope blade with the same power source, we found that the illumination was reduced less than with the standard Macintosh covered by a LaryGard.
Neopterin as a marker of immunostimulation: an investigation in anaesthetic workplaces
Authors: Gruber G. , Lirk P. , Amann A. , Keller C. , Schobersberger W. , Hoffmann G. , Fuchs D. , Rieder J.
Published: March 2003

Summary Personnel working in operating theatres and recovery rooms are exposed to a variety of noxious substances. The results of studies of the effects of occupational exposure on immune parameters are conflicting. Neopterin is an acknowledged marker of immunostimulation. Urinary neopterin levels of 58 anaesthetists and anaesthetic nurses were measured over a 3‐week period. Neopterin analyses were performed using high performance liquid chromatography. Neopterin levels were within the normal range for all subjects. Younger subjects (aged ≤ 35 years) had significantly higher urinary neopterin concentrations than older subjects (aged > 35 years). The present study is the first to investigate the influence of anaesthetic exposure on neopterin levels. No evidence of immunostimulation was found.
Effect of cricoid pressure on the ease of fibrescope‐aided tracheal intubation
Authors: Asai T. , Murao K. , Johmura S. , Shingu K.
Published: March 2003

Summary We studied the reasons for difficulty with tracheal intubation over a fibrescope, and whether cricoid pressure facilitated intubation, in 50 patients. After induction of anaesthesia and neuromuscular blockade in 10 patients (phase 1), we attempted to clarify the reasons for difficulty in advancing a tracheal tube over an orally‐inserted fibrescope, by observing through another fibrescope that was inserted nasally into the pharynx. In the next 40 patients (phase 2), we studied the effect of cricoid pressure on the success rate of tracheal intubation over the fibrescope. After a fibrescope (with a tracheal tube over it) had been inserted orally into the trachea, patients were randomly allocated to receive either criocoid pressure or sham pressure, and the success rate of intubation within 60 s was assessed. In phase 1, the tube was advanced into the trachea without difficulty in three of 10 patients. In the remaining seven patients, the tube impacted on the epiglottis in one patient and on the arytenoid cartilage in another two patients, and the tube migrated into the hypopharynx in the remaining four patients. In phase 2, tracheal intubation was successful within 60 s in seven of 21 patients (33%) without cricoid pressure, compared with 12 of 19 patients (63%) when cricoid pressure was applied (95% CI for difference 2–59%; p = 0.04). We conclude that cricoid pressure facilitates fibrescope‐aided tracheal intubation.
A peripheral nerve stimulator for nerve location controlled by the scrubbed anaesthetist
Authors: Ayoub C. , Lteif A. , Rizk M. , Khalili Z. , Aoude S.
Published: March 2003

This newly designed peripheral nerve stimulator allows the scrubbed anaesthetist performing a nerve block to adjust the electrical current output needed for localisation of the target nerve without the need for an assistant.
Anaesthesia for cardioversion: a comparison of sevoflurane and propofol*
Authors: Karthikeyan S. , Balachandran S. , Cort J. , Cross M. H. , Parsloe M.
Published: March 2003

Summary This study compared the induction time, haemodynamic changes, recovery characteristics and patient satisfaction for sevoflurane and propofol when used as the main anaesthetic agents for cardioversion. Sixty‐one unpremedicated patients scheduled for elective cardioversion were anaesthetised with either inhaled sevoflurane 8% or an intravenous propofol target‐controlled infusion set at 6 µg.ml−1. There was no significant difference in induction time between the two groups: mean (SD) = 90.1(40) s in the sevoflurane group vs. 83.7(35) s in the propofol group. Mean (SD) time to recovery was significantly shorter in the sevoflurane group than in the propofol group: 318 (127) s vs. 738 (355) s, respectively, p < 0.001. At recovery, the patients in the propofol group had significantly lower systolic and diastolic blood pressures than those in the sevoflurane group, p < 0.001. The incidence of complications was low in both groups, with similar patient satisfaction expressed after the procedure. We conclude that sevoflurane is a suitable choice for anaesthesia for cardioversion and may provide greater haemodynamic stability than a target‐controlled infusion of propofol.
A comparison of anaesthetic techniques for shock wave lithotripsy: the use of a remifentanil infusion alone compared to intermittent fentanyl boluses combined with a low dose propofol infusion*
Authors: Burmeister M. A. , Brauer P. , Wintruff M. , Graefen M. , Blanc I. , Standl T. G.
Published: March 2003

Summary This study examined the intra‐operative and postoperative characteristics of a remifentanil infusion alone, or intermittent fentanyl bolus admistration combined with a propofol infusion, for the anaesthetic management of patients undergoing shock wave lithotripsy. One of the key parameters investigated was the time to discharge. Fifty patients scheduled for extracorporeal shock wavelithotripsy (ESWL) were randomly allocated to receive either a continuous infusion of 0.2–0.4 µg.kg−1.min−1 of remifentanil (Group 1) or a bolus of 3 µg.kg−1 fentanyl followed by a continuous infusion of propofol at a rate of 2 mg.kg−1.h−1 with additional boluses of 0.05 mg fentanyl administered as required (Group 2). Both anaesthetic techniques were found to provide satisfactory analgesia and intra‐operative conditions for ESWL. However, patients in the remifentanil Group 1 showed a higher incidence of nausea (52% vs. 0%, p < 0.01) and retching (36% vs. 0%, p < 0.01) 120 min following ESWL compared to Group 2. This resulted in prolonged discharge times (p < 0.01) in this group. We found that remifentanil used as the sole agent failed to demonstrate any advantage over the combination of fentanyl/propofol with regard to rapid recovery and discharge following anaesthesia for extracorporal shock wave lithotripsy.
The effect of auricular acupuncture on anaesthesia with desflurane
Authors: Taguchi A. , Sharma N. , Ali S. Z. , Dave B. , Sessler D. I. , Kurz A.
Published: March 2003

In most acupuncture studies it is difficult or even impossible to conduct a truly double‐blind trial. However, this is possible when treatments are carried out on anaesthetised patients. Because acupuncture provides analgesia, we tested the hypothesis that needle stimulation of a combination of four ear acupoints would significantly reduce anaesthetic requirement. Ten healthy volunteers were anaesthetised with desflurane and randomly assigned to no treatment or acupuncture; the alternative treatment was given on a subsequent study day. Auricular acupuncture was performed with needles placed at the Shen Men, Thalamus, Tranquiliser and Master Cerebral Points on the right ear. Anaesthetic requirement, determined by the Dixon up‐and‐down method, was defined by the average desflurane concentration that prevented purposeful movement of the extremities in response to noxious electrical stimulation. Volunteers required a greater desflurane concentration to prevent movement on the control than on the acupuncture day: 4.9 (0.7; SD) vs. 4.4 (0.8) vol. %, p = 0.003. Acupuncture thus reduced anaesthetic requirement by 8.5 (7)%.
The management of pain following day‐case surgery
Authors: McHugh G. A. , Thoms G. M. M.
Published: March 2003

The object of this study was to assess patients' experience of pain management following day surgery. One hundred and two patients agreed to take part in a telephone survey, 2 and 4 days following day surgery. The majority of patients (73%) were broadly satisfied with the quality of pain management they received, however, there was room for improvement. Despite modern anaesthesia and surgery, 17% of patients surveyed reported having severe pain immediately following day‐case surgery. The majority (82%) of patients left the day‐case ward in pain and an even higher proportion (88%) had pain at some time between 2 and 4 days postoperatively. Severe levels of pain following discharge from hospital were a concern for 21% of patients. It was reported that day‐case staff did not always ask patients whether they were in pain. Communication with patients is vital in the delivery of optimal care. More support and more information are needed to manage patients' pain effectively, whilst in the day‐case wards and also following discharge, at home.
A comparison of simulated difficult intubation with multiple‐use and single‐use bougies in a manikin*
Authors: Annamaneni R. , Hodzovic I. , Wilkes A. R. , Latto I. P.
Published: March 2003

Summary In a randomised cross‐over study, 20 anaesthetists attempted to place a multiple‐ or single‐use bougie in the trachea of a manikin, in which a grade 3 Cormack and Lehane laryngoscopic view was simulated. The anaesthetists made two attempts at placement with each bougie and were blinded to success (tracheal placement) or failure (oesophageal placement). The success rates for the first attempts with the multiple‐ and single‐use bougies were 85 and 15%, respectively [mean (95% CI) difference between the two bougies 70% (40–84%); p < 0.001]. The success rates for the second attempts were similar to those for the first attempts with both bougies. There is an increased risk of failure to intubate the trachea when using a single‐use bougie, and this must be weighed against the unquantified risk of cross‐infection from prions when using a multiple‐use bougie.
Geometric constraints on composition of sediment derived from erosional landscapes
Authors: Paola Chris , Swenson John B.
Published: March 2003

Although unroofing sequences are well known in the stratigraphic record, there is no general theory for estimating relevant basic quantities such as the time history of sediment production from a particular unit or the degree of mixing between successive units. Here we investigate the production of sediment from layered source rocks that are milled off by steady‐state erosional topography. The shape of the sediment‐production function for milling off a thin horizontal layer is given by the derivative of the hypsometric function, in the form of area contained within contours as a function of contour altitude. The time‐scale for the production function, the ‘topographic mixing time’, is set by the topographic relief divided by the uplift rate. The production function for a sharp transition from one unit to another is given directly by the hypsometric function. The effects of stratal dip parallel to the mean slope of the erosional topography and finite layer thickness can be accounted for to a first approximation by simple geometric corrections to the mixing time.

Finite layer thickness also has the effect of smoothing the production function although most natural hypsometric functions are smooth enough that this effect is relatively weak. The quality of an unroofing sequence can be measured in terms of the ‘sharpness’ of separation of successive peaks in sediment production produced by milling off a sequence of geometrically similar layers. This peak sharpness can be parameterized by a ratio of the interval between successive peaks in sediment production to topographic mixing time. By this measure, the quality of unroofing sequences is controlled by two parameters: the ratio of layer thickness to topographic relief, and the dip angle. The dip angle in concert with topographic mixing exerts a strong control on the degree of signal segregation; in particular, production of cleanly segregated signals for dip angles greater than about 15° requires very high ratios of layer thickness to relief. Hence identification of distinct unroofing sequences may place significant and useful constraints on the attitude and/or thickness of units in the eroding stratigraphy.
Sediment accumulation along a glacially impacted mountainous coastline: north‐east Gulf of Alaska
Authors: Jaeger John M. , Nittrouer Charles A. , Scott Nicole D. , Milliman John D.
Published: March 2003

Tectonically active coastal regions of the world recently have been suggested to supply the bulk of sediment from land to the oceans. Seabed sampling on the continental shelf and in coastal embayments of the north‐east Gulf of Alaska (Alsek River to Prince William Sound) was performed to examine the temporal and spatial variability of sediment accumulation in a mountainous coastal setting. Cores of varying lengths (30–300 cm) were collected at 84 stations to provide information on sedimentary processes using radiochemical (210Pb and 137Cs) techniques. Four types of 210Pb activity profiles were observed, dominantly reflecting steady‐state sediment accumulation. However, nonsteady‐state profiles also were measured, resulting in part from episodic deposition near glacier‐fed rivers and on the Copper River Delta. Sediment accumulation rates in the eastern half of the study area are highest at midshelf depths (≈100 m) (≥10 mm yr−1) and near rivers draining the Bering Glacier (≈20 mm yr−1). On the Copper River Delta, sediment accumulation rates are highest for the delta front (> 20 mm yr−1) and decrease westward along the sediment dispersal route. Total annual sediment accumulation is 90–140×106 tons yr−1 on the shelf in the study area. Annual sediment accumulation for the total marine environment in the study area (including Icy and Yakutat Bays) exceeds 250×106 tons yr−1, potentially making this region the largest sink for sediment in North America. Spatial patterns in sediment accumulation on the shelf are similar between centennial and Holocene time‐scales, reflecting the dominance of the Copper River and Bering and Malaspina glaciers as sediment sources. Temporal variability in accumulation rates between centennial and Holocene time‐scales exists for portions of the study area near fiords and demonstrates the considerable changes that occur in sediment supply during glacial advances and retreats.
Hormonal effects of MPV‐2213ad, a new selective aromatase inhibitor, in healthy male subjects. A phase I study
Authors: Ahokoski Outi , Irjala Kerttu , Huupponen Risto , Halonen Kaija , Salminen Eeva , Scheinin Harry
Published: March 2003

Aims
 A novel non‐steroidal competitive inhibitor of the aromatase enzyme, MPV‐2213ad, was entered into an open dose‐escalation study. The objective of this study was to investigate the tolerability and efficiency of this new compound with assessment of the hormonal effects after study drug administration.

Methods
 MPV‐2213ad was given to 39 healthy male volunteers. Single increasing oral doses of 0.003, 0.03, 0.3, 3, 9, 30 and 100 mg were given to three subjects at each dose level, after which ten subjects received the 300 mg dose and eight subjects the highest 600 mg dose of MPV‐2213ad.

Results
 Serum oestradiol levels were suppressed by 58–65% when MPV‐2213ad was given at doses between 0.3 and 30 mg. A reduction in serum oestradiol levels by 83% from baseline was achieved with the 300 mg dose. No additional decrease was seen with the highest dose. The suppression lasted longer with higher doses of MPV‐2213ad. After the 300 and 600 mg doses serum oestradiol returned to baseline within 4 days. Marked increases in serum concentrations of testosterone, androstenedione, 17‐OH‐progesterone, LH and FSH were also observed at doses between 100 and 600 mg of MPV‐2213ad. The drug was well‐tolerated and the adverse events were mild or moderate including hot flushes, mild vertigo, nausea, acne and gastrointestinal discomfort.

Conclusions
 MPV‐2213ad has a potent, dose‐dependent inhibitory effect on serum oestradiol. It was selective for the aromatase enzyme with no signs of adreno‐cortical suppression or haematological or biochemical toxicity.
How reproducible is bilateral forearm plethysmography?
Authors: Petrie John R. , Ueda Shinichiro , Morris Andrew D. , Murray Lilian S. , Elliott Henry L. , Connell John M. C.
Published: March 2003

Aims
 In studies using strain‐gauge forearm plethysmography to measure changes in forearm blood flow (FBF) during intra‐arterial infusions of vasoactive substances, measurements are often made in both arms simultaneously and the change in ratio of the infused and control arms used to express responses. However, the reproducibility of bilateral plethysmography in this setting has not been addressed in published studies. The unilateral technique remains in use, and forearm vascular resistance (FVR), an alternative method of expressing responses, is used by some investigators. We have assessed: (a) the intra‐subject variability of bilateral FBF measurements (FBF ratios) at rest, after unilateral forearm exercise, and during intra‐arterial infusions of vasoconstrictor substances; (b) whether bilateral plethysmography is more reproducible than unilateral plethysmography; and (c) the reproducibility of FVR (unilateral and bilateral).

Methods
 Study 1 Nine healthy subjects attended 3 study days, 1 week apart. FBF was measured at rest and after 2 min of standardized unilateral forearm exercise; between‐day intra‐subject variability was expressed as coefficients of variation (CV) calculated using two‐way analysis of variance (ANOVA). Study 2 Five healthy subjects attended 2 study days when FBF was measured during incremental infusions of noradrenaline (15, 30, 150, 300 pmol min−1 ) and angiotensin II (1, 5, 10, 50 pmol min−1 ); for each individual subject at each dose intra‐subject variability was assessed using the difference between responses (percentage change from baseline) on days 1 and 2.

Results
 Study 1 At rest, intra‐subject variability (CV) of baseline FBF ratios was 19% compared with 31% (left) and 39% (right) for unilateral FBF measurements. After ipsilateral exercise, unilateral FBF measurements were more reproducible (32 vs 17%) than FBF ratios; by 20 min after exercise, the previous pattern had been re‐established (19 vs 27%). Intra‐subject variability (CV) of baseline FVR ratio and post‐exercise FVR was 14%. Study 2 Inter‐quartile ranges of the differences between responses on days 1 and 2 (FBF ratios vs FBF) were: angiotensin II 14 vs 18%; noradrenaline 16 vs 27%.

Conclusions
 FBF ratios are more reproducible than unilateral FBF measurements at rest (CV 19%vs 39%) and for measuring responses to intra‐arterial infusions of vasoconstrictor substances. FVR may have a small reproducibility advantage. Non‐experimental stimuli can cause significant and misleading changes in measured responses if unilateral measurements are used; it is therefore recommended that responses to intra‐arterial infusions should be measured using bilateral forearm plethysmography with the results expressed as FBF ratios.
Comparison of the effects of nadolol and bisoprolol on noradrenaline‐evoked venoconstriction in man in vivo
Authors: Abdelmawla A. H. , Langley R. W. , Szabadi E. , Bradshaw C. M.
Published: March 2003

Aims
 In an attempt to explore the possible involvement of venodilator β‐adrenoceptors in the constrictor response of the human dorsal hand vein to noradrenaline, we examined the ability of nadolol, a non‐selective β1/β2‐adrenoceptor antagonist, and bisoprolol a selective β1‐adrenoceptor antagonist, to potentiate the response.

Methods
 Twelve healthy male volunteers participated in three weekly sessions. In each session nadolol (40 mg), bisoprolol (5 mg) or placebo was ingested, and (‐) noradrenaline acid tartrate (0.33–33.33 ng min−1 ) was infused locally into the dorsal hand vein 2 h after the ingestion of the drugs. Changes in vein diameter were monitored with the dorsal hand vein compliance technique. Subjects were allocated to treatments and sessions according to a double‐blind balanced cross‐over design. Systolic and diastolic blood pressure, and heart rate were also measured.

Results
 Noradrenaline produced dose‐dependent venoconstriction which was antagonized by bisoprolol but remained unaffected by nadolol (ANOVA with repeated measures: F(2,22)=5.07, P<0.025; Dunnett's test: placebo vs nadolol; t=0.35, df=22, k=3, NS; placebo vs bisoprolol; t=2.83, df=22, k=3, P<0.01 ). Mean (±s.e. mean) log ED50s (ng min−1 ) were 0.44±0.15 (placebo), 0.73±0.11 (bisoprolol) and 0.50±0.21 (nadolol); mean (95% CI) differences were 0.29 (−0.005, 0.58) for placebo vs bisoprolol and 0.06 (−0.35, 0.46) for placebo vs nadolol. Both active drugs significantly (compared with placebo, P<0.05) decreased (mean change from pretreatment±s.e. mean) heart rate (bisoprolol −16.08±2.01; nadolol −11.67±2.06) and systolic blood pressure (bisoprolol −15.0±0.80; nadolol −9.47±0.18).

Conclusions
 The failure of nadolol and bisoprolol to potentiate noradrenaline‐evoked venoconstriction argues against the involvement of masked venodilator β‐adrenoceptors in the response. The mechanism underlying the antagonism of noradrenaline‐evoked venoconstriction by bisoprolol remains to be elucidated.
Lacidipine: effects on vascular pressor responses throughout the dosage interval in normotensive subjects
Authors: Ueda Shinichiro , Donnelly Richard , Panfilov Vsevolod , Morris Andrew D. , Elliott Henry L.
Published: March 2003

Aims
 To assess the duration and consistency of the pharmacological activity of the dihydropyridine calcium antagonist drug, lacidipine.

Methods
 Eight healthy normotensive young males participated in a double‐blind randomised crossover comparison of single and multiple doses (for 2 weeks) of lacidipine and placebo. The calcium antagonist effects were quantified at 2, 6 and 24 h post dose by the extent of the attenuation of the pressor responses to the intravenous administration of the vasoconstrictors angiotensin II and noradrenaline.

Results
 After 2 weeks of treatment, lacidipine consistently and significantly attenuated the pressor responses to both agents at 2 h post dose. At 6 and 24 h post dose there was a significant and progressive decline in the effectiveness of lacidipine in attenuating the pressor responses and for the response to angiotensin II there was no statistically significant effect at either 6 or 24 h post dose.

Conclusions
 These results indicate that there is an obvious ‘peak’ in the pharmacological activity of lacidipine at about 2 h post dose and that this activity is not fully and consistently maintained throughout 24 h.
Prescription patterns of diuretics in Dutch community‐dwelling elderly patients
Authors: Van Kraaij Dave J. W. , Jansen René W. M. M. , De Gier Johan J. , Gribnau Frank W. J. , Hoefnagels Willibrord H. L.
Published: March 2003

Aims
 To describe age‐ and gender‐related prescription patterns of diuretics in community‐dwelling elderly, and to compare diuretics to other cardiovascular (CV) medications.

Methods
 Cross‐sectional study of patient‐specific prescription data derived from a panel of 10 Dutch community pharmacies. Determination of proportional prescription rates and prescribed daily dose (PDD) of diuretics, cardiac glycosides, nitrates, angiotensin converting enzyme (ACE) inhibitors, β‐adrenoceptor blockers, and calcium channel blockers in all 5326 patients aged 65 years or older dispensed CV medications between August 1st, 1995 and February 1st, 1996.

Results
 Diuretics were prescribed to 2677 of 5326 patients (50.3%), 1325 patients (24.9%) using thiazides and 1198 patients (22.5%) using loop diuretics. Prescription rates of loop diuretics increased from 15.1% in patients aged 65–74 years to 37.2% in patients aged 85 years or older. Rates also increased for digoxin and nitrates. Rates for thiazide diuretics remained unchanged with age; rates for β‐adrenoceptor blockers, ACE inhibitors and calcium channel blockers declined with age. Thiazides were prescribed to 30.1% of women compared with 16% of men (P<0.001). Average PDD was 135±117% of defined daily dose (DDD) for loop diuretics, and highest for bumetanide (245±2.01% of DDD, equivalent to 2.5±2.0 mg). Average PDD was 74±40% of DDD for thiazides, and highest for chlorthalidone (100±49% of DDD, equivalent to 25±12 mg).

Conclusions
 Important characteristics of diuretic usage patterns in this elderly population were a steep increase in loop diuretic use in the oldest old, a large gender difference for thiazide use, and high prescribed doses for thiazides.
Pharmacokinetic and pharmacodynamic drug interactions between digoxin and macrogol 4000, a laxative polymer, in healthy volunteers
Authors: Ragueneau Isabelle , Poirier Jean‐Marie , Radembino Nathalie , Sao Anne Buu , Funck‐Brentano Christian , Jaillon Patrice
Published: March 2003

Aims The aim of this study was to examine the bioequivalence between a single oral dose of digoxin administered alone and with a coadministration of macrogol 4000 (a laxative polymer) in 18 healthy volunteers.

Methods This was an open, randomised, two‐way cross‐over study, with a single dose oral administration of 0.5 mg digoxin administered alone or in combination with macrogol 4000, 20 g day−1 during 8 days. Pharmacokinetics of digoxin, heart rate and PR ECG interval at rest were assessed.

Results Macrogol 4000 coadministration was associated with a 30% decrease of digoxin AUC and a 40% decrease in its Cmax (P<0.05). Digoxin tmax and t1/2,z were not significantly altered. Heart rate and PR interval did not differ during the two therapeutic sequences, digoxin alone and digoxin in combination.

Conclusions Macrogol 4000 coadministration interacts with single‐dose digoxin pharmacokinetics. This is most likely due to a reduction of the intestinal absorption of digoxin. However, there was no consequence of this interaction on heart rate and AV conduction.
Identification of the human cytochrome P450 enzymes involved in the in vitro metabolism of artemisinin
Authors: Svensson  , Ashton
Published: March 2003

Aims The study aimed to identify the specific human cytochrome P450 (CYP450) enzymes involved in the metabolism of artemisinin.

Methods Microsomes from human B‐lymphoblastoid cell lines transformed with individual CYP450 cDNAs were investigated for their capacity to metabolize artemisinin. The effect on artemisinin metabolism in human liver microsomes by chemical inhibitors selective for individual forms of CYP450 was investigated. The relative contribution of individual CYP450 isoenzymes to artemisinin metabolism in human liver microsomes was evaluated with a tree‐based regression model of artemisinin disappearance rate and specific CYP450 activities.

Results The involvement of CYP2B6 in artemisinin metabolism was demonstrated by metabolism of artemisinin by recombinant CYP2B6, inhibition of artemisinin disappearance in human liver microsomes by orphenadrine (76%) and primary inclusion of CYP2B6 in the tree‐based regression model. Recombinant CYP3A4 was catalytically competent in metabolizing artemisinin, although the rate was 10% of that for recombinant CYP2B6. The tree‐based regression model suggested CYP3A4 to be of importance in individuals with low CYP2B6 expression. Even though ketoconazole inhibited artemisinin metabolism in human liver microsomes by 46%, incubation with ketoconazole together with orphenadrine did not increase the inhibition of artemisinin metabolism compared to orphenadrine alone. Troleandomycin failed to inhibit artemisinin metabolism. The rate of artemisinin metabolism in recombinant CYP2A6 was 15% of that for recombinant CYP2B6. The inhibition of artemisinin metabolism in human liver microsomes by 8‐methoxypsoralen (a CYP2A6 inhibitor) was 82% but CYP2A6 activity was not included in the regression tree.

ConclusionsArtemisinin metabolism in human liver microsomes is mediated primarily by CYP2B6 with probable secondary contribution of CYP3A4 in individuals with low CYP2B6 expression. The contribution of CYP2A6 to artemisinin metabolism is likely of minor importance.
Entry‐into‐human study with the novel immunosuppressant SDZ RAD in stable renal transplant recipients
Authors: Neumayer  , Paradis  , Korn  , Jean  , Fritsche  , Budde  , Winkler  , Kliem  , Pichlmayr  , Hauser  , Burkhardt  , Lison  , Barndt  , Appel‐Dingemanse
Published: March 2003

Aims To evaluate the tolerability of single oral SDZ RAD doses in stable renal transplant recipients and the pharmacokinetics of ascending SDZ RAD doses when coadministered with steady‐state cyclosporin A microemulsion (Neoral).

Methods This randomized, double‐blind, placebo‐controlled, sequential study involved 54 patients in six treatment groups; a different SDZ RAD dose (0.25, 0.75, 2.5, 7.5, 15, 25 mg) was assessed in each group. Patients received a single oral dose of SDZ RAD (n=6) or placebo (n=3) with their usual Neoral dose. SDZ RAD and cyclosporin A pharmacokinetic parameters were determined.

Results All SDZ RAD doses were well tolerated, with no discontinuations due to adverse events, serious adverse events, or deaths. Similar proportions of patients receiving SDZ RAD and placebo had at least one adverse event (44% and 50%, respectively). Mean changes in laboratory variables (baseline to endpoint) showed no clinically meaningful differences between SDZ RAD and placebo groups. SDZ RAD was absorbed rapidly and showed dose‐proportional pharmacokinetics (dose: 2.5–25 mg), based on systemic exposure. Multiple postabsorptive phases in the pharmacokinetic profile indicate tissue distribution. The elimination half‐life ranged from 24 to 35 h across the five highest dose groups. Pharmacokinetics were similar in men and women. Co‐administration of escalating single oral SDZ RAD doses did not affect steady‐state cyclosporin A pharmacokinetics.

Conclusions SDZ RAD was well tolerated; safety profiles of SDZ RAD and placebo were similar. SDZ RAD pharmacokinetics were dose‐proportional across the range 2.5–25 mg in conjunction with cyclosporin A‐based therapy, according to systemic exposure. Cyclosporin A pharmacokinetics were not affected by coadministration of single oral doses of 0.25–25 mg SDZ RAD.
A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs
Authors: García Rodríguez  , Duque  , Castellsague  , Pérez‐Gutthann  , Stricker
Published: March 2003

Aims The aim of this cohort study was to estimate the risk of clinical acute liver injury among users of oral antifungals identified in the general population of the General Practice Research Database in UK.

Methods The cohort included 69 830 patients, 20–79 years old, free of liver and systemic disease, who had received at least one prescription for either oral fluconazole, griseofulvin, itraconazole, ketoconazole, or terbinafine between 1991 and 1996.

Results Sixteen cases of acute liver injury were identified and validated. Ten cases occurred during nonuse of oral antifungals with a background rate of 0.6 per 100 000 person‐months (95% confidence interval 0.3,1.1). Five cases occurred during current use of oral antifungals. Two were using ketoconazole, another two itraconazole, and one terbinafine. Incidence rates of acute liver injury were 134.1 per 100 000 person‐months (36.8,488.0) for ketoconazole, 10.4 (2.9–38.1) for itraconazole, and 2.5 (0.4,13.9) for terbinafine. The remaining case was associated with past use of fluconazole. Ketoconazole was the antifungal associated with the highest relative risk, 228.0 (95% confidence interval 33.9,933.0), when compared with the risk among nonusers, followed by itraconazole and terbinafine with relative risks of 17.7 (2.6,72.6) and 4.2 (0.2,24.9), respectively.

Conclusions Ketoconazole and itraconazole were the two oral antifungal associated with a marked increase of clinical acute liver injury. The risk associated with ketoconazole should be taken into account when prescribing it as initial treatment for uncomplicated fungal infections.
Cytochrome P450 isoform selectivity in human hepatic theobromine metabolism
Authors: Gates Simon , Miners John O.
Published: March 2003

Aims The plasma clearance of theobromine (TB; 3,7‐dimethylxanthine) is known to be induced in cigarette smokers. To determine whether TB may serve as a model substrate for cytochrome P450 (CYP) 1A2, or possibly other isoforms, studies were undertaken to identify the individual human liver microsomal CYP isoforms responsible for the conversion of TB to its primary metabolites.

Methods The kinetics of formation of the primary TB metabolites 3‐methylxanthine (3‐MX), 7‐methylxanthine (7‐MX) and 3,7‐dimethyluric acid (3,7‐DMU) by human liver microsomes were characterized using a specific hplc procedure. Effects of CYP isoform‐selective xenobiotic inhibitor/substrate probes on each pathway were determined and confirmatory studies with recombinant enzymes were performed to define the contribution of individual isoforms to 3‐MX, 7‐MX and 3,7‐DMU formation.

Results The CYP1A2 inhibitor furafylline variably inhibited (0–65%) 7‐MX formation, but had no effect on other pathways. Diethyldithiocarbamate and 4‐nitrophenol, probes for CYP2E1, inhibited the formation of 3‐MX, 7‐MX and 3,7‐DMU by ≈55–60%, 35–55% and 85%, respectively. Consistent with the microsomal studies, recombinant CYP1A2 and CYP2E1 exhibited similar apparent Km values for 7‐MX formation and CYP2E1 was further shown to have the capacity to convert TB to both 3‐MX and 3,7‐DMU.

Conclusions Given the contribution of multiple isoforms to 3‐MX and 7‐MX formation and the negligible formation of 3,7‐DMU in vivo, TB is of little value as a CYP isoform‐selective substrate in humans.