Plasma Half-disappearance Time Research Articles

Delayed disappearance of human compared to porcine insulin in a patient with the insulin autoimmune syndrome

The insulin autoimmune syndrome is characterised by high titres of autoantibody to insulin, a high circulating concentration of total insulin and later, reactive hypoglycaemia. We have studied a patient with this syndrome whose insulin autoantibody bound exclusively human insulin. This permitted us to investigate the disappearance of bound (human) and unbound (porcine) insulin in the same patient, using i.v. injections of 0.075 U/g of each insulin on separate days. The peak plasma free insulin concentration following porcine insulin was four times greater than that following the same dose of human insulin. The plasma disappearance half-time of porcine insulin following injection was 11 min compared with 32 min following human insulin injection, and the area beneath the disappearance curve of free insulin during the 120 min of sampling was greater for porcine insulin by a factor of 3.15. The nadir in plasma glucose occurred at 45 min following procine insulin and at 90 min following human insulin injection. The restoration of basal glucose concentration was correspondingly slower following human insulin, but the absolute fall in glucose achieved was no different. There was no evidence of insulin resistance. Insulin autoantibodies can seriously disturb the kinetics and effect of free insulin.

Renal dose response and pharmacokinetics of atrial natriuretic factor in dogs.

The present studies investigated the dose-plasma level-response relationships with the use of increasing doses of atrial natriuretic factor [ANF-(99-126)] administered by constant infusion in conscious dogs. The preinfusion plasma immunoreactive ANF increased 12, 19, 23, and 35 times during 45-min consecutive infusions of 50, 75, 125, and 175 ng.kg-1.min-1, respectively. Over this pharmacological range, natriuresis increased linearly with the infused dose (r = 0.99, n = 5) to a maximum response of +1,550%, despite the significant gradual fall of blood pressure, which attained a minimum of 83 mmHg (-26%) at 125 ng.kg-1.min-1. There was no change of glomerular filtration rate (GFR) or renal plasma flow at any dose. A very similar renal response was found in 13 other dogs infused with the highest dose only in which the pharmacokinetic parameters of ANF-(99-126) were estimated. Metabolic clearance rate during the infusion was 1.09 +/- 0.19 l/min. The postinfusion decay curve of plasma immunoreactive ANF was best described by a biexponential function. Plasma disappearance half time was 1.44 min during the rapid phase and 10.3 min during the slow phase of elimination. The results show that 1) natriuretic response to ANF in the pharmacological range is dose dependent and occurs despite a pronounced hypotension, 2) increase in GFR is not a prerequisite of ANF-induced natriuresis, and 3) ANF is rapidly eliminated from the circulation, suggesting an intensive uptake and/or degradation in the target tissues.

In Vivo Characterization of Recombinant Factor VIII in a Canine Model of Hemophilia A (Factor VIII Deficiency)

Abstract Infusion studies of recombinant factor VIII were performed in hemophilic (factor VIII-deficient) animals. Functional activity was determined using a standardized model of bleeding and kinetic characteristics charted by performing assays of factor VIII functional and antigenic activities over time. To obtain an adequate comparison with plasma-derived factor VIII, a crossover study in two animals was performed in which each animal received either recombinant factor VIII or a highly purified plasma-derived factor VIII on day 1 and the alternative three days later (day 4). Both factor VIII preparations were functionally effective with complete correction of the cuticle bleeding time occurring one hour after infusion. The observed recovery was full and close to predicted for both preparations. The survival curves obtained for both functional and antigenic activities for both preparations were virtually identical and within the anticipated range determined from previous experiments using infusions of conventional factor VIII preparations. The plasma half-disappearance time (T 1/2) for recombinant factor VIII and plasma-derived factor VIII was 9.2 and 7.9 hours, respectively. Plasma samples obtained following infusion were subjected to chromatography on Sepharose 4B. The elution profile of factor VIII antigen activity was compared with that obtained with the infusates. A clear shift in profile was observed with the plasma samples, suggesting complexing of the infused factor VIII material with circulating canine von Willebrand factor (vWF). The elution profile of vWF antigen was superimposable, thus providing further evidence in support of this assumption. The study provided evidence that recombinant factor VIII possesses full functional activity in vivo, binds to circulating vWF, and exhibits normal recovery and survival characteristics.

In vivo characterization of recombinant factor VIII in a canine model of hemophilia A (factor VIII deficiency)

Infusion studies of recombinant factor VIII were performed in hemophilic (factor VIII-deficient) animals. Functional activity was determined using a standardized model of bleeding and kinetic characteristics charted by performing assays of factor VIII functional and antigenic activities over time. To obtain an adequate comparison with plasma-derived factor VIII, a crossover study in two animals was performed in which each animal received either recombinant factor VIII or a highly purified plasma-derived factor VIII on day 1 and the alternative three days later (day 4). Both factor VIII preparations were functionally effective with complete correction of the cuticle bleeding time occurring one hour after infusion. The observed recovery was full and close to predicted for both preparations. The survival curves obtained for both functional and antigenic activities for both preparations were virtually identical and within the anticipated range determined from previous experiments using infusions of conventional factor VIII preparations. The plasma half-disappearance time (T 1/2) for recombinant factor VIII and plasma-derived factor VIII was 9.2 and 7.9 hours, respectively. Plasma samples obtained following infusion were subjected to chromatography on Sepharose 4B. The elution profile of factor VIII antigen activity was compared with that obtained with the infusates. A clear shift in profile was observed with the plasma samples, suggesting complexing of the infused factor VIII material with circulating canine von Willebrand factor (vWF). The elution profile of vWF antigen was superimposable, thus providing further evidence in support of this assumption. The study provided evidence that recombinant factor VIII possesses full functional activity in vivo, binds to circulating vWF, and exhibits normal recovery and survival characteristics.

Effect of subcutaneous injection of a long-acting analogue of somatostatin (SMS 201–995) on plasma thyroid-stimulating hormone in normal human subjects

SMS 201-995 (SMS), a synthetic analogue of somatostatin (SRIF) has been shown to be effective in the treatment of the hypersecretion of hormones such as in acromegaly. However, little is known about the effects of SMS on the secretion of thyroid-stimulating hormone (TSH) in normal subjects. In this study, plasma TSH was determined with a highly sensitive immunoradiometric assay, in addition to the concentration of SMS in plasma and urine with a radioimmunoassay, following subcutaneous injection of 25, 50, 100 μg of SMS (4 subjects/dose) or a placebo (6 subjects) to normal male subjects, at 0900 h after an overnight fast. The plasma concentrations of SMS were dose-responsive and the peak levels were 1.61±0.09, 4.91±0.30 and 8.52±1.18 ng/ml, which were observed at 30, 15 and 45 min after the injection of 25, 50 and 100 μg of SMS, respectively. Mean plasma disappearance half-time of SMS was estimated to be 110±3 min. Plasma TSH was suppressed in a dose dependent manner and the suppression lasted for at least 8 hours. At 8 hours after the injection of 25, 50 and 100 μg of SMS, the plasma TSH levels were 43.8±19.4, 33.9±9.4 and 24.9±3.2%, respectively, of the basal values. The results suggest that SMS suppresses secretion of TSH from its suggest that SMS suppresses secretion of TSH from the normal thyrotrophs in man and thus also that attention should be paid to possible hypothyroidism during the long-term treatment of patients such as those with acromegaly with this potent analogue of SRIF.

An examination of the role of insulin dimerisation and negative cooperativity using the biological properties of the despentapeptide and deshexapeptide insulins.

The C-terminus of the insulin B chain is essential for dimerisation and expression of negative cooperativity. In order to evaluate the possible physiological role of these phenomena, we have studied the properties in vivo and in vitro of despentapeptide insulin (B26-30 deleted), derived from beef insulin, and deshexapeptide insulin (B25-30 deleted), derived from pork insulin. These materials do not dimerise and have 15% and 0% retention of negative cooperativity respective. Lipogenesis potencies in rat adipocytes were: despentapeptide insulin 19.9 +/- 0.3%; deshexapeptide insulin 19.9 +/- 1.5%. Binding potencies in adipocytes were: despentapeptide insulin 22.6 +/- 7.8%; deshexapeptide insulin 13.2 +/- 3.3%. Metabolic clearance rates were reduced compared to insulin (insulin = 19.1 +/- 0.9; despentapeptide insulin = 9.7 +/- 0.8; deshexapeptide insulin = 6.4 +/- 0.6 ml . min-1 . kg-1 at plasma concentration 0.5 nmol/l). Hypoglycaemic potencies were reduced for both analogues (40% and 30%) when calculated on the basis of plasma concentration although both analogues and insulin were equally effective at lowering plasma glucose concentration in equimolar doses. Plasma half-disappearance time was prolonged (despentapeptide insulin = 7.3 +/- 0.5; deshexapeptide insulin = 9.1 +/- 0.2 min). Both analogues were full agonists and conformed to the general relationship between in vitro and in vivo properties seen with a wide range of modified insulins. They resemble other analogues with modifications which reduce receptor affinity without impairing dimerisation or negative cooperativity. The results do not support a physiological role for dimerisation or negative cooperativity.

Subcutaneous administration of gonadotropin-releasing hormone: absorption kinetics and gonadotropin responses.

To evaluate the suitability of the sc route for the pulsatile delivery of GnRH, plasma GnRH, LH, and FSH levels were measured by RIA in five women with hypothalamic amenorrhea after sc injection of single doses of 2.5, 5, and 10 micrograms GnRH. The results were compared with those obtained after bolus iv injection of 10 micrograms GnRH. After sc injection, plasma GnRH levels rose to a dose-related maximum after 5-10 min and fell to less than 10% of the peak value by 90 min. The mean plasma disappearance half-time was 24 min (range, 18-30 min). After bolus iv injection, an initial rapid phase of disappearance (t1/2, 2.8 min) was followed by a slower phase (t1/2, 33 min), falling within the 95% confidence intervals for the disappearance half-time after sc administration (12-36 min). The patterns of LH response to sc and iv GnRH were similar, with maximum levels reached between 20 and 30 min after injection, then declining to 50-69% of the peak value by 90 min after sc injection and 61% of the peak value 90 min after iv injection. There was no significant difference between peak LH responses to 10 micrograms iv and sc doses of GnRH [15.2 +/- 2.5 (+/- SEM) vs. 13.2 +/- 2.2 IU/L]. Subcutaneous administration of three consecutive GnRH pulses at 90-min intervals to four women resulted in gonadotropin responses to each GnRH pulse. We conclude that sc GnRH administration results in pulsatile plasma GnRH and gonadotropin responses, the latter resembling those seen after iv GnRH. These results confirm the suitability of the sc route for pulsatile GnRH delivery.

Plasma disappearance half-time and metabolic clearance rate of exogenous human growth hormone-releasing hormone-(1-44)-NH2 in normal subjects.

By means of human growth hormone-releasing hormone (hGHRH)-RIA using an antiserum directed toward the C-terminal region of hGHRH-(1-44)-NH2, the plasma disappearance half-time and metabolic clearance rate (MCR) of immuoreactive hGHRH (IR-hGHRH) were examined in normal subjects after an iv bolus injection of synthetic hGHRH-(1-44)-NH2 (1 microgram/kg BW). The disappearance of IR-hGHRH from plasma was characterized by a biexponential decay curve, with initial distribution and subsequent metabolic t1/2 value of 5.0 +/- 1.0 and 29.6 +/- 5.4 min (mean +/- SE), respectively. The MCR of IR-hGHRH was 6.1 +/- 1.2 ml/min X kg. The volume of distribution of IR-hGHRH was 3.3 +/- 0.4 liters. The molecular size of the plasma IR-hGHRH was not different from that of hGHRH-(1-44)-NH2 for at least 90 min after the injection of hGHRH-(1-44)-NH2 when examined by gel-filtration chromatography. This prolonged clearance of hGHRH from human plasma relative to that of other hypothalamic hormones may in part explain the sustained plasma GH rises after hGHRH injection in man.

Hemodynamics and oxygen transport after partial and total blood exchange with pyridoxalated polyhemoglobin in dogs.

The effects of a pyridoxalated polyhemoglobin solution (SFH-PLP)n-solution) on cardiovascular hemodynamics and oxygen transport were investigated in a model of partial and total blood exchange in seven dogs. Cardiac output, mean arterial pressure and heart rate were essentially unchanged, even after total blood exchange, due to the long plasma half-disappearance time of (SFH-PLP)n (36 h) and due to the addition of albumin to the solution. The oxygen-binding capacity of (SFH-PLP)n was 1.1 to 1.2 ml O2/g hb. Oxygen availability was reduced to about 50%, resulting from the low hemoglobin concentration and the decreased oxygen-binding capacity of (SFH-PLP)n. Since cardiac output did not increase, O2-consumption was maintained by an increase in O2-extraction from 21 to about 50%. However the decrease in mixed venous PO2 to values not below 30 mmHg (4.00 kPa) proves the sufficient unloading capacity of (SFH-PLP)n. The adequate tissue oxygenation of (SFH-PLP)n could be demonstrated by the lack of a metabolic acidosis, the essentially unchanged PO2-histograms of the skeletal muscle and the only moderate decrease in mixed venous PO2. Four dogs survived for more than 3 days; three of them were long-term survivors. This suggests that oxygen supply was maintained by (SFH-PLP)n until red blood cells were restored.

A bivariate radioimmunoassay for arginine vasopressin and the synthetic antidiuretic agent 1-deamino-8- d-arginine vasopressin (desmopressin)

Pairs of radioimmunoassays, each of which include a two-dimensional matrix of standards, have been previously employed to resolve specificity problems in steroid immunoassay. In this study the bivariate radioimmunoassay principle has been applied to simultaneous measurement of plasma antidiuretic hormone, arginine vasopressin, and the synthetic antidiuretic agent 1-deamino-8- d-arginine vasopressin (desmopressin), by utilizing two arginine vasopressin antisera which show significantly different cross-reactivities with the synthetic analog. Data processing consists of mathematical representation of two curved dose-response surfaces followed by solution of this pair of nonlinear simultaneous equations for the unknown arginine vasopressin and desmopressin concentrations. Details of numerical procedures are given in the Appendix. The assay appears entirely adequate in terms of sensitivity, accuracy, and precision for measurement of these antidiuretic agents in clinical samples. No evidence of significant covariance in estimated concentrations could be detected but precision of estimation is (not unexpectedly) a function of the concentration of both agents. The plasma disappearance half-time of desmopressin (probably the second of a biphasic disappearance) was estimated as 37 min in one normal subject, which is in good agreement with a previously reported value of 30 min.

Auranofin versus injectable gold: Comparison of pharmacokinetic properties

The new oral gold compound auranofin differs pharmacokinetically from the existing injectable gold compounds such as gold sodium thiomalate. Following a standard 50 mg intramuscular injection of gold sodium thiomalate, plasma gold levels rise sharply, peak between 400 and 800 μg/dl in approximately two hours, then decline to approximately 300 μg/dl by seven days. With repeated 50 mg weekly injections, stable plasma concentrations are gradually achieved, although absolute levels vary greatly among individual subjects. On the other hand, auranofin is associated with lower (50 to 70 μg/dl) and more predictable plasma concentrations. Singledose kinetic studies using isotopically labelled gold show that the plasma disappearance half-time for gold sodium thiomalate is relatively rapid (approximately six days) compared with 17 days for auranofin. Both compounds are retained within the body over proonged periods. Retention of auranofin is much less, about 1 percent of the original tracer dose remaining at 180 days, compared with more than 30 percent retention of gold sodium thiomalate. Excretory pathways are notable different. The majority of gold sodium thiomalate (greater than 70 percent) is excreted by the kidneys, with the remaining fraction appearing erratically in the stool. In contrast, the enteric pathway represents the major excretory route for auranofin, with nearly 85 percent of the dose eventually recoverable in the stool and less than 15 percent in the urine. In human subjects, parenterally administered gold is almost universally dispersed among body tissues, although highest concentrations occur in the organs of the reticuloendothelial system and the adrenal and renal cortices. Comparable studies are not available for auranofin, but animal studies show comparatively less affinity for liver, kidney, and spleen. To date, attempts to correlate the pharmacokinetics of the injectable gold compounds with clinical response and toxicity have been largely unsuccessful. The distinctive pharmacokinetic profile of auranofin, when compared with gold sodium thiomalate, may nonetheless account in part for the clinical and pharmacologic differences between these compounds.

Predominance of renal and absence of hepatic metabolism of pancreatic polypeptide in the dog

Pancreatic polypeptide (PP) metabolism was studied in the dog. Metabolic clearance rate (MCR) of PP was found to be 9.5 +/- 0.9 ml . kg-1 . min-1, accounted for predominantly by renal extraction (34.9 +/- 2.6% of exogenous PP), which comprised 45.5 +/- 5.8% of total PP clearance. Hepatic extraction of both endogenous (-9.9 +/- 6.1%) and exogenous (2.2 +/- 1.4%) PP infused to pharmacological levels was negligible, as was its splanchnic extraction (4.2 +/- 0.9%). Renal organ clearance of exogenous PP (3.7 +/- 0.3 ml . kg-1 . min-1) closely approximated that of inulin (3.6 +/- 0.3 ml . kg-1 . min-1), indicating that renal PP metabolism occurs entirely by glomerular filtration without contribution from peritubular uptake mechanisms. Urinary PP, chromatographically indistinguishable from that in plasma but quantitatively accounting for less than 1% of overall renal PP uptake, indicated virtually complete renal degradation of the peptide to nonimmunoreactive fragments. Renal PP extraction was shown to be nonsaturable. Plasma half disappearance time of PP was 10.1 +/- 1.0 min and apparent distribution space 307 +/- 39 ml/kg. Linkage between the hepatic action and degradation of insulin and glucagon has been proposed, and in this light absent hepatic PP extraction is noteworthy. This finding, reminiscent of the hepatic handling of metabolically inert C-peptide and biologically inactive glucagon peptides, is consistent with the absence of demonstrable physiological function of PP.

Preparation and evaluation of pyridoxalated-polymerized human hemoglobin

A solution of hemoglobin has several potential applications as a blood substitute. However, because of high oxygen affinity ( P 50 ∼ 14 mm Hg) and short vascular retention time of hemoglobin (plasma half-disappearance time ∼ 3.5 hr), a solution of hemoglobin presents limitations for its general use in blood replacement therapy. To overcome these limitations crystalline hemoglobin was modified by pyridoxalation and subsequent polymerization. Pyridoxalation yielded a product with a P 50 ranging from 23 to 26 mm Hg. The pyridoxalated hemoglobin was then polymerized with glutaraldehyde and the final modified hemoglobin showed a P 50 of 19 to 22 mm Hg. The modified hemoglobin was tested in vitro for coagulation activities. The results indicated that no adverse coagulant activity was demonstrated by the modified products. In vivo studies in the rat have shown that pyridoxalated-polymerized hemoglobin has a plasma half-disappearance time of about 25 hr. The data demonstrated that a solution of pyridoxalated-polymerized hemoglobin, because of its lower oxygen affinity and longer vascular retention than unmodified hemoglobin, has significant potential as a basis for an efficient resuscitation solution.

Modified Hemoglobin Solution as a Resuscitation Fluid

Hemoglobin solution, as a potential oxygen-carrying resuscitation fluid in blood volume replacement therapy, has two limitations: higher oxygen affinity (P50 approximately 12-16 mm Hg) and shorter vascular retention time (plasma half-disappearance time approximately 2-4 h) of free hemoglobin as compared to hemoglobin in the red cells. To overcome these two limitations, several investigators have used a variety of reactions and procedures for the modification of the hemoglobin molecule. This article presents a review of the modifications of the hemoglobin, including reactions with different agents for the intra- or intermolecular cross-linking of hemoglobin, reactions with pyridoxal phosphate with or without subsequent polymerization, and manipulations for the encapsulation of hemoglobin to obtain artificial cells. The P50 and the vascular retention time of the products obtained are indicated whenever they have been reported in the literature. The oxygen transport characteristics of a resuscitation fluid, in general, and of modified hemoglobin solution, in particular, have been correlated to the oxygen dissociation curve and to the hemoglobin concentration.

Hepatic and renal metabolism of somatostatin-like immunoreactivity. Simultaneous assessment in the dog.

The hepatic and renal metabolism of somatostatin-like immunoreactivity (SLI) was assessed simultaneously in an in vivo dog model. The hepatic extraction of this peptide was 29.4 +/- 2.3% and was similar for endogenous and infused exogenous SLI. The renal extraction was 62.3 +/- 5%. The renal clearance of SLI was significantly greater than that of inulin indicating that the peptide is handled by peritubular uptake from postglomerular blood in addition to glomerular filtration. In both organs SLI extraction was not saturable even at arterial concentrations in excess of 100 times physiological range. The overall metabolic clearance rate of SLI was 19.7 +/- 1.6 ml/kg per minute of which 32.7 +/- 4.6% was contributed by hepatic and 37 +/- 4.9% by renal uptake mechanisms. The plasma half disappearance time of exogenously infused SLI was 1.9 +/- 0.3 min. The studies indicate that in the dog, the liver and kidney are both major sites of SLI metabolism, together accounting for 70.0 +/- 8.7% of the metabolic clearance of the peptide.

Distribution volume, metabolic clearance and plasma half disappearance time of exogenous luteinizing hormone releasing hormone in normal women and women with obesity and anorexia nervosa.

Synthetic LRH was infused into normal women and women with obesity and anorexia nervosa to determine the distribution volume (DV), metabolic clearance rate (MCR) and half disappearance time (t 1/2) of plasma LRH. In normal women, the DV of LRH ws 12.1 +/- 0.9 (mean +/- SE) 1, the MCR was 1478.9 +/- 39.8 ml/min (28.5 +/- 1.2 ml/min/kg body weight) and the initial t 1/2 was 5.6 +/- 0.4 min. In obese patients the DV (20.6 +/- 1.5 l) was significantly higher than that in normal subjects (P < 0.005), but the MCR and t 1/2 were not significantly different from those in normal subjects. In patients with anorexia nervosa the DV and MCR were 6.5 +/- 1.1 l and 621.8 +/- 110.5 ml/min (17.9 +/- 2.4 ml/min/kg body weight), respectively, which were both significantly lower than those in normal subjects (P < 0.02), while the t 1/2 (7.3 +/- 0.1 min) was longer than in normal subjects (P < 0.02). These data suggest that 1) the abnormal responses of some hormones to provocation tests observed in obese patients and patients with anorexia nervosa should be evaluated in consideration of changes in the DV and metabolic clearance of hormones in these conditions, and 2) in patients with anorexia nervosa changes in MCR and t 1/2 may reflect low metabolism of LRH.

Studies of circulating parathyroid hormone in man using a homologous amino-terminal specific immunoradiometric assay.

Circulating immunoreactive parathyroid hormone (PTH) was measured by a homologous, amino-terminal, specific, immunoradiometric assay in man. In forty-two healthy subjects the concentrations ranged between < 40 pg/ml and 120 pg/ml. No hormone could be detected in the sera of eleven patients with hypoparathyroidism, but the concentrations were clearly elevated in six patients with pseudohypoparathyroidism (range 190-1120 pg/ml). In thirty-five patients with primary hyperparathyroidism the mean (+/- SEM) concentration was 283.4 +/- 42.4 pg/ml (range 100-1350 pg/ml). A significant positive correlation was demonstrated between immunoassayable hormone and serum calcium concentrations in these patients. In nine patients PTH concentrations were measured before and after parathyroidectomy. In all of them they were elevated pre-operatively but fell to the normal range after parathyroidectomy. The disappearance of exogenously administered synthetic human PTH (1-34) from the circulation of two normal subjects was rapid with an apparent plasma half-disappearance time (t1/2) between 2 and 3 min; the metabolic clearance rate was 12.9 and 9.0 ml. kg-1 . min-1 respectively. Similarly, the disappearance of endogenous, amino-terminal, immunoreactive PTH from the circulation of two patients with primary hyperparathyroidism after parathyroidectomy was rapid; the apparent t1/2 was approximately 3 min. Homologous amino-terminal specific immunoassays for PTH can thus be useful for the study of both the acute, and chronic, changes of circulating hormone in man and represent an improvement over heterologous unselected assay systems.

Plasma clearance and plasma half-disappearance time of exogenous thyrotropin-releasing hormone and pyroglutamyl-N3im-methyl-histidyl prolineamide.

The plasma clearance rate (PCR) and plasma half-disappearance time (t1/2) of TRH was compared to the PCR and t1/2 of pyroglutamyl-N3im-methyl-histidyl prolineamide (methyl-TRH), a more potent analog of TRH in normal subjects. The PCR for TRH was 1500 +/- 329 (SD) ml/min, which was significantly greater than the PCR of methyl-TRH (783 +/- 96 ml/min). The t1/2 of TRH was 6.2 min compared to a t1/2 of 11.5 min for methyl-TRH. The slower clearance of methyl-TRH is probably due to the increased resistance to degradation by serum enzymes of methyl-TRH compared to TRH.

Serum Ferritin During Infection.

In order to follow the dynamics in the reaction of iron kinetic variables to acute infection, 8 renal transplantation patients were followed with test samples every second or third day for about two months. It was found that they just as previously shown in otherwise healthy subjects, responded to acute infection with a rise in serum ferritin levels, sometimes to very high values. In most cases the ferritin elevation started within two days after the onset of fever. The peak was reached within a week, except when very high values were obtained. The fall in serum ferritin after recovery from infection was much faster than in previously investigated groups of patients: the plasma half disappearance time for ferritin in one case was but 1.5 days. Transferrin did not change in response to infection. The expected fall in serum iron during infection was often absent and sometimes obscured by unexpected, sharp peaks in serum iron, which bore a temporal relationship to episodes of transplant rejection in 7 of 12 cases.

Total and partial blood exchange in the rat with hemoglobin prepared by crystallization.

Hemoglobin, prepared by crystallization, has been used as a blood substitute in total (91 to 93%) and partial (70 to 76%) blood replacement studies. Exchange transfusions have been carried out in laboratory animals to a total blood replacement of 91 to 93 per cent with hemoglobin or with albumin solutions. When albumin was used, all animals died at approximately ten minutes after transfusion was completed, whereas all animals transfused with hemoglobin survived for five hours and displayed normal activity during this time. In these studies the plasma half-disappearance time of hemoglobin was 3.5 hours and body distribution of 51Cr-labeled hemoglobin, as a percentage of initial levels, has shown six per cent in the kidney, six per cent in the liver, 10.5 per cent in the marrow and 13 to 14 per cent in the urine at three hours after transfusion. Survival was obtained with all animals transfused with hemoglobin or albumin solutions to a partial blood replacement of 70 to 76 per cent. However, the oxygen capacity of the circulating fluid in the hemoglobin transfused animals was about three times greater than that found in the corresponding albumin-transfused controls. Values of hemoglobin, hematocrit, platelets, and P50 returned to normal pretransfusion levels within five to seven days.