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The primary objective of this study was to determine in vivo tissue/blood partition coefficients of propofol for use in physiological modelling of its pharmacokinetics. The sheep was used as an animal model. In the main series of experiments, crossbred ewes received a bolus of propofol 1% (Diprivan) followed by an infusion during which blood concentrations were measured at intervals. After 2 h, the sheep were killed with an injection of potassium chloride, and tissue samples were taken for storage at -20 degrees C and subsequent analysis. Tissue/blood partition coefficients depend on the amount of triglyceride which accumulates in blood from the propofol vehicle; for blood, free of added triglyceride, the following coefficients were calculated: brain, 3.23; heart, 5.94; kidney, 2.46; spleen, 1.86; semimembranosus muscle, > or = 1.61; triceps muscle, > or = 1.47. Calculated tissue/water coefficients were 35 times greater. There was indirect evidence of extraction of propofol by the lungs.

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In planning a study of the pharmacokinetics of propofol in sheep, contradictions were noted in the literature with regard to loss of propofol during storage of blood samples. This prompted a study of such loss from samples of sheep blood and plasma during storage at room temperature, +4 degrees C and -20 degrees C, for up to 17 days, over a range of concentrations from 1 to 20 micrograms/mL. Samples were drawn from 22 different sheep. Analysis was by the method of Adam et al. (1981). The best estimate of the overall mean loss rate was 0.7% per day with 95% confidence limits of 0.3% to 1.2% per day. The loss rate increased nonsignificantly with storage temperature. There were very small nonsignificant differences of loss rate between plasma and blood, between different concentrations, and between genders. There were significant differences of loss rate between sheep--up to about 2% per day in blood or plasma from any one sheep.

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alpha 2-adrenoceptor agonist drugs can cause respiratory changes leading to a short period of hypoxaemia in sheep. It has been suggested that this is due to transient platelet aggregation and pulmonary microembolism. If platelet aggregation were to follow platelet activation in response to the administration of alpha 2 agonists, plasma thromboxane levels would be expected to rise. This study was carried out to measure plasma thromboxane B2 concentrations before and after the intravenous administration of the alpha 2-agonist drug xylazine at a dose of 0.1 mg/kg. It was found that the plasma thromboxane concentration rose by 320% and, furthermore, the rise was prevented by the prior administration of atipamezole hydrochloride (0.125 mg/kg), an alpha 2-adrenoceptor antagonist.

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The pharmacokinetics of thiopentone sodium administered intravenously as a single dose (11 mg/kg) were studied in acepromazine pre-medicated horses and ponies in which anaesthesia was maintained with either halothane (Group 1) or isoflurane (Group 2). The results showed that the disposition kinetics of thiopentone in horses and ponies were best described by a three-compartment open model. In plasma, a very short initial distribution phase in both horses and ponies, half-life 1.4 +/- 1.2 min (mean +/- SD) and 1.3 +/- 0.7 min, respectively, was obtained, which was followed by a second comparatively slower redistribution phase, half-life 16 +/- 12 min and 11 +/- 5 min, respectively. The volume of distribution for the drug was large, especially in the ponies which received isoflurane (1127 +/- 86 ml/kg), compared to the horses which received halothane (742 +/- 89 ml/kg). The drug had a somewhat shorter elimination half-life in the horses (147 +/- 21 min) than in than ponies (222 +/- 44 min), but no obvious difference in clearance of the drug was observed between the horses (3.5 +/- 0.5 ml/min/kg) and ponies (3.6 +/- 0.8 ml/min/kg).

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Nebulized antibiotic therapy in cystic fibrosis is an established procedure. The present study was designed to quantitate deposition, and assess its relation to the disease state. Twenty seven children and young adults with cystic fibrosis (mean 11.6 years, range 4-23 years, 12 females) were studied to establish the quantity and pattern of deposition of nebulized tobramycin in the respiratory tract. A single (120 mg) dose of nebulized 99 m technetium-labelled tobramycin was administered, and imaged with a gamma-camera. The mean penetration index (which compares the distribution of 81 m-Krypton gas with Tc-radioaerosol) was also used to measure peripheral deposition efficiency. The aerosol mass median diameter (MMAD) for the compressor-nebulizer system used was 5.3 u, measured with the Malvern Mastersizer. Serial sputum samples were fluroimmunoassayed for tobramycin in nine patients. A mean of 8.0 (SEM 1.0) mg tobramycin reached the lungs. There was no relationship between the total pulmonary deposition and indices of pulmonary damage in cystic fibrosis. Sixteen percent of the lung tobramycin reached the periphery. The greater the lung damage as indicated by FEV1 and Chrispin-Norman scores, the smaller the proportion of pulmonary tobramycin that reached the periphery. The mean penetration index increased with increase in the FRC, but bore no relation to other respiratory function tests or to chest X-ray scores. Sputum tobramycin concentrations reached levels bactericidal for Pseudomonas aeruginosa. Airway obstruction and damage affected the proportion of pulmonary tobramycin reaching the periphery. The proportion of tobramycin reaching the lungs was small and variable.(ABSTRACT TRUNCATED AT 250 WORDS)

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We made a prospective study of the incidence and natural history of algodystrophy and associated changes in bone mineral density in the ankles and feet of 60 consecutive patients who had suffered unilateral fractures of the tibial shaft. At bone union, 18 patients showed signs of algodystrophy. Its development was independent of the type of fracture management and of the severity of injury. Patients with algodystrophy lost significantly more bone mineral than did those without but the degree of this loss was independent of the type of treatment and of the time to fracture union. In most cases the symptoms resolved within six months of fracture union but in four patients they were still present at one year and two of these had not returned to work.

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OBJECTIVE: To determine whether a small fixed perioperative dose of warfarin would prevent deep vein thrombosis after total hip replacement. DESIGN: Prospective, randomised, double blind placebo controlled trial. SETTING: Winford Orthopaedic Hospital, Bristol. SUBJECTS: 148 patients having primary total hip replacement. INTERVENTION: Warfarin 1 mg given daily for one week before and three weeks after surgery. MAIN OUTCOME MEASURE: Deep vein thrombosis diagnosed by the iodine-125 labelled fibrinogen uptake method. RESULTS: Deep vein thrombosis occurred in 25 (34%) of the patients given warfarin and 19 (26%) of the controls (difference 8%; 95% confidence interval -6.8% to 22.8%). CONCLUSION: Fixed minidose warfarin does not prevent deep vein thrombosis after total hip replacement.

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1. Tissue perfusion was measured in seven sheep by the radioactive microsphere method. 2. The sheep were anaesthetised and ventilated to a near normal arterial carbon dioxide tension. 3. Cardiac output was measured utilizing the Fick principle as applied to thermodilution and at the end of the investigation the sheep were killed by an overdose of anaesthetic. 4. The results were compared with previously published values for conscious sheep and anaesthetised horses and found to be similar when known variations in body composition and physiology were considered.

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Radioiodinated monoclonal antibodies (MCA) were administered by the lumbar route into the cerebrospinal fluid (CSF) of four patients with malignant leptomeningeal disease. Evidence suggesting uptake of 131I-MCA by tumour sites was seen in scintigrams. Dosimetry calculations were carried out, assuming that a proportion of the administered radionuclide was bound as a thin layer on the CSF surfaces of the meninges. The percentage injected dose and the clearance curves for the head and four spinal segments were obtained by scintigraphy after administration of tracer amounts of 131I-MCA (7-18 MBq). Although radioisotope levels in the central nervous system (CNS) fell, as determined by both external scintillation counting and direct CSF sampling, a marked difference in the measurements developed with respect to time. The ratio of these two measurements reached a maximum of 49:1, 7 days after monoclonal antibody administration. Patients subsequently received therapeutic amounts (870-1600 MBq) of 131I-MCAs, resulting in clinical remissions and prolonged survival. The mean absorbed radiation dose was estimated as 3.9 cGy.MBq-1 to the thoraco-lumbar region of the spine and 0.51 cGy.MBq-1 to the outer surface of the brain. The maximal dose delivered to the surface of the CNS in the region of the spine and brain was 5800 and 600 cGy, respectively.

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The blood content of tissue in eight anaesthetized sheep and three anaesthetized horses was measured using chromium labelled autologous red blood cells. 2. Approximately half the total blood volume was found to be distributed within the body tissues and, with the exception of the spleen and fat, the distribution was similar in these two species.

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Bone density of the radius was measured using both standard photon absorptiometry and X-ray computed tomography (CT) scanning, and of the femur using CT, in 21 young women with amenorrhea and estrogen deficiency due to hyperprolactinemia, 8 due to ovarian failure or weight loss, 17 postmenopausal women with bone fractures presumed to be due to osteoporosis, and 36 young normal controls. Bone density in the postmenopausal women was reduced by 18-20% in the radius and 11% in the femur (p less than 0.001). In the hyperprolactinemic group bone density was significantly reduced only in the femur (by 4%, p less than 0.01). Bone density appeared to be reduced in the other young amenorrheic women both in the radius (by 2-5%) and the femur (3%) but the difference was not significant, although the group was small. This and other studies of bone density suggest the need for prophylactic treatment to prevent osteoporosis in young women with amenorrhea and estrogen deficiency, whatever the cause.

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In a single-centre prospective trial 200 consecutive patients undergoing thoracic surgery were randomised to receive one of two prophylactic regimes against deep vein thrombosis (DVT). These were 5000 units of subcutaneous heparin twice a day, alone or combined with the wearing of graded compression stockings. The diagnosis of DVT was made clinically and with 131I labelled fibrinogen. Six DVTs developed in the stocking group and 11 in the non-stocking group. The results suggest that the use of stockings reduces the incidence of DVT when added to herparin but the difference is not statistically significant. To obtain a predictive index for the development of DVT, discriminant analysis was applied to the control and stocking groups separately and combined. Five simple clinical variables gave a true positive prediction rate, for the combined group, of 94% and a false positive prediction rate of 26%.

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Monoclonal antibody UJ13A, radiolabelled with 131I, was intravenously administered to patients with primary brain tumours. The antigen recognised by UJ13A is present on most neuroectodermally derived tissue. The ratio of uptake in tumour to normal brain, assessed by scintigraphy, improved with time. Maximal tumour uptake occurred between 4 and 48 h. Dynamic and static scintigrams indicated some early sequestration of radiolabelled antibody by the liver. Tumours were surgically resected in seven patients at various intervals after antibody administration showing tissue to blood ratios increasing with time in all parts of the lesion (viable and necrotic tumour, cyst fluid), and in normal brain. The highest tissue to blood ratio in viable tumour was 5.1 at 16 days after injection. In tissues resected 2-3 days after injection there was relatively greater uptake in the viable tumour compared to necrotic tumour and cyst fluid. In contrast, tissues resected later (6-16 days) showed greater uptake in ischaemic tissue than viable tumour, suggesting diffusion was an important factor influencing tumour uptake. The amount of radioactivity per gram of tumour tissue was less than 0.005% of the injected dose. Future studies are needed using different antibodies, antibody fragments and additional methods of optimising delivery.

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A mathematical model of the cerebrospinal fluid (CSF) flow dynamics found in hydrocephalic infants with myelomeningocele lesions was constructed using criteria obtained from analogous clinical situations where 125I-labelled and 131I-labelled ortho-iodobenzoyl-amino-acetic acid (hippuran) had been employed to measure CSF flow dynamics. The quantitative results from this study allowed clinical data to be assessed and the importance of various CSF transfer mechanisms to be discussed. Our mathematical model indicates that the majority of radiopharmaceutical passes from the cerebral reservoir (the ventricles) into the blood. Experimental evidence indicates that the principal mechanism responsible for this movement is the bulk flow of CSF between its sites of production in the choroid plexus and absorption by the arachnoid villi.

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The biodistribution of a radiolabelled monoclonal antibody (123I-NDOG2) was studied in patients with ovarian tumour. It was found that the uptake patterns in known tumour sites was variable and that the clearance of the agent from the vascular pool was due to renal excretion of the radionuclide and the redistribution of the radioactively labelled compound into other compartments. The mean (+/- SD) plasma clearance time was 20.8 (+/- 2.3) h and the ratios of target (tumour) to background (thigh) ranged between 1.4 and 4.8. The ratio between the plasma radioactivity at either 3.5 or 20 h after administration was calculated relative to the initial plasma radioactivity. These values (0.79 and 0.48, respectively) were incorporated into an image-subtraction technique that allowed for redistribution outside the vascular pool. A whole-body dose equivalent to 16.3 mu Sv MBq-1 (60.4 mrem.mCi-1) was calculated.

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Standard data for the horse which can be used in physiologically based mathematical computer modelling are presented. The data includes figures for tissue mass, density and perfusion, obtained by measurement mainly from horses weighing 200 to 300 kg. Other related parameters such as mean transit times and tissue blood volume have been calculated and included in the actual values listed for a 250 kg horse.

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Muscle perfusion was studied in conscious and anaesthetised horses by monitoring the clearance of a locally injected bolus of saline containing radioactive xenon (133Xe). The mean of all the measurements made from the brachiocephalicus and semimembranosus muscles in conscious subjects was 1.29 ml/min/100 g while in anaesthetised subjects it was 0.40 ml/min/100 g. The significance of these results is discussed in relation to the clinical occurrence of post anaesthetic myositis.

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An estimation of the radiation dose to mans' testes, the critical organ, for radiosulphate (Na2(35)SO4) has been made by a combination of studies on rats and human volunteers. The radiation dose to rats testes and the rate of disappearance of radiosulphate from the blood and urine of humans have been increased. The calculated radiation dose of 7.7 muGy/MBq to mans' testes is lower than previously reported.

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Using readily available beta and gamma detectors, combined measurements of exchangeable sodium, exchangeable potassium, total body water and extracellular fluid volume using the isotopes 24Na, 43K, 3H and 35S were made in ten normal subjects. These measurements were repeated 1-6 weeks later so that an index of precision for each isotope study could be calculated. For such measurements the precision was 55 mmol for exchangeable sodium, 149 mmol for exchangeable potassium, 1.26 litres for total body water and 1.11 litres for extracellular fluid volume. The precision of our method is the best so far reported using readily available apparatus. These results may encourage further studies on different pathological conditions in man to be undertaken in peripheral laboratories.

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