Change in erythropoietin pharmacokinetics following hematopoietic transplantation.

Pre-clinical studies have demonstrated that bone marrow ablation has a profound effect in decreasing erythropoietin (EPO) elimination. The study's objective was to determine in humans if EPO pharmacokinetics (PKs) are perturbed following bone marrow ablation. EPO PK studies were performed in eight subjects, aged 4 to 61 years, undergoing fully myeloablative hematopoietic stem cell transplantation. Serial PK studies using intravenous injection of recombinant human EPO (92+/-2.0 U/kg) (mean+/-SEM) were carried out during four periods of altered marrow integrity: baseline pre-ablation, post-ablation pre-transplant, early post-transplant pre-engraftment, and late post-transplant full engraftment. Compared with baseline, post-ablation pre-transplant and early post-transplant EPO PKs demonstrated declines in clearance increases in terminal elimination half-life of 36 and 95%, respectively. Clearance and half-life returned to baseline following full engraftment. The association of EPO elimination with decreased bone marrow activity in patients undergoing transplantation conclusively establishes the bone marrow as a key determinant of EPO elimination in humans.

Increased erythropoiesis and elevated erythropoietin in infants born to diabetic mothers and in hyperinsulinemic rhesus fetuses.

The pathogenesis of the increased erythrocytosis and extramedullary erythropoiesis observed in infants of diabetic mothers (IDM) has been obscure. In the present studies, IDM were found to have elevated umbilical plasma erythropoietin (Ep) concentrations by radioimmunoassay. 22 of 61 IDM (36%) had levels above the range of 28 nonasphyxiated, appropriately grown normal infants. In 16 controls and 20 IDM, plasma Ep correlated directly with plasma insulin (P less than 0.001, r = 0.73). To investigate this relationship further, a chronic rhesus model was studied with continuous fetal hyperinsulinemia for 21 d in utero in the last third of pregnancy. In five experimental fetuses, plasma insulin levels averaged 4,210 microU/ml at delivery, whereas plasma Ep was above the range of six controls. In addition, the experimental fetuses had elevated reticulocyte counts in umbilical cord blood. The mechanism for the increased plasma Ep associated with hyperinsulinemia in the fetus is unexplained but may be mediated by fetal hypoxia.

Nonenzymatic glycosylation of erythrocytic proteins in normal and diabetic subjects. Enzymes of nucleoside and nucleotide metabolism.

A modification of the technique of Glyco-Gel affinity column chromatography has been employed to separate glycosylated proteins from nonglycosylated proteins of hemolysates. When glycosylation in hemolysates of 11 type I diabetic subjects was compared with that from 7 normal subjects, significant increases were found in glycosylation of hemoglobin (Hb) (12.1 +/- 6.0% versus 4.7 +/- 0.5%) and purine nucleoside phosphorylase (PNP) (5.3 +/- 3.0% versus 2.1 +/- 0.5%). However, no differences were found for nucleoside diphosphokinase (NDPK) (1.5 +/- 1.1% versus 1.0 +/- 0.4%) and adenylate kinase (AMPK) (0.5 +/- 0.4% versus 0.7 +/- 0.2%). Linear relationships were seen between glycosylated Hb and glycosylated PNP (r = 0.97) or glycosylated NDPK (r = 0.81). On incubation of hemolysates from normal individuals with high glucose (1500 mg/dl or 83 mM) and NaCNBH3 (20 mM), linear increases in the degrees of glycosylation were seen with time. After 18 h, the percentages of glycosylation of Hb, PNP, NDPK, and AMPK were increased from normal values to 31, 24, 11, and 3, respectively. When partially purified human erythrocytic PNP was incubated with various monosaccharides (20 mM) in the presence of NaCNBH3 for 6 h, glycosylation increases of 2-5-fold were seen in the order ribose greater than mannose greater than galactose greater than glucose.

Neonatal morbidities in infants of mothers with glucose intolerance in pregnancy.

Of 1839 pregnant women screened prospectively, 52 were identified to have glucose intolerance. Ten additional pregnant women identified as having glucose intolerance before the universal screening were also included in the study cohort. These 62 patients were followed in a perinatal high-risk clinic with weekly plasma glucose determinations. The patients were treated with diet and, in addition, 21 of 62 were treated with insulin therapeutically. By observational cohort design, the infants and a comparable number of matched controls were evaluated for evidence of neonatal morbidities and classified into percentile for birth weight. Compared with the control group, the operative mode of delivery, the mean birth weight, the birth-weight percentile, the male/female ratio, the frequency of low Apgar score (less than or equal to 6 at 1 min), and the number of infants with congenital anomalies were significantly higher in the infants born to the glucose-intolerant mothers. Although the mean maternal blood sugar was maintained within a reasonably euglycemic range, the usual neonatal morbidities were not eliminated entirely. Further understanding and management of glucose intolerance in pregnancy is necessary to further diminish or eliminate neonatal morbidities.

Chronic hyperinsulinemia in the fetal rhesus monkey: effects on hepatic enzymes active in lipogenesis and carbohydrate metabolism.

Hyperinsulinemia was produced in fetal rhesus monkeys for 21 days in the last third of gestation by subcutaneous pork insulin injected at 19 U a day. Plasma insulin concentrations in treated fetuses (N = 4) were 3525 microU/ml. There was no difference in paired pre- and post-treatment fetal plasma glucose concentration. Activity of the hepatic enzymes that promote glucose utilization (glucokinase and hexokinase) and glycolysis (phosphofructokinase, pyruvate kinase, and pyruvate dehydrogenase) was unaffected. Similarly, glycogen metabolism enzymes (active and inactive synthase and phosphorylase) were unaltered. Two gluconeogenic enzymes (PEPCK and glucose-6-phosphatase) were diminished in the treated group compared with controls. Fetal hyperinsulinemia enhanced lipogenic and NADPH-producing enzyme activities, as evidenced by a twofold increase in fatty acid synthase and in citrate cleavage enzyme activity. Malic enzyme was absent. Hyperinsulinemia with euglycemia (1) increases the activity of enzymes that participate in lipogenesis, (2) decreases some of those controlling gluconeogenesis, and (3) has no effect on the enzymes of glycolysis.

Receptor-based model accounts for phlebotomy-induced changes in erythropoietin pharmacokinetics.

Previous clinical studies have demonstrated two distinctive pharmacokinetic behaviors of erythropoietin (EPO): changes in pharmacokinetics (PK) after a period of rhEPO treatment and nonlinear pharmacokinetics. The objective of this work was to study the temporal changes in EPO's PK following phlebotomy in order to propose possible mechanisms for this behavior. Five healthy adult sheep were phlebotomized on two separate occasions 4-6 weeks apart to hemoglobin levels of PK 3-4 g/dL. PK parameters were estimated from the concentration-time profiles obtained following repeated intravenous bolus PK studies using tracer doses of biologically active 125I-rhEPO. Based on the changes in clearances, a PK model was derived to provide a mechanistic receptor-based description of the observed phenomena. Phlebotomy resulted in a rapid increase in the EPO plasma concentration, which peaked at 760 +/- 430 mU/mL (mean +/- SD) at 1.8 +/- 0.65 days, and which coincided with a transient reduction in EPO clearance from prephlebotomy values, i.e., from 45.6 +/- 11.2 mL/hr/kg to 24.3 +/- 9.7 mL/hr/kg. As plasma EPO levels returned toward baseline levels in the next few days, a subsequent increase in EPO clearance was noted. EPO clearance peaked at 90.2 +/- 26.2 mL/hr/kg at 8.5 +/- 3.3 days and returned to baseline by 4-5 weeks postphlebotomy. The proposed model derived from these data includes positive feedback control of the EPO receptor (EPOR) pool. The model predicts that: 1) the initial reduction in EPO plasma clearance is due to a transient saturation of EPORs resulting from the phlebotomy-induced high EPO concentration; and 2) the EPOR pool is expandable not only to compensate for EPOR loss but also to adjust to a greater need for EPORs/progenitor cells to restore hemoglobin (Hb) concentration to normal levels.

Somatomedins and insulin in diabetic pregnancies: effects on fetal macrosomia in the human and rhesus monkey.

The concentrations of the somatomedins (SMs) insulin-like growth factors I and II (SM-C/IGF-I and IGF-II) were measured by RIA in six normal and seven insulin-dependent diabetic pregnant women and their infants at delivery. SM-C/IGF-I and IGF-II levels in the two groups of women were similar. Maternal IGF-II concentrations correlated with maternal hemoglobin AIc levels (r = 0.68) and infant birth weight ratios (actual birth weight/expected 50th percentile sex-corrected birth weight for gestation age; r = 0.54). SMC/IGF-I and IGF-II levels in umbilical plasma in infants of diabetic mothers did not differ from those in control infants, but were lower than the corresponding maternal values. In contrast, umbilical plasma levels of C-peptide immunoreactivity were significantly elevated in the infants of diabetic mothers (2.25 +/- 1.85 (+/-SD) vs. 0.34 +/- 0.15 pmol/ml; P less than 0.01). The infant birth weight ratio was logarithmically correlated with the umbilical plasma C-peptide immunoreactivity (r = 0.78). SM levels were also measured by radioreceptor assay in five normal and five hyperinsulinemic rhesus monkey fetuses. When chronic hyperinsulinemia was produced by continuous SC infusion of insulin in the fetal rhesus monkey, the fetal birth weight ratio was also found to be logarithmically correlated with the fetal plasma insulin concentration (r = 0.81). The fetal SM peptide content was elevated only in the fetuses with plasma insulin levels greater than 3000 microU/ml. The fetal weight gains in response to hyperinsulinemia in the human and rhesus are similar. Since fetal SM levels in the humans and monkeys were not significantly different in the two groups, our data suggest that insulin plays the predominant role in stimulating human and subhuman primate excess fetal weight gain of the infant of the diabetic mother during the latter part of gestation.

Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants.

DESIGN AND METHODS: We hypothesized that treatment with recombinant human erythropoietin (r-HuEPO) would stimulate erythropoiesis and would thereby reduce the need for erythrocyte transfusions in preterm infants. We treated 157 preterm infants born at 26.9 +/- 1.6 weeks of gestation who weighed 924 +/- 183 g at birth with either subcutaneous r-HuEPO (100 U/kg/d, 5 days per week) or placebo for 6 weeks in a randomized, double-blind, controlled clinical trial. All patients received oral iron and were managed according to uniform conservative transfusion guidelines. RESULTS: Treatment with r-HuEPO was associated with fewer erythrocyte transfusions (1.1 +/- 1.5 per infant in the r-HuEPO group versus 1.6 +/- 1.7 per infant in the placebo group; P = .046) and with a reduction in the volume of packed erythrocytes transfused (16.5 +/- 23.0 mL versus 23.9 +/- 25.7 mL per infant; P = .023). Overall, 43% of the infants in the r-HuEPO group and 31% of placebo-treated infants were transfusion-free during the study (P = .18). The volume of blood removed for laboratory tests and the need for respiratory support at the start of treatment had major effects on transfusion requirements independent of r-HuEPO. Reticulocyte counts were higher during treatment in the r-HuEPO group (P = .0001), and r-HuEPO-treated infants had higher hematocrit values at the end of the study (32% versus 27.3% in the placebo group; P = .0001). We found no differences in the incidence of major complications of prematurity between the treatment groups. CONCLUSION: We conclude that treatment with r-HuEPO at a weekly dose of 500 U/kg stimulates erythropoiesis, moderates the course of anemia, is associated with a reduction in erythrocyte transfusions, and appears safe in very low birth weight preterm infants who are receiving iron supplements. Conservative transfusion criteria, minimization of phlebotomy losses, and treatment with r-HuEPO are complementary strategies to reduce erythrocyte transfusions in these infants.

Recombinant human erythropoietin vs transfusions in the treatment of anemia of prematurity. A cost-benefit analysis.

OBJECTIVE: To evaluate the costs relative to the benefits of using recombinant human erythropoietin (rHuEPO) therapy as an alternative to red blood cell (RBC) transfusions in infants with anemia of prematurity. DESIGN: A cost-benefit analysis of rHuEPO therapy was performed based on its use in very-low-birth-weight premature infants. SETTING AND PATIENTS: Data were drawn from published studies or were provided by the University of Iowa Hospitals and Clinics, Iowa City. MAIN OUTCOME MEASURES: Costs and benefits were analyzed as a comparison of incurred costs to averted costs. Incurred and averted costs of rHuEPO therapy and RBC transfusions included direct product costs and estimates of costs of adverse events. The analysis was viewed in terms of net savings. Sensitivity analysis was performed. RESULTS: The base case analysis yielded a net loss of $299.48 per infant. A 54% reduction in the direct product costs of rHuEPO therapy yielded a break-even point. No other variations in the sensitivity analysis resulted in a net savings. CONCLUSION: Using assumptions based on the current state of clinical research, it appears that routine use of rHuEPO with supplemental RBC transfusions would not generate any cost savings as an alternative to RBC transfusions alone. As further evidence is compiled on the efficacy of rHuEPO therapy in very-low-birth-weight premature infants, the true costs may be better established.

Maternal alcohol abuse is associated with elevated fetal erythropoietin levels.

The erythropoietin levels in mixed cord serum of 40 infants born to drinking women were compared with those of 24 infants born to abstinent women. Twenty infants born to drinkers had signs of fetal alcohol effects. Thirty-five percent of the erythropoietin levels in mixed cord serum of infants of drinking mothers were above the normal range. Further, the elevation in fetal erythropoietin level correlated with maternal alcohol intake; infants of mothers consuming at least 300 g of ethanol weekly (28) had significantly higher (P less than .025) umbilical erythropoietin levels (median 66 mU/mL, range 10-2500) compared with infants of mothers consuming 150-300 g of ethanol weekly (median 37 mU/mL, range 23-215) or infants of control women (median 32 mU/mL, range 11-73). The subgroup analysis between infants with and without fetal alcohol effects showed no differences in umbilical erythropoietin levels. Maternal alcohol ingestion during pregnancy is associated with elevated umbilical erythropoietin levels, but whether this is a direct effect of ethanol or is induced by chronic fetal hypoxemia remains unclear.

Amniotic fluid erythropoietin correlates with umbilical plasma erythropoietin in normal and abnormal pregnancy.

In the human fetus, elevated plasma erythropoietin levels have been found in high-risk pregnancies at delivery. We examined the relationship of amniotic fluid erythropoietin and umbilical plasma erythropoietin at delivery in 17 normal pregnancies, 41 hypertensive pregnancies, and 37 insulin-treated diabetic pregnancies terminated by elective cesarean section without labor. An additional 27 insulin-treated diabetic patients were studied after undergoing variable durations (86-1184 minutes) of labor. Erythropoietin was analyzed using a highly sensitive and specific radioimmunoassay technique. Fetal plasma erythropoietin concentrations were elevated above the control upper range (50.3 mU/mL) in 59% of the hypertensives and in 38% of the diabetics. The amniotic fluid erythropoietin values were significantly lower than the umbilical plasma erythropoietin values in each study group. Although the umbilical plasma erythropoietin values in the abnormal pregnancy groups differed considerably from the corresponding levels in the controls, the ratio of amniotic fluid erythropoietin to umbilical plasma erythropoietin was approximately the same in controls, hypertensives, and diabetics. Furthermore, the plasma and amniotic fluid levels (In transformed) correlated highly significantly in all three individual groups in absence of labor. In the diabetic labor group, this relationship was nonsignificant. We conclude that in the absence of labor, amniotic fluid erythropoietin reflects fetal plasma erythropoietin. We speculate that amniotic fluid erythropoietin may be an antepartum indicator of fetal hypoxemia.

Maternal age and screening for gestational diabetes: a population-based study.

The American College of Obstetricians and Gynecologists (ACOG) has recommended screening for gestational diabetes, using a 50-g, 1-hour glucose challenge (threshold for further testing 140 mg/dL or higher), for all pregnant women aged 30 or older and for younger women with risk factors. In order to assess these recommendations, we collected demographic and historic data on 6214 pregnant women representing a population of universally screened individuals. Of 125 cases of gestational diabetes diagnosed (ACOG criteria), 70 patients (56%) were under the age of 30. In addition, 44% of gestational diabetics had no risk factors. The cost per case diagnosed would be $190 with the ACOG recommendations, $192 if the age for routine screening were lowered to 25 years or more, and $222 if universal screening were practiced. Using the ACOG recommendations, 35% of gestational diabetes would go undiagnosed, with little cost savings.

Glycohemoglobin in postpartum women.

As women giving birth to large for gestational age (LGA) infants are at risk for glucose intolerance during pregnancy, fasting plasma glucose (FPG) and glycohemoglobin levels (Hb AIc) were studied in the immediate postpartum period (less than 10 days). These laboratory tests, in addition to infant birth weights and perinatal histories in a group of 146 women whose infants were above the 95th percentile for gestational age, were compared with those of a group of women whose infants were appropriate for gestational age (AGA: above the 25th percentile but below the mothers 75th percentile) as well as with those of a group of control mothers without diabetic risk factors. Mean Hb AIc and FPG were elevated in the mothers of the LGA infants. When either the LGA group alone or all 3 groups together were analyzed by linear regression, significant relationships were observed for maternal Hb AIc versus FPG (P less than .001); maternal Hb AIc versus birth weight corrected for gestational age (P less than .001); and maternal FPG versus birth weight corrected for gestational age (P less than .001). In addition, infant weight correlated with maternal prepregnancy weight (r = .36), maternal weight gain in pregnancy (r = .23), and maternal height (r = .17), but not with any of the paternal anthropometric features studied. Twenty-six women with LGA infants underwent postpartum oral glucose tolerance tests before discharge. Four had abnormal results and all had Hb AIc values above SD of the nonrisk control values (5.8% total Hb). Of the 16 mothers of LGA infants with FPG levels greater than 85 mg/dl (above SD of the nonrisk control values), 7 (44%) also had Hb AIc levels of more than 5.8%. Moreover, on retrospective analysis, the LGA infants manifested increased perinatal morbidity (P less than .05) compared to the combined control groups.

Erythropoietin in human fetuses with immune hemolytic anemia and hydrops fetalis.

OBJECTIVE: To determine whether plasma erythropoietin is increased in fetuses with anemia due to Rh isoimmunization. METHODS: Hemoglobin and erythropoietin were measured in samples obtained by funipuncture from 15 fetuses with Rh isoimmunization (gestational age 26.2 +/- 5.0 weeks, mean +/- standard deviation) and from 13 control fetuses (23.1 +/- 6.7 weeks). Hemoglobin and erythropoietin also were determined in umbilical cord blood collected at birth from 20 term fetuses delivered by elective cesarean. RESULTS: Fetuses with Rh isoimmunization had lower hemoglobin and higher plasma erythropoietin measurements than mid-gestation controls (6.1 +/- 3.9 versus 10.7 +/- 1.5 g/dL and 105.5 +/- 168.1 versus 12.5 +/- 3.1 mU/mL, P < .05, respectively). Hemoglobin and plasma erythropoietin increased with gestational age in control fetuses. There was an inverse association between hemoglobin and plasma erythropoietin in control and Rh-isoimmunized fetuses (r = -0.56, P < .005). Using multiple linear regression, hemoglobin and gestational age were associated independently with plasma erythropoietin (overall F2,25 = 12.3, multiple r2 = 0.49, P < .001). Despite marked decreases in hemoglobin, fetuses below 24 weeks' gestation had minimal increases in plasma erythropoietin compared to fetuses above that gestational age. Mildly anemic Rh-isoimmunized fetuses (hemoglobin 11.6 +/- 2.0 g/dL) delivered vaginally had significantly higher erythropoietin levels in umbilical cord plasma than Rh-isoimmunized fetuses with comparable hemoglobin (10.9 +/- 3.5 g/dL) delivered by elective cesarean without labor (1246 +/- 856 versus 106 +/- 66 mU/mL, respectively, P < .05). CONCLUSION: Fetuses with anemia at mid to late gestation respond with increases in plasma erythropoietin, but these changes are substantially attenuated before 24 weeks' gestation.

Adaptive responses during anemia and its correction in lambs.

There is limited information available on which to base decisions regarding red blood cell (RBC) transfusion treatment in anemic newborn infants. Using a conscious newborn lamb model of progressive anemia, we sought to identify accessible metabolic and cardiovascular measures of hypoxia that might provide guidance in the management of anemic infants. We hypothesized that severe phlebotomy-induced isovolemic anemia and its reversal after RBC transfusion result in a defined pattern of adaptive responses. Anemia was produced over 2 days by serial phlebotomy (with plasma replacement) to Hb levels of 30-40 g/l. During the ensuing 2 days, Hb was restored to pretransfusion baseline levels by repeated RBC transfusion. Area-under-the-curve methodology was utilized for defining the Hb level at which individual study variables demonstrated significant change. Significant reciprocal changes (P < 0.05) of equivalent magnitude were observed during the phlebotomy and transfusion phases for cardiac output, plasma erythropoietin (Epo) concentration, oxygen extraction ratio, oxygen delivery, venous oxygen saturation, and blood lactate concentration. No significant change was observed in resting oxygen consumption. Cardiac output and plasma Epo concentration increased at Hb levels <75 g/l, oxygen delivery and oxygen extraction ratio decreased at Hb levels <60 g/l, and venous oxygen saturation decreased and blood lactate concentration increased at Hb levels <55 g/l. We speculate that plasma Epo and blood lactate concentrations may be useful measures of clinically significant anemia in infants and may indicate when an infant might benefit from a RBC transfusion.

Erythropoietin pharmacokinetics in premature infants: developmental, nonlinearity, and treatment effects.

Erythropoietin (EPO) pharmacokinetic studies were performed in premature infants (birth weight < 1.25 kg) and normal adults. Infants were divided into two subgroups on the basis of whether they received chronic treatment with recombinant human EPO (rhEPO; 500 IU.kg-1.wk-1 for 6 wk) beginning at 2-4 wk of life. Ten adults and seven rhEPO-treated infants underwent intravenous pharmacokinetic studies at escalating rhEPO doses: 10, 100, and 500 IU/kg. To test for pharmacokinetic developmental and treatment effects, an equal number of non-EPO- and EPO-treated infants were studied with 100 IU/kg on the last day of treatment. Compared with adults, very low birth weight infants demonstrated significantly greater plasma clearance and distribution volume and significantly shorter fractional elimination times (FET) and mean residence time (MRT) at all three rhEPO doses. Both infants and adults demonstrated nonlinear EPO elimination, i.e., increasing rhEPO dosing was associated with decreasing plasma clearance and increasing FET and MRT. In the absence of rhEPO treatment there were no pharmacokinetic differences between the two subgroups of infants studied 6 wk apart. In contrast, the rhEPO-treated infant subgroup demonstrated a significant increase in clearance and a decrease in FET and MRT following 6 wk of treatment. Enhancement of rhEPO efficacy in the prevention and treatment of anemia in premature infants may require higher doses administered in a progressively increasing fashion.

A system approach to pharmacodynamics. Plasma iron mobilization by endogenous erythropoietin in the sheep fetus; evidence of threshold response in spontaneous hypoxemia.

At present, nearly all infants with birth weights of < 1 kg receive blood transfusions for treatment of clinical signs of tissue hypoxia resulting from anemia of prematurity. In contrast to the successful use of recombinant human erythropoietin (rhEp) in adults, treatment of anemic neonates with rhEp to stimulate red cell production and reduce the need for transfusions that pose serious infectious and immunologic risk has not been effective. The present study investigates the pharmacodynamics (PD) of endogenous erythropoietin (Ep) in sheep fetuses to determine possible causes for the poor rhEp response in early development. The dynamic relationship between plasma Ep and plasma iron resulting from spontaneous hypoxemic episodes is investigated by PD system analysis. The erythropoietic effect of Ep is measured in terms of the mobilization of plasma iron needed in the production on new erythrocytes. A hysteresis minimization approach is employed to determine the intrinsic PD dose-response relationship (transduction) of Ep. The dose-response relationship shows a well-defined threshold level that has to be exceeded before Ep begins to show a significant effect on plasma iron. It is postulated that the threshold mechanism may serve a useful purpose during early development by reducing the risk of the fetus developing a pathological degree of polycythemia and hyperviscosity in the relatively hypoxemic fetal environment. At the same time, the threshold serves the purpose of providing a needed response to more severe pathologic hypoxemic episodes. The occurrence of anemia during subsequent postnatal life when PaO2 levels increase markedly may be the inevitable, but unfortunate corollary of a continuation of this mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Kinetic evaluation of nonlinear drug elimination by a disposition decomposition analysis. Application to the analysis of the nonlinear elimination kinetics of erythropoietin in adult humans.

The disposition-decomposition analysis (DDA) methodology enables isolation of the overall elimination and distribution effects in pharmacokinetics and facilitates analysis which focuses on drug elimination kinetics and does not require a specific structured modeling of drug distribution processes. A computer algorithm enables a curve fitting and a kinetic estimation by integration of the convolution type integrodifferential equation in the DDA. The approach is demonstrated in an analysis of the nonlinear disposition kinetics of erythropoietin (Epo) in 10 healthy, adult human subjects who each received 10, 100, and 500 U/kg i.v. bolus doses of Epo. The nonlinearity is analyzed according to a Michaelis-Menten type nonlinear elimination function, considering simultaneous fitting to the data from all three doses in each subject. The simultaneous fittings produced estimates of the Michaelis-Menten parameters (mean, % cv) Vm (901 mU/mL/h, 19.4%) and km (4814 mU/mL, 24.6%). A linear clearance parameter is defined as the asymptotic clearance value approached when the drug level decreases toward zero. The degree of nonlinearity reached from various dosings was quantified in terms of a clearance ratio which is defined as the ratio between the linear clearance and the clearance estimated for the maximum drug concentration encountered at the given dose level. The subjects showed very little nonlinearity at the 10 U/kg dosing with a mean clearance ratio of 1.07 (2.1% CV) A statistically significant increase in the degree of nonlinearity was observed in the Epo elimination kinetics as the dosing level was increased to 100 and 500 U/kg, reaching clearance ratios of 1.66 (14% CV) and 4.33 (27% CV), respectively. A zero value for the global elimination rate parameter in all 30 dosings indicates that Epo's elimination is entirely accounted for by nonlinear pathway(s).

Expanded Möbius syndrome.

A woman presented at 33 weeks gestation with reduced fetal movements and a nonreactive nonstress test. Fetal ultrasound examination revealed a peculiar unilateral arm tremor. At emergency cesarean section, performed for fetal indications, a 1,672-gm male infant was delivered requiring intubation for feeble respiratory effort. After delivery the neonate was transiently hypertonic and later hypotonic. Continuing ventilatory support at minimal settings was necessary. The work-up for aneuploidy, metabolic disorders, and infection was negative. The infant died after being removed from ventilatory support on day 22. Postmortem examination revealed extensive bilateral brain gliosis and mineralization without evidence of inflammation, partial absence of cranial nerve nuclei III-XI, and a total absence of cranial nerve roots VI-XI. Together these finding are compatible with a diagnosis of expanded Möbius syndrome.

Association of fetal and maternal carboxyhemoglobin levels in normal and Rh-alloimmune pregnancies.

OBJECTIVE: To compare paired antepartum fetal/maternal COHb ratios in whole blood from control and alloimmunized pregnancies and to examine the relationships between fetal and maternal COHb. METHODS: COHb levels were measured in paired fetal and maternal blood samples obtained at cordocentesis in 47 control and 16 Rh-alloimmunized pregnancies. COHb was determined by gas chromatography. Results were analyzed by t-test, regression and analysis of covariance. RESULTS: Although fetal/maternal COHb ratios for control and alloimmunized pregnancies were not statistically significantly different, i.e. 1. 11+/-0.04 and 1.26+/-0.09, respectively (P=0.09), fetal COHb levels were higher in Rh-alloimmunized fetuses (P=0.0002). Fetal COHb levels were also higher than paired maternal levels among the alloimmunized group (P=0.011), but not among the control group (1. 04+/-0.04, P=ns). In univariate regression analysis, fetal and maternal COHb levels were significantly correlated with one another in both control (r=0.52, P=0.0002) and alloimmunized pregnancy groups (r=0.52, P=0.05). Comparison of the slopes of the fetal versus maternal COHb plots for the two groups showed a significant difference (P=0.02), with the alloimmunized group having the steeper slope. CONCLUSION: Differences in the antepartum fetal-maternal COHb relationships in control and alloimmunized groups likely reflect increased endogenous CO production among alloimmunized fetuses as a result of pathologic hemolysis.