Biokinetics and estimation of dose from 99mTc-labelled polyclonal human immunoglobulin (HIG).

Recently, polyclonal unspecific human immunoglobulin was suggested as a new agent for the localization of inflammatory lesions. Little information about the biodistribution of this radiopharmaceutical was reported so far. To obtain further information, 99mTc-labelled human immunoglobulin (HIG) was administered to a volunteer with presumed normal biokinetics. The absorbed doses to the organs were calculated according to the MIRD concept. The scintigraphic images at 1, 2, 4 and 24 h post injection demonstrated a prolonged activity retention in the blood and high activity in the kidneys, bladder and also in the liver. No significant uptake in the bowels and the marrow could be observed over the whole period of study. 27.4% of the administered activity was excreted in the urine within 24 h. The calculated organ absorbed doses, all in microGy/MBq, were estimated as follows: whole body 2.7, liver 7.3, spleen 12.0, kidneys 15.3, lungs 3.2, marrow 9.6 and gonads 17.0. From these results an effective dose equivalent of 7.9 x 10(-3) mSv/MBq was calculated. The cancer risk estimate of 5 x 10(-5), using 370 MBq 99mTc-HIG, may be considered quite low in comparison to other scintigraphic methods of diagnosing inflammation.

[The absorption of colostral immunoglobulins in newborn piglets. II. Effect of water or glucose solutions on the permeability of the newborn intestine]. / Untersuchungen über die Absorption der kolostralen Immunoglobuline bei neugeborenen Ferkeln. II. Mitteilung: Einfluss von Wasser oder von Glukoselösung auf die Durchlässigkeit des neugeborenendarmes.

The extent and the duration of the passage of intact proteins from the intestinal lumen into the bloodstream of newborn piglets was investigated. A total of 48 piglets from 4 litters were used in groups of 6 animals per experiment. The piglets were removed from the sow immediately after birth and placed in individual boxes of an automatic feeding device. Liquids were offered in trays, access to which was controlled by electronically operated gates. Volumes of 25 ml were allotted in hourly intervals. Porcine colostrum (6 x 25 ml) or bovine colostrum (24 x 25 ml) were either offered immediately, or after a 24 h fasting period without or with access to tap water. Two groups received 24 hourly rations of a 13 % glucose solution prior to the onset of feeding with porcine and bovine colostrum, respectively. The plasma levels of immunoglobulins were assessed by radial diffusion in blood samples drawn from a subcutaneous abdominal vein. The passage of intact proteins ceases between 12-18 hrs after the onset of feeding. Both the time course of the passage and the maximal levels achieved are unaffected after previous fasting or after tap water allowances only for 24 hrs. Previously fed glucose solution--in contrast--closes the gut barrier to subsequently ingested proteins. There was no difference in the postexperimental weight developments between groups.

Technetium-99m-human polyclonal IgG radiolabeled via the hydrazino nicotinamide derivative for imaging focal sites of infection in rats.

The biologic behavior of human polyclonal immunoglobulin (IgG) radiolabeled with technetium-99m (99mTc) by a novel method, via a nicotinyl hydrazine derivative, was evaluated in rats. Technetium-99m- and indium-111-IgG were co-administered to normal rats and biodistribution was determined at 2, 6, and 16 hr. The inflammation imaging properties of the two reagents were compared in rats with deep-thigh infection due to Escherichia coli. Blood clearance of both antibody preparations was well described by a bi-exponential function: (99mTc-IgG: t1/2 = 3.82 +/- 0.89 and 57.52 +/- 1.70 hr. 111In-IgG: 3.93 +/- 0.117 and 40.71 +/- 1.26 hr). Biodistributions in the solid organs were similar, however, small but statistically significant differences were detected: 99mTc-IgG greater than 111In-IgG in lung, liver, and spleen; 99mTc-IgG less than 111In-IgG in kidney and skeletal muscle (p less than 0.01). At all three imaging times, target-to-background ratio and percent residual activity for the two compounds were remarkably similar. These studies establish that human polyclonal IgG labeled with 99mTc via a nicotinyl hydrazine modified intermediate is equivalent to 111In-IgG for imaging focal sites of infection in experimental animals.

Postinjection kinetics of antepartum Rh immune globulin.

The disappearance kinetics of a standard dose of 300 micrograms of Rh immune globulin given at 28 weeks' gestation was investigated. Ten Rh-negative unsensitized women were given 300 micrograms of Rh immune globulin at 28 weeks and blood samples were drawn at weekly intervals until delivery. Sera were titrated with Ror red blood cells in a saline solution-antiglobulin method. Titers ranged from 1 to 4 by the first week after injection. In nine of 10 patients the titers were zero at 49 to 70 days after injection. With R2R2 red blood cells and LISS, papain, polybrene, or a combination of methods, Rh immune globulin could still be detected until delivery in four of the nine patients. Because these serologic methods can detect 5 ng/ml anti-D, five of 10 subjects may not have been protected for 8 to 29 days before delivery. This study indicates that a titer of less than or equal to 4 is expected for passively acquired anti-D during pregnancy, and that antepartum administration of Rh immune globulin may not always produce detectable passive antibody for as long as theoretically predicted.

Enterocyte ultrastructure and uptake of immunoglobulins in the small intestine of the neonatal lamb.

Although the small intestine of the sheep is relatively mature at birth, there are still vacuolated enterocytes present for at least 2 days in distal regions. In the distal regions, vacuolated cells possess a range of vesicle morphology which might be indicative of at least 2 separate routes for enterocyte handling of proteins taken up from the lumen. The localisation of immunoreactive immunoglobulins within the enterocytes, presumably of colostral or milk origin, in both proximal (non-vacuolated) and distal (vacuolated) regions, does not follow patterns which suggest orderly renewal at closure. It is suggested that closure is not solely brought about by epithelial cell replacement.

Pharmacokinetics of intravenous immunoglobulin in neonates.

Intravenous immunoglobulin (IVIG) may be a therapeutic adjunct to antibiotic treatment of neonatal infections. We examined the pharmacokinetics and safety of IVIG in human neonates. Thirty neonates with suspected sepsis were randomly assigned either to a treatment (receiving either 250, 500, or 1,000 mg/kg of IVIG plus antibiotics) or control (antibiotics alone) group. The 500 mg/kg dose produced a rise in total IgG for greater than 8 and in group B streptococcus (GBS) type-specific IgG for greater than 4-14 days. The type-specific antibody elevation varied with the amount of pathogen-specific antibody and dose of IVIG. Pharmacokinetic analysis suggests a Vdss of 42 ml/kg, Cl of 3.0 ml/kg/day, a biphasic elimination curve, and a terminal elimination half-life of 24.2 days. No toxicity was observed. These data may be valuable in determining optimal dosing schedules for IVIG in treating or preventing neonatal infections.

In vivo and in vitro deposition of immunoglobulin aggregates in the mouse eye.

The possible role of specific mechanisms involved in the adherence process of immune aggregates to tissue components of the mouse eye was investigated in an experimental animal model. Passive intravenous administration of immunoglobulin aggregates to mice, resulted in the localisation of these aggregates in various organs, including the eye. In the eye a strong localisation was seen in the episcleral capillary plexus, whereas only a weak deposition was seen in the iris, ciliary body and choroid. No deposits were seen in the retina. To investigate the role of specific receptors for immune complexes in the eye, in vitro experiments were performed, whereby immunoglobulin aggregates were layered on cryostat sections of the mouse eye. These in vitro studies also showed an adherence of immune aggregates to the episcleral capillary region, but furthermore a deposition on mast cells scattered throughout the extra-ocular muscles. The in vitro binding of immunoglobulin aggregates to the episcleral capillary plexus could be inhibited by high concentrations of Fc fragments and monomeric IgG, but not with Fab fragments or 0.5 M NaCl. The in vitro adherence of aggregates to mast cells could not be blocked by the inhibitors employed in our study and could therefore be distinguished from the interaction of aggregates with the episcleral capillary plexus. These results indicate that the ocular deposition of immunoglobulin aggregates in the episcleral capillary plexus of the mouse eye is (immune) specific and mediated by Fc receptors.

Antibody-dependent enhancement of human immunodeficiency virus type 1 infection.

Two components of human serum enhance human immunodeficiency virus type 1 (HIV-1) infection and mask HIV-1 neutralising antibody activity. The first is heat-stable, unique to HIV-1 seropositive sera, and is removed by protein-A chromatography. The second is heat-labile and ubiquitous; it is found in normal serum and is removed by heating at 60 degrees C for 1 h or by treatment with cobra venom anticomplementary protein. Additionally, complement component C3 deficient serum lacks the labile activity although Clq deficient serum contains the labile factor. The data suggest that the two components are antibody and the alternative pathway of complement fixation. The mechanism of action does not involve an increase in either complement-mediated cytolysis or syncytium formation. The activity has been identified in 11 of 16 patients tested to date.

Disposition of an immunoglobulin intravenous preparation in very low birth weight neonates.

To assess the disposition, tolerance, and toxicity of an intravenous preparation of immunoglobulin (IGIV) in very low birth weight (VLBW) neonates, we administered single doses of 500 or 750 mg/kg to 20 neonates with birth weights between 750 and 1500 g during the first week of life. The infusion of this product was well tolerated. Modest changes in hemoglobin, hematocrit, and total hemolytic complement occurred as expected. Hepatic toxic effects were not detected. Mean peak IgG concentrations were 1564 and 1316 mg/dL for the high-dose and low-dose groups, respectively. Mean IgG concentrations were very similar for both groups on postinfusion days 1, 4, 7, 14, 21, and 28. IgG concentrations remained above 300 mg/dL in seven of 10 infants in each group by day 21, and in six of the high-dose group and seven of the low-dose group by day 28. Mean elimination half-lives were 22.6 and 22.8 days in the high-dose and low-dose groups, respectively. These data provide a basis for assessment of potential efficacy of IGIV in the prevention of late-onset infection in VLBW neonates.