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Biomedical subjects

W T Phillips

Publications and source records attributed to W T Phillips.

At least 19 recordsLinked to original sources

Kinetics of liposome-encapsulated hemoglobin after 25% hypovolemic exchange transfusion.

Liposome-encapsulated hemoglobin (LEH) is being developed as an oxygen therapeutic. In this work, we evaluated a neutral formulation of PEGylated LEH for its circulation and distribution properties in rodent models of 25% hypovolemic exchange transfusion. About 25% of blood in rats and rabbits was exchanged with LEH that had been previously labeled with 99mTc radionuclide. The distribution of 99mTc-LEH was followed by gamma camera imaging and intermittent blood sampling during 48 h, and counting the tissue-associated radioactivity after necropsy at 48 h. On the basis of circulation kinetics, the half-life of 99mTc-LEH in blood was 30 and 39.8 h in rats and rabbits, respectively. Apart from blood, major organs of accumulation of LEH after 48 h included liver (rats, 10.3% and rabbits, 5.4% of injected dose) and spleen (rats, 2.4% and rabbits, 0.8% of injected dose). The results demonstrate that LEH circulates for a prolonged time after administration and that the animals tolerate at least 25% of blood exchange without any distress. Subsequent to the enhanced uptake in the RES, the rats clear LEH from the circulation faster than the rabbits.

Animals↗

Neutral and anionic liposome-encapsulated hemoglobin: effect of postinserted poly(ethylene glycol)-distearoylphosphatidylethanolamine on distribution and circulation kinetics.

To prepare long-circulating liposomes, poly(ethylene glycol) (PEG)-lipid is usually mixed with other lipid components before vesicle formation. PEG-lipids can also be postinserted in the outer layer of liposomes after the preparation. In this study, PEG-distearoylphosphatidylethanolamine was incorporated by postinsertion technique into liposome-encapsulated hemoglobin (LEH) carrying neutral or negative charge. Postinsertion technique improved the encapsulation efficiency of hemoglobin from about 0.0017 to 0.017 (hemoglobin/phospholipid, molar ratio) for a similar lipid composition. Thus, neutral, anionic, PEG-neutral, and PEG-anionic LEHs were made and labeled with technetium-99m to follow their biodistribution. A small dose of LEH (approximately 15 mg of phospholipid) was injected intravenously in rabbits, and its distribution was monitored by blood sampling, gamma camera imaging, and tissue radioactivity counting on necropsy. The 24-h blood levels of neutral, PEG-neutral, anionic, and PEG-anionic LEHs were 14, 40.3, 13.1, and 35.7% of injected dose, respectively; calculated T(1/2) values of circulation were 8.9, 19.3, 9.6, and 16.5 h, respectively. PEGylation also influenced accumulation of LEH in the reticuloendothelial system. Liver uptake of neutral LEH dropped from 52.1 to 19.1%, whereas that of anionic LEH came down from 35.3 to 11.5% on PEGylation. In contrast, PEGylation increased the spleen uptake by 8.5- and 2.5-fold for neutral and anionic LEH, respectively. The results demonstrate that PEGylation by postinsertion not only improves the circulation t1/2 of LEH but also enhances hemoglobin content inside the vesicles for better oxygen-carrying capacity.

Animals↗

Circulation and biodistribution profiles of long-circulating PEG-liposomes of various sizes in rabbits.

To determine the largest size of liposomes that can retain stealth behavior conferred by poly(ethylene glycol)-DSPE, neutral liposomes were studied in rabbits for their circulation and distribution. Five sizes (136.2, 165.5, 209.2, 275 and 318 nm) of liposomes (DSPC, Cholesterol, PEG-DSPE and alpha-tocopherol, 90:80:4.5:3.9 molar ratio) were made by extrusion technique and radiolabeled with technetium-99m (Tc-99m) to follow their distribution through 24 h. Although all liposomes showed prolonged circulation in blood, the amount still in circulation at 24 h was dependent on their size. Radioactivity accumulation in spleen progressively increased with increase in size of the liposomes. In the size range of approximately 160-220 nm, liver uptake was minimum, spleen uptake was moderate while the amount of circulating liposomes was maximum. Gamma camera scintigraphy corroborated the distribution pattern of liposomes on necropsy. Images within 1h showed high blood pool activities for liposomes of all sizes. However, at 24h, the blood pool activity was diminished for 275 nm and negligible for 308 nm liposomes; the smaller sized liposomes (136.2-209.2 nm) continued to show high blood pool activity. The amounts of radioactivity still circulating at 24h were 46.4, 50.4, 46.8, 36.2 and 14.5% for 136.2, 165.5, 209.2, 275 and 318 nm liposomes, respectively. Corresponding circulation T(1/2)s were 21.7, 26.5, 24.9, 18.7 and 8.9h, respectively. Thus, the optimum size of PEG-liposomes for prolonged circulation in rabbits is 160-220 nm. Beyond this range, the stealth property of PEG-liposomes is significantly compromised and the distribution is characterized by high RES accumulation.

Analysis of Variance↗

Accumulation of PEG-liposomes in the inflamed colon of rats: potential for therapeutic and diagnostic targeting of inflammatory bowel diseases.

Therapeutic intervention in inflammatory bowel diseases (IBDs) is often associated with severe toxicity related to the nonspecific and ubiquitous interaction of drugs with the organs and tissues. In order to prevent side effects from aggressive and prolonged treatment with glucocorticoids and immunosuppressive agents, preferential accumulation of these potent drugs in diseased tissue is desired. In this work, we report that liposomes show a remarkable tendency to accumulate in inflamed colon of rats with experimental colitis. The disposition of liposomes was monitored by labeling them with Tc-99m followed by gamma camera imaging, and determining biodistribution of radioactivity in various organs. The images showed distinct accumulation of radioactivity in the colon of rats with colitis, while the abdomen of normal rats was conspicuously free of any visible radioactivity. Although images acquired 4 h after Tc-99m-liposome injection were clear enough for diagnostic indication, the real potential of liposomes for drug delivery was evident in 24 h images where the major organs of liposome accumulation were dwarfed by intense colon activity in animals with colitis. On necropsy, 13.5% +/- 5.48 of the activity accumulated in the inflamed colon as compared to only 0.1% in the normal colon, giving a target-to-nontarget ratio of 135. The blood borne radioactivity was 9% +/- 2.12 (colitis) and 25.7% +/- 4.27 (normal), indicating that the decrease in circulating liposomes is associated with an increase in liposome accumulation in the inflammatory site. The other two major organs that accumulated liposomes were spleen (10.7% normal vs. 11% colitis) and liver (8% normal vs. 10.1% colitis). In conclusion, this study demonstrates the innate propensity of liposomes to accumulate in the sites of inflammation and potential of liposomes loaded with therapeutic drugs or diagnostic agents for targeting colitis.

Animals↗

Evaluation of [(99m)Tc] liposomes as lymphoscintigraphic agents: comparison with [(99m)Tc] sulfur colloid and [(99m)Tc] human serum albumin.

This study investigates the use of [(99m)Tc] liposomes for the detection of sentinel lymph nodes. A variety of [(99m)Tc] liposome formulations were compared with common lymphoscintigraphic agents including [(99m)Tc] regular-sulfur colloid (SC), [(99m)Tc] 0.22 microfiltered-SC, [(99m)Tc] reduced heating time 0.22 microfiltered-SC, and [(99m)Tc] human serum albumin (HSA) in rabbits. Images were acquired for the first 60 minutes and at 24 hours, followed by tissue biodistribution study. All agents except [(99m)Tc] regular SC demonstrated good migration from the injection site. Agents were retained in the popliteal node at 24 hours to varying degrees as follows: both [(99m)Tc] filtered SC preparations > [(99m)Tc] regular SC > [(99m)Tc] liposomes > [(99m)Tc] HSA. [(99m)Tc] liposome imaging can be used to develop novel liposome compositions with improved lymph node diagnostic and drug delivery characteristics.

Animals↗

Use of (99m)Tc-labeled liposomes encapsulating blue dye for identification of the sentinel lymph node.

UNLABELLED: Colloidal radiopharmaceuticals are commonly used in combination with blue dye for localization of the sentinel node. Liposomes are colloidal particles composed of spontaneously forming lipid spheres that can carry a wide variety of diagnostic and therapeutic agents. Conventional liposomes are poorly retained in lymph nodes (<2% of the subcutaneously injected dose). We have previously described a system for increasing the retention of liposomes in the lymph nodes by approximately 7-fold. This system is comprised of subcutaneously injected biotin-coated liposomes, followed by an adjacent injection of avidin. When the avidin moves into the lymphatic vessels, it causes aggregation of the biotin-coated liposomes that are also in the process of migrating through the lymphatic vessels. These aggregated liposomes become entrapped in the next encountered lymph node. In this study, we use this novel lymph node delivery system with liposomes that encapsulate blue dye, resulting in intense blue staining of the sentinel node. These liposomes can also be labeled with (99m)Tc, permitting scintigraphic imaging and radioguided probe localization of the sentinel node. METHODS: Liposomes coated with biotin and coencapsulating blue dye and glutathione were labeled with (99m)Tc using hexamethylpropyleneamine oxime. Rabbits were subcutaneously administered 0.3 mL (99m)Tc-biotin-liposomes containing blue dye in both hind feet, followed by a subcutaneous injection (0.3 mL) of 5 mg avidin in only one hind foot (experimental). The other hind foot served as a control. RESULTS: Labeling efficiencies (mean +/- SEM) for liposomes encapsulating blue dye were 92.1% +/- 1.9%. Necropsy at 24 h revealed that the popliteal node on the experimental leg receiving the avidin was intensely blue stained compared with virtually no blue coloration of the control node. Tissue counts of these nodes were 12.2 +/- 1.5 percentage injected dose (%ID) in the experimental node compared with 1.2 +/- 0.1 %ID in the control nodes (P<0.0001). CONCLUSION: Biotin-liposomes encapsulating blue dye can be successfully labeled with (99m)Tc, providing a convenient option for the visualization and radiolocalization of the sentinel node. This biotin-liposome/avidin system may also have potential for the delivery of therapeutic drugs and radiopharmaceuticals to lymph nodes.

Animals↗

Novel method of greatly enhanced delivery of liposomes to lymph nodes.

Intravenously administered liposomes are versatile carriers for drugs, contrast agents, biologics, and DNA. Liposomes and other colloidal particles are currently under investigation as lymph node delivery vehicles. After s.c. injection, conventional liposomes move into the lymphatic vessels, but are poorly retained in each draining lymph node (<2% injected dose). In this report, we describe a novel method for greatly enhancing the retention of liposomes in the lymph nodes. This system is comprised of a s.c. injection of biotin-coated liposomes in an area where lymph node targeting is desired, followed by an adjacent s.c. injection of avidin. As the avidin moves through the lymphatic vessels, it causes aggregation of biotin-coated liposomes that are also in the process of migrating through lymphatic vessels. These aggregated liposomes become trapped in the next encountered lymph node. In the present study, experimental rabbits were s.c. administered biotin-coated liposomes in both hind feet, followed by an adjacent injection of avidin, whereas control rabbits were administered biotin-coated liposomes in both hind feet without the avidin. At 24 h, rabbits receiving avidin retained 13.7% of the injected liposomes in popliteal nodes and 2.3% in iliac nodes, whereas control rabbits retained only 1.7% of the liposomes in popliteal nodes and 0.3% in iliac nodes. Blood and liver uptake of the biotin-coated liposomes was greatly decreased in the experimental rabbits receiving avidin. This novel liposome delivery system may prove useful for the delivery of chemotherapeutic drugs, vaccine antigens, and biologic agents to lymph nodes.

Animals↗

Polyethylene glycol-modified liposome-encapsulated hemoglobin: a long circulating red cell substitute.

A major obstacle in the development of red cell substitutes has been overcoming their short circulation persistence. In this study, distearoyl phosphoethanolamine polyethylene glycol 5000 (PEG-PE) (10 mol%) was added to the formulation of liposome-encapsulated hemoglobin (LEH) to decrease reticuloendothelial system uptake and prolong LEH circulation persistence. PEG-LEH was radiolabeled with technetium-99m, infused into rabbits (25% of blood pool at 1 ml/min) (n = 5), and monitored by scintigraphic imaging at various times out to 48 h. At 48 h, animals were sacrificed, and tissue samples were collected for counting in a scintillation well counter. Tissue distribution data at 48 h revealed that 51.3 +/- 3.4% of the technetium-99m-PEG-LEH remained in circulation, a greater than 3-fold increase in the circulation half-life compared with circulation half-lives previously reported for non-PEG-containing LEH formulations. The liver had the greatest accumulation at 48 h (12.7 +/- 0.7%), followed by bone marrow (6.2 +/- 0.1%), whereas the spleen had only 1.4 +/- 0.2%. The addition of PEG-PE to the LEH formulation greatly prolongs the circulation persistence of LEH and represents a significant step in the development of red cell substitutes with prolonged oxygen delivery.

Animals↗

Effect of spinal cord injury on the heart and cardiovascular fitness.

The use of various FES protocols to encourage increases in physical activity and to augment physical fitness and reduce heart disease risk is a relatively new, but growing field of investigation. The evidence so far supports its use in improving potential health benefits for patients with SCI. Such benefits may include more efficient and safer cardiac function; greater stimulus for metabolic, cardiovascular, and pulmonary training adaptations; and greater stimulus for skeletal muscle training adaptations. In addition, the availability of relatively inexpensive commercial FES units to elicit muscular contractions, the ease of use of gel-less, reusable electrodes, and the increasing popularity of home and commercial upper body exercise equipment mean that such benefits are likely to be more accessible to the SCI population through increased convenience and decreased cost. The US Department of Health and Human Services has identified those with SCI as a "special population" whose health problems are accentuated, and so need to be specifically addressed. FES presents "a clear opportunity.... For health promotion and disease prevention efforts to improve the health prospects and functional independence of people with disabilities." As a corollary to this, the Centers for Disease Control and Prevention have recommended the development of techniques to prevent or ameliorate secondary disabilities in persons with a SCI. Patients with SCI have an increased susceptibility to cardiac morbidity and mortality in the acute and early stages of their injury. Most of these patients make an excellent adaptation except when confronted with infection or hypoxia. SCI by itself does not promote atherosclerosis; however, in association with multiple secondary conditions related to SCI, along with advancing age, patients with SCI are predisposed to relatively greater risk of heart disease. The epidemiologic significance of this is reflected in demographic studies that indicate an increasing number of SCI patients becoming aged. Currently 71,000 (40%) of the total 179,000 patients with SCI living in the United States are older than 40 years, and 45,000 have injuries sustained more than 20 years earlier. In addition, new injuries in the older population are increasing (currently 11% of all injuries), and some of these new patients with SCI already have pre-existing cardiac disease. Studies have demonstrated that improved lifestyle, physical activity, lipid management, and dietary restrictions can affect major risk factors for coronary artery disease. Therefore an aggressive cardiac prevention program is appropriate for patients with SCI as part of their rehabilitation. At a given submaximal workload, arm exercise is performed at a greater physiologic cost than is leg exercise. At maximal effort, however, physiologic responses are generally greater in leg exercise than arm exercise. Arm exercise is less efficient and less effective than lower body exercise in developing and maintaining both central and peripheral aspects of cardiovascular fitness. The situation is further compounded in SCI because of poor venous return as a result of lower-limb blood pooling, as a result of lack of sympathetic tone, and a diminished or absent venous "muscle pump" in the legs. This latter mechanism perhaps contributes the greatest diminution in the potential for aerobic performance in the SCI population. Obtaining a cardiopulmonary training effect in individuals with SCI is quite possible. Current studies indicate decreases in submaximal HR, respiratory quotient, minute ventilation, and oxygen uptake, with increases in maximal power output, oxygen uptake, minute ventilation, and lactic acid. Individuals with SCI have been shown to benefit from lower limb functional electrical stimulation (FES)-induced exercise. Studies have consistently reported increases in lower limb strength and cycle endurance performance with these protocols, as well as improvements in metabolic and

Autonomic Nervous System Diseases↗

Dual radiolabeled liposomes: biodistribution studies and localization of focal sites of infection in rats.

Liposomes encapsulating both glutathione and deferoxamine were labeled with 99mTc-HMPAO and 111In-oxine at the same time. These dual radiolabeled liposomes were intravenously injected in rats with S. aureus infection in thigh. The target-to-background ratio (T/BG) increased from 2.9 at 2 h to 4.4 at 8 h in 99mTc images. In 111In images, T/BG of 5.5 at 8 h increased to 10.5 by 48 h. The 24-h spleen uptake of 111In- and 99mTc-liposomes was 24.14%ID and 8.91%ID. In femur, 99mTc-liposomes remained at approximately 10.5%ID, but 111In-liposomes increased from approximately 11%ID at 4 h to approximately 25.5%ID at 24 h. The simultaneous presence of 99mTc and 111In in the liposomes resulted in good early (2-8 h) as well as delayed (24-48 h) images delineating the infection site.

Animals↗

Augmented upper body contribution to oxygen uptake during upper body exercise with concurrent leg functional electrical stimulation in persons with spinal cord injury.

The purpose of this pilot study was to compare the contribution of upper body musculature to VO2 with and without concurrent leg FES (LFES). Eight subjects with spinal cord injury, lesion levels range C6-T12, performed upper body exercise (UBE) during no LFES (NOS), LFES at 40 mA (LOS), and 80 mA (HIS), at rest, 60% and 80% of VO2peak. Resting VO2 values were obtained during NOS, LOS and HIS conditions and were then subtracted from their respective whole body VO2 values to give an estimate of upper body VO2. Small and non significant increases were found in the HIS vs NOS condition at 60% VO2peak. Larger differences of 7.8% were found in the HIS vs NOS condition at 80% VO2peak (11.35+/-3.8 ml kg(-1) min(-1) to 12.24+/-4.0 ml kg(-1) min(-1)), although this too was not significant, perhaps due to the small number of subjects in this study and the consequently low statistical power to detect a significant difference. We discuss the implications for these preliminary results in the context of the existing literature on this topic.

Adult↗

Blood redistribution and circulatory responses to submaximal arm exercise in persons with spinal cord injury.

The purpose of this study was to evaluate responses to submaximal arm exercise (20%, 40%, and 60% of peak power output) using four conditions to support the circulatory redistribution in persons with spinal cord injury (SCI). Five males with tetraplegia (TP) and four males with paraplegia (PR) exercised 1) sitting, 2) supine, and 3) sitting with the addition of a) an anti-gravity suit (anti-G), b) elastic stockings and abdominal binder, and c) functional electrical stimulation of the leg muscles. Compared to sitting, the following significant changes were observed: in the supine position, heart rate (HR) decreased (PR: 104 vs 118 b/min, TP: 76 vs 92 b/min) and stroke volume (SV) increased (PR: 132 vs 116 ml, TP: 96 vs 83 ml). The anti-G suit induced a decrease in heart rate (PR: 104 vs 118 b/min, TP: 87 vs 92 b/min) and a decrease in oxygen uptake (VO2) in PR. Stockings only affected TP, i.e. a decrease in heart rate with 5 b/min and an increase in stroke volume with 13 ml/beat. Functional electrical stimulation produced an increase in VO2 (PR: 1.00 vs 0.95 l/min, TP: 0.68 vs 0.53 l/min) and a rise in stroke volume in TP. Results indicate that the methods employed to support the circulatory redistribution have different working mechanisms and, in addition, that the effects are different for TP and PR probably because of differences in active muscle mass, sympathetic impairment and blood pressure values.

Adult↗

Imaging experimental osteomyelitis using radiolabeled liposomes.

UNLABELLED: We evaluated radiolabeled liposomes (liposomes labeled both with 99mTc and 111In) for the early detection of osteomyelitis in an experimental model. METHODS: Liposomes, containing 5% polyethylene glycol-distearoyl phosphatidylethanolamine with encapsulated glutathione and deferoxamine, were prepared and labeled with 99mTc and 111In by a previously described method. Acute osteomyelitis was induced in male New Zealand rabbits by intramedullary injection of sodium-morrhuate and Staphylococcus aureus in the tibial bone marrow. Serial imaging studies, consisting of radiolabeled liposome imaging (2-4 mCi 99mTc and 75-125 microCi 111In), 99mTc-methylene diphosphonate (MDP) (3-5 mCi) and 67Ga-citrate (500 microCi), were performed starting at the third day after injection. Each radionuclide study was separated by at least 2 days. The animals also underwent radiography of the lower extremities. The animals were then killed and the infected tibia was excised for histopathology. RESULTS: For interpreting relative efficacy of individual radiopharmaceuticals, only animals showing positive histopathological findings (n = 9) were considered. Radiographs (Days 12, 13) were conclusive for osteomyelitis in only 3 rabbits. Radiolabeled liposome imaging (Days 4-6) showed positivity in 8 cases and was equivocal in 1. Though the lesion could be delineated as early as 8 hr postinjection in the 99MTc window, the best target-to-nontarget ratio (T/NT) of 1.86 +/- 0.19 was obtained at 48 hr in the 111In window. Three-phase 99mTc-MDP scan (Day 7) was positive in only 5 rabbits with 3 hr T/NT of 1.6 +/- 0.23. Galium-67-citrate images (Days 9-11) were positive in 8 cases and equivocal in 1, the mean 48 hr T/NT being 1.74 +/- 0.24. These results show liposomes are better than 99mTc-MDP for imaging bone infection. Given the early localization and better quality of the images, radiolabeled liposomes also exhibited advantages over 67Ga-citrate for detection of acute osteomyelitis.

Acute Disease↗

Role of complement in rats injected with liposome-encapsulated hemoglobin.

Previous studies have documented that liposome-encapsulated hemoglobin (LEH) can cause a rapid and transient thrombocytopenia following intravenous injection into small animals. The present study evaluated the role of complement during the LEH-induced thrombocytopenia in rats. We have compared changes in platelet levels in the blood, platelet organ distribution, and total hemolytic complement levels following intravenous administration of LEH in control and complement-depleted rats. Changes in platelet organ distribution at various times after LEH administration were monitored by labeling autologous platelets with indium-111 (111In)-oxine and imaging the 111In-platelets with a gamma camera after reinjection. Platelet counts were determined by light-scattering methods and by following 111In radioactivity at various times after LEH administration. Platelet levels did not significantly change for the complement-depleted rats during the 60 min following an injection of LEH, whereas thrombocytopenia (40% decrease) was noted within 4 min post-LEH-injection for control rats with a gradual return to baseline circulating platelet levels within 60 min. This drop in circulating platelets was correlated with a rapid redistribution of 111In-platelets from the circulation to the lungs and liver, whereas complement-depleted rats showed no transient movement of the 111In-platelets from the circulation. Baseline complement levels of 21.6 +/- 2.2 CH50/ml for control rats and 0.2 +/- 0.1 CH50/ml for complement-depleted rats did not significantly change during the 60 min following LEH administration. This study suggests that complement must be present during LEH-induced transient thrombocytopenia, as complement-depleted rats underwent no thrombocytopenia, and that the transient LEH-induced thrombocytopenia may be associated with complement activation.

Animals↗

Accelerated gastric emptying of glucose in Zucker type 2 diabetic rats: role in postprandial hyperglycaemia.

Patients with early non-insulin-dependent diabetes mellitus (NIDDM) empty glucose solutions from their stomachs more rapidly than non-diabetic control subjects, and this exacerbates postprandial hyperglycaemia. To determine if accelerated gastric emptying occurred in a rat model of NIDDM and influenced postprandial hyperglycaemia, gastric emptying of glucose was measured, and the effect of slowing the gastric emptying rate on postprandial hyperglycaemia was observed. We tested eight male obese Zucker diabetic rats and eight age-matched lean Zucker controls at 10-13 weeks of age to measure gastric emptying of glucose (by gamma scintigraphy). Rats fasted overnight were gavaged with 30% glucose at 1 ml/100 g body weight. Separately, six Zucker diabetic rats and six lean controls were tested for sensitivity to the inhibitory effects of cholecystokinin and secretin on gastric emptying. The diabetic rats emptied glucose significantly faster than controls (t1/2 = 37.3 +/- 1.5 vs 58.8 +/- 2.3 min in controls), and aging exaggerated this differential. Camostat, a stimulant of cholecystokinin and secretin release, added to the glucose meal significantly slowed gastric emptying (t1/2 = 123 +/- 23 and 166 +/- 19 min, diabetic vs lean, respectively), and significantly reduced postprandial hyperglycaemia in diabetic rats. Compared to Zucker lean controls, Zucker diabetic rats were as sensitive (cholecystokinin) or more sensitive (secretin) to gastrointestinal hormones that inhibit gastric emptying. The results demonstrate accelerated gastric emptying in a rat model of NIDDM, consistant with similar observations in humans with early NIDDM. These results also support the proposal that interventions to slow gastric emptying improve glucose control in this disease.

Animals↗

Use of oxygen-15 to measure oxygen-carrying capacity of blood substitutes in vivo.

A method for determining oxygen-carrying capacity of blood substitutes has been developed using the short-lived cyclotron-produced positron-emitting isotope 15O. This method measures the oxygen-carrying capacity of the blood substitutes in vivo in the presence of red blood cells and allows determination of changes in the oxygen-carrying capacity over time after exchange transfusion. This method is applied to the blood substitutes of liposome-encapsulated hemoglobin (LEH) and cell-free hemoglobin (Hb). We have used 15O (half-life of 2 min) to quantitate the lung uptake and tissue delivery of [15O2]LEH. Lung uptake studies were performed in intubated, catheterized rats after a 40% exchange transfusion of bovine LEH (LEBH; 0.68 g Hb/kg body wt), human hemolysate LEH (LEHH; 1.0 g Hb/kg body wt), or free bovine hemoglobin (SFHS; 0.56 g Hb/kg body wt). A bolus inhalation of 15O2 (3-5 mCi) was given at 15 min, 3 h, and 24 h post-transfusion. Arterial blood samples were collected, spun, and separated into LEH, red blood cell, and plasma fractions. 15O activity and hemoglobin content were determined for each fraction. Oxygen-carrying capacity was calculated as a percentage of the original red blood cell fraction removed. For LEBH, the carrying capacity was 15% at 15 min, 13% at 3 h, and 1% at 24 h. For LEHH, the carrying capacity was 30% at 15 min, 26% at 3 h, and 19% at 24 h. The marked decrease in carrying capacity at 24 h for LEBH compared with LEHH was attributable to the increased formation of methemoglobin in the circulating LEBH rather than increased removal from circulation, because total hemoglobin concentrations measured for both LEH samples decreased at a similar rate during the 24 h. The presence of methemoglobin reductase and other naturally occurring antioxidants in the LEHH may be responsible for maintaining the higher levels of oxyhemoglobin. Oxygen-carrying capacity for SFHS also decreased over time but at a much sharper rate compared with both LEH formulations. The carrying capacity for SFHS of 8% measured at 15 min decreased to 0.3% at 3 h and undetectable levels at 24 h. This sharper decrease in carrying capacity for SFHS is attributable to the rapid removal of the hemoglobin from circulation.

Animals↗

Accelerated gastric emptying in hypertensive subjects.

UNLABELLED: The phenomenon of accelerated gastric emptying has been previously reported in two conditions that are considered to be part of the insulin-resistance syndrome: namely, noninsulin-dependent diabetes (NIDDM) and increased body mass index (BMI). No previous studies have assessed the rate of gastric emptying in patients with essential hypertension, another disease considered to be part of the insulin-resistance syndrome. METHODS: Scintigraphic gastric emptying studies were performed on nine hypertensive subjects and on nine sex-, age-, ethnicity and BMI-matched controls. RESULTS: Subjects with hypertension had significantly more rapid gastric half-emptying times (gastric T50) (40.0 +/- 6.9 min versus 56.6 +/- 3.7 min, p = 0.02) than controls. There was an inverse relationship between average glucose during the first 30 min and 60 min of the oral glucose tolerance test with the gastric half-emptying time (Spearman rank correlation coefficient rs = -0.64, p = 0.0045 and rs = -0.48, p = 0.0428, respectively). CONCLUSION: The occurrence of accelerated gastric emptying in hypertensive subjects, in addition to that previously reported in subjects with NIDDM or increased BMI, suggests the possibility that accelerated gastric emptying may be a common finding in insulin resistant states.

Adult↗