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The 14C-tripalmitin breath test has been used routinely in our institution for the diagnosis of fat malabsorption as well as for the differential diagnosis of malabsorption due to pancreatic insufficiency. The test was performed in 124 patients over a period of about three years. The sensitivity and specificity of the test for fat malabsorption were better than 85.7 and 87.0%, respectively, with the efficiency better than 86.4%. When used in conjunction with Viokase administration, the test is useful as a means of separating pancreatic malabsorption patients from patients with other forms of malabsorption.

We have compared three analytical systems for the measurement of serum thyroxine: enzyme-linked immunoassay (EIA), fluorescent immunoassay (FIA) and a radioimmunoassay (RIA). These were evaluated with respect to their precision, accuracy, analytical sensitivity and sample throughput. The RIA is more sensitive than the EIA (10 microgram/L vs. 35 Ug/L. Both systems have excellent precision (X = 86 ug/L, C.V.RIA = C.V.EIA = 4.6%). Both the EIA and RIA demonstrate good accuracy with recovery of between 97-98% of added thyroxine. The FIA has an apparent sensitivity between that of the RIA and EIA (25 microgram/L), but a precision consistently lower than the other two systems (C.V. = 7.4%, X = 86 microgram/L). Patients' results by RIA compared well with those from EIA )r = 0.91, P less than 0.05), but a poor correlation was found with FIA (r = 0.865, P greater than 0.05). Although not fully automated, the EIA performed on the Abbott ABA-100 analyzer has a sample throughput equal to the automated RIA system (Micromedic, Concept 4).

Enalaprilat, the active metabolite of enalapril, and its lysine analogue lisinopril are potent nonsulfhydryl angiotensin-converting enzyme inhibitors. Earlier studies from our laboratories demonstrated that neither drug is significantly metabolized, and both are almost exclusively eliminated by renal excretion. This report compares the renal excretory mechanisms for these structurally related compounds in the rat. After an iv, 1-mg/kg dose, ratios of renal clearance (CLR) of unbound drug to glomerular filtration rate (GFR) for enalaprilat and lisinopril were 2.72 +/- 0.70 and 1.01 +/- 0.18, respectively, suggesting that enalaprilat, but not lisinopril, was actively secreted by the kidneys. Treatment with probenecid and p-aminohippuric acid, potent competitive inhibitors for the renal anionic transport system, caused a profound decrease in the renal clearance of enalaprilat to the level of GFR. The CLR/fu.GFR, where fu is the unbound fraction, became 1.10 +/- 0.09 and 1.25 +/- 0.25, respectively. These results and the fact that quinine, a potent inhibitor for the cationic transport system, had little effect on the renal clearance of enalaprilat indicated that enalaprilat is secreted by the organic anion transport system. On the other hand, probenecid, p-aminohippuric acid, and quinine had no effect on the renal clearance of lisinopril, suggesting that lisinopril is eliminated exclusively by glomerular filtration.

The ECG and the determination of serum enzymes creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) may be falsely normal early in acute myocardial infarction. Myoglobin, an oxygen-carrying protein found in cardiac muscle and striated skeletal muscle, presents an attractive alternative to CPK and LDH in the emergency department setting for identification of acute myocardial infarction. Myoglobin levels may be elevated in the serum within one hour after myocardial cell death with peak levels reached within four to six hours. We report a study of 59 patients presenting to a community hospital with chest pain and subsequent hospitalization. Twenty-one had an acute myocardial infarction. Presenting (0 hour) myoglobin determination was positive in 13 of 21 individuals, while CPK-MB was positive in only three. Serum myoglobin elevation at three hours identified all 21 patients with myocardial infarction with the CPK-MB determination positive in 19. Serum myoglobin elevation may permit early identification of myocardial infarction, with subsequent verification using CPK-MB determination, allowing appropriate intensive care admission for careful monitoring of these patients.

To determine the functional capabilities of the parathyroid glands, 17 EDTA infusions were given to 11 children (ages 1 month to 12 years) and to two mothers of four of the children. Serum ionized Ca fell from 4.1 mg/dl to 3.4 mg/dl. Excessive parathyroid hormone responses were elicited during seven of nine EDTA infusions in five children and in one adult with hypophosphatemic rickets, during the active phase of rickets. In four of five subjects with problems related to hypercalcemia, borderline low or undetectable PTH responses were elicited. Three relatively normal PTH responses were obtained, two in an infant after phosphate-induced hypocalcemic tetany was corrected, and one in a child with a malabsorption syndrome. The renal tubular reabsorption of phosphate was inversely related and the urinary cyclic AMP excretion was positively related to the PTH response. Thus EDTA infusions in infants and children might be useful in the identification of hyper-, normo-, or hypoparathyroid states and would be of value in defining the functional condition of the parathyroid glands in children with deranged Ca or P metabolism.

In vitro dissolution profile testing of 12 generic 6-propyl-2-thiouracil (PTU) formulations indicated significant differences in their solubilities in water and in 0.1N hydrochloric acid. Two products, representing the extremes of solubility, were subsequently tested for bioavailability. Bioavailability data from euthyroid, hyperthyroid, and hypothyroid beagle dogs indicated that the rate of PTU absorption varied appreciably between the two generic products studied. These results were consistent with the in vitro dissolution data. Comparisons of the pharmacokinetic parameters obtained for the euthyroid beagle dog to those reported for euthyroid man12 indicated that the beagle dog is an adequate model for PTU disposition in man. These combined results suggest that all generic formulations of PTU are not the same and that the most soluble product may be desirable in situations where rapid absorption is important, such as thyroid storm.

Serum prostatic acid phosphatase (PAP), measured by three different technics, was used to screen 560 men over 50 years of age for prostatic cancer. All three PAP procedures failed to detect the one subject found to have prostatic cancer on physical examination and confirmed by biopsy, and all assays had a significant number of "falsely" elevated PAP levels. Four PAP assays were assessed in 80 men undergoing prostatic biopsy/removal in whom histologic examination of prostatic tissue was made. Clinical sensitivity and specificity for detecting those patients with and without prostatic cancer ranged from 20-57% and 54-95%, respectively, with the monoclonal enzyme immunoassay being the most sensitive but the least specific, and the traditional enzyme assay being the most specific but insensitive. In men with diagnosed prostatic cancer undergoing radiation or chemotherapy, the assays were useful in distinguishing between those with active and inactive disease. The authors conclude that serum PAP assays, irrespective of the type of procedure used, has no place in screening for prostatic cancer, a minimal role in establishing a definitive diagnosis, but a useful role in monitoring therapy.

To elucidate the changes in mineral metabolism and blood concentrations of calciotropic hormones which accompany GH therapy, we studied 12 GH-deficient children for 5 days before and for 1 week after high dose (5 IU/day) GH therapy, and again at 1 month, 3 months, and 1 yr of replacement therapy (0.1 IU/kg to a maximum dose of 2 IU three times weekly). All responded with acceleration of height velocity, and bone ages advanced appropriately. Fasting serum ionized calcium levels did not change: 4.11 +/- 0.06 (SEM) mg/dl before, 4.19 +/- 0.05 for the week of high dose therapy, and 4.20 +/- 0.14 during replacement therapy. Likewise, fasting serum parthormone did not vary: 38.9 +/- 2.6 muleq/ml before to 44.1 +/- 9.2 at 1 yr. Twenty four-hour nephrogenous cyclic AMP (NcAMP) did not vary over the first week (1.2 +/- 0.7 nmol/dl glomerular filtrate before, 1.3 +/- 0.4 after 1 week), but increased to 5.3 +/- 1.9 after 1 yr (alpha less than 0.001). The response of ionized calcium and parathormone to a standardized disodium EDTA infusion of 50 mg/kg also did not change. The mean fasting serum calcitonin level was not different before therapy (29.4 +/- 2.8 pg/ml), after 1 week (21.5 +/- 1.8), or after 1 yr (42.4 +/- 11.0). However, the mean serum 1,25-dihydroxyvitamin D concentration rose from 33.1 +/- 3.3 pg/ml before therapy to 68.3 +/- 12.3 on the seventh day of high dose therapy (alpha less than 0.01), returning to pretherapy values by 1 month. We conclude that high dose GH therapy in GH-deficient children raises 1,25-dihydroxyvitamin D concentration acutely, but that long term, physiological replacement therapy does not cause such an effect. Because NcAMP excretion rose in the absence of an increase in serum parathormone concentration, we conclude that GH sensitizes the kidney to a cAMP-mediated effect of parathormone.

Serum thyroxine concentrations were measured sequentially in eight healthy male volunteers after the oral administration of one of two brand name, commercially available thyroxine tablets. In all cases, levels peaked at 2 hours and did not return to baseline values until 24 hours after dosing. From 2 through 10 hours, statistically significant elevations in serum thyroxine concentrations were observed. Such fluctuations may be important in evaluating laboratory results in patients receiving replacement doses of thyroxine.

A radioimmunoassay with sufficient sensitivity to detect the recently discovered, circulating peptide YY in the majority of healthy adults has been developed. The antiserum to synthetic peptide YY raised in rabbits essentially showed no cross-reactivity with bovine or porcine synthetic pancreatic polypeptide, neurotensin, or neuropeptide Y, but cross-reacted to the extent of 0.03% with synthetic peptide HI. The minimum detectable limit of the assay for plasma peptide YY was 20 pg/ml with coefficients of variation less than 16%. The immunoreactivity of peptide YY isolated from healthy adult plasma had a gel-filtration chromatographic profile similar to that of synthetic peptide YY. Fasting levels of peptide YY in plasma from 127 of 137 (92.7%) ostensibly healthy adults were measurable and showed a log-normal distribution. Using the maximum-likelihood estimation method, we calculated the normal range to be 13-178 pg/ml with a geometric mean value of 49 pg/ml. The fasting plasma peptide YY levels showed no significant age or sex dependency.

Lovastatin is a pro-drug lactone whose open chain beta-hydroxy-acid (HA) is a potent inhibitor of hydroxymethylglutaryl-CoA-reductase and thus of cholesterol synthesis. Because the liver is the major site of cholesterolgenesis, it is the principal target organ for agents of this class. In animals, lovastatin is not as well absorbed as HA given per se, but that fraction that is absorbed reaches the portal circulation largely unchanged and is more efficiently extracted by the liver, after which it is reversibly biotransformed to HA and irreversibly to other enzymatically active products. These, like HA, maintain high hepatic gradients relative to all tissues examined. The minimal systemic burden for HA is attributable in part to the metabolic equilibrium, lovastatin in equilibrium HA, the opposing reactions for which appear to be present in most tissues. Excretion is very largely biliary in all species. Detailed comparisons of absorption, distribution, metabolism, and excretion profiles presented here and elsewhere indicate dogs to be the most appropriate paradigm for humans for study of lovastatin disposition.

Autologous canine 131I-fibrinogen labeled by a chloramine-T method was examined to determine whether the fibrinogen had been altered by the iodination procedure as suggested by other investigators. Before and after radioiodination, clottability of the fibrinogen was always equal to or greater than 89 percent. Gel chromatography studies revealed that labeled fibrinogen behaved as unlabeled fibrinogen and no high molecular weight material was found. Gamma camera scintigraphy reflected the chromatography results, as iodinated material did not appear in the liver or spleen until 48 to 72 hours. The slow-moving component of the whole blood clearance curves, respresenting undenatured fibrinogen, had a mean half-life of 61.4 +/- 5.1 hours (+/- S.E.M.) and comprised 51.5 +/- 7.5 percent of the initial activity. Similarly, a mean falf-life of 53.4 +/- 2.0 hours and 59.6 +/- 7.7 percent initial activity wwere attributed to fibrinogen according to the plasma clearance curves as determined by trichloracetic acid precipitation. The results clearly demonstrated that chloramine-T iodination of fibrinogen can yield an excellent product, biologically and chemically, which is free from macroaggregates.

Sixteen neonates, ranging in gestational age from 27 to 41 weeks and in postnatal age from birth to 8 days, were evaluated for their renal response to an endogenous PTH stimulus in 22 separate experiments. The PTH stimulus was generated by the decreased serum ionized Ca that accompanies exchange transfusion with citrated blood. The neonates increased their serum PTH from 95.8 +/- 13.1 to 133.9 +/- 15.4 microliterEq/ml (mean +/- SEM) during the transfusion, while increasing their urinary cAMP from 0.77 +/- 0.11 to 1.45 +/- 0.22 nmol/ml, and their urinary P from 12.9 +/- 2.6 to 30.6 +/- 6.1 mg/dl in the four hours following the exchange transfusion. This response was not related to postnatal or gestational age. We speculate that lack of renal responsiveness to PTH does not play a major role in the pathogenesis of early neonatal hypocalcemia.

Mineral metabolism in the cerebrospinal fluid (CSF) of children is poorly understood. Recent reports have suggested a neuroregulatory role for calcitonin. We examined the hypotheses that in children (1) CSF levels of calcium and phosphorus might be low, (2) CSF levels of magnesium might be higher than serum levels of magnesium, and (3) immunoreactive calcitonin might be present in the CSF. We examined serum and CSF samples of 45 children, aged 8 days to 16 years, undergoing spinal taps for suspected meningitis or as part of leukemia therapy. Both serum and CSF levels of calcium correlated with those of magnesium. There was no correlation for CSF levels vs serum levels of calcium, magnesium, or phosphorus. The CSF levels of calcium and phosphorus were lower than the serum levels of these elements, but the CSF levels of magnesium were higher than the serum levels of magnesium. Calcitonin was detected in the CSF of 8% of samples assayed (range, 14 to 175 ng/L [14 to 175 pg/mL]). Two of these five samples had bacteriologically proven meningitis, and two samples were from patients less than 2 months of age. The CSF levels of calcitonin did not correlate with the serum levels of calcitonin. Thus, in children CSF levels of calcium and phosphorus are low, CSF levels of magnesium are higher than the serum levels, and the level of immunoreactive calcitonin is usually not present in the CSF but possibly is elevated in meningitis and early infancy.

We used a combination of radioiodine scanning and quantitative radiation dosimetry to evaluate responses to therapeutic irradiation with 131I in 76 patients with thyroid adenocarcinoma. Fifty patients received 131I treatment for ablation of residual thyroid tissue after surgical thyroidectomy, and 26 had 131I treatment for metastatic thyroid cancer. Successful ablation was observed in patients receiving higher radiation doses to the thyroid--about 4.4 times those in patients whose lesions were not ablated--largely because of a longer effective half-life of 131I in residual thyroid tissue in the patients with ablated lesions. Patients with metastases that persisted after 131I therapy tended to have more advanced disease and received significantly lower radiation doses per millicurie of administered 131I than did persons whose lesions responded to treatment. Initial 131I treatment resulting in radiation doses of at least 30,000 rad to thyroid remnants and 8000 rad to metastases was associated with a significant increase in the rate of response to therapy.

Little information is currently available concerning the uptake of porphyrins by pancreatic tumors, or the effect of photodynamic therapy (PDT) on pancreatic cancer. In Syrian golden hamsters (n = 33), the organ distribution of 125I-labeled dihematoporphyrin ether (DHE) was studied in a pancreatic cancer model. In the same animal model the effect of PDT was studied using a gold vapor laser for energy delivery 3 hr after the injection of DHE (n = 7). DHE was 2.4 times more concentrated in the pancreatic tumor than in the nontumorous pancreas at 3 hr. Simultaneously there was a considerable accumulation of DHE in the surrounding gastrointestinal tract, causing perforation of the duodenum and jejunum with resultant death in four (57%) animals after PDT. Photodynamic therapy caused extensive tumor necrosis without any obvious effect on the nontumor-bearing pancreas. Damage to the surrounding tissue in the hamster indicates that precautions should be taken if PDT is to be used clinically in pancreatic cancer. Intratumoral injection of DHE may give higher drug concentrations with greater specificity for tumor treatment.

Serum vitamin B12 (B12) levels of 53 patients (15 with pernicious anemia) and 42 healthy volunteers were determined using crude intrinsic factor (IF), pure IF, and a mixture of crude IF + R-protein blocking agent (block IF). The radioassay using pure IF showed less sample-to-sample variation in nonspecific binding than the radioassay using block IF. The mean B12 levels in 42 healthy subjects were significantly higher with crude IF (499 +/- 23 pg/ml, 1 s.e.m.) than with pure IF (408 +/- 29 pg/ml) or with block IF (407 +/- 22 pg/ml). B12 levels were abnormally low in all 15 patients with pernicious anemia by pure IF (less than 100 pg/ml), in 14 patients by block IF (less than 150 pg/ml), and in only seven patients by crude IF (less than 200 pg/ml). Our data confirm previous reports that B12 deficiency can be diagnosed more reliably by measuring serum B12 levels with etiher pure IF or block IF.

One hundred and eight "exchange" blood transfusions were done on 61 newborn infants. Baseline serum PTH concentrations and the PTH rise in response to citrate-induced hypocalcemia were studied. Baseline PTH values increased with postnatal age, particularly after the first three days of life. The acute response of PTH to citrate-induced hypocalcemia appears within ten minutes following the initiation of exchange transfusion and was shortlived in spite of further decline of serum ionized calcium. The dominant effect of postnatal age over gestational age was demonstrated: postnatally older but gestationally less mature infants exhibited greater responsiveness than postnatally younger, but gestationally more mature, infants. The PTH response during exchange transfusion was blunted in hypomagnesemic infants. Since lower serum magnesium concentrations were also present during the first three days of life, a separate effect of serum magnesium concentrations on parathyroid responsiveness cannot be ruled out in this study.

It is customary to use the LD50 response as a criterion for the evaluation of chemical radioprotection. The increased urinary excretion of deoxycytidine (CdR) in irradiated rats has been shown to be a linear dose--response relationship up to 200 R, thus making it possible to consider such a response as a criterion for chemical radioprotection evaluation at sub-lethal irradiation levels. Rats were subjected to 200 R X-irradiation with various chemical protectors and without chemical protectors, urine was collected 24 hours after irradiation, and the CdR levels in the urine analysed. A dose-reduction factor (DRF) was determined for 24-hour urinary excretions of CdR for chemically protected and non-protected rats. The DRF values are within 6 per cent of those reported by other investigators using LD50 as the response criterion for serotonin, cysteine, MEA and PAPP but differ for WR-2721 and WR-2823. Agreement using WR-2721 and WR-2823 compounds is only obtained when the toxicity effect of the compound is taken into consideration.

Osteodystrophy frequently accompanies severe childhood hepatobiliary disease. Proposed causes include malabsorption of vitamin D and calcium, and diminished 25-hydroxylation of vitamin D. Two children, ages 23 and 35 months, with radiographic and biochemical evidence of rickets with extrahepatic biliary atresia, were treated with 1,25-dihydroxyvitamin D3. The minimal effective therapeutic dose and efficacy of 1,25-(OH)2D3 in the treatment of rickets associated with severe childhood hepatic disease were determined. Oral 1,25-(OH)2D3 was ineffective at doses of 0.10 microgram/kg/day. Parenteral doses of 0.20 microgram/kg/day effectively produced radiographic, bone mineral (photon absorptiometric), and biochemical evidence of healing. The need for four times the physiologic dose of 1,25-(OH)2D3 by the parenteral route suggested enhanced catabolism of, or end-organ resistance to, 1,25-(OH)2D3 in our patients with severe cholestatic liver disease treated with phenobarbital.

Placental permeability and metabolism of parathyroid hormone (PTH) 125I was studied in 5 gravid ewes during the last trimester. The mean plasma half-life was 38 +/- 0.8 and 22.6 +/- 2.7 min in the fetus and ewe, respectively. There was minimal placental transfer of PTH 125I in either the fetal to maternal and maternal to fetal directions. Fetal calcium homeostasis is probably not affected directly by changes in maternal serum PTH levels, and maternal calcium homeostasis probably is not affected directly by changes in fetal serum PTH concentrations.

In 64 maternal-infant pairs, we tested the hypotheses that serum calcitonin, serum gastrin, and plasma glucagon concentrations are elevated in infants at risk for early neonatal hypocalcemia, and that elevated serum gastrin and plasma glucagon result in elevated serum calcitonin and low serum calcium values in neonates. Serum Ca declined significantly in neonates at 24 hours of age, and was inversely correlated with serum calcitonin. Cord serum calcitonin, gastrin, and plasma glucagon concentrations rose significantly at 24 hours of age. Cord calcitonin was significantly higher in preterm compared with term infants, and there was no significant difference between asphyxiated and nonasphyxiated preterm neonates; in term neonates cord calcitonin concentration was inversely correlated with Apgar scores at 1 and 5 minutes. Cord calcitonin was not correlated with cord gastrin or glucagon. Cord and 24-hour gastrin and glucagon values were not related to prematurity; cord glucagon, but not gastrin, was related to birth asphyxia. We conclude that (1) serum calcitonin, gastrin, and plasma glucagon values rise postnatally; cord calcitonin is elevated in preterm and in asphyxiated term infants; serum calcitonin concentration does not correlate with the elevated serum gastrin and plasma glucagon values; and at 24 hours of age, decreased serum Ca is correlated with serum calcitonin, and hence calcitonin might play a role in the pathogenesis of early neonatal hypocalcemia.

Fifty-six diabetic mothers and their infants were studied prospectively from birth. Twenty-one of 56 IDM had serum Mg less than or equal to 1.5 mg/dl, on at least one occasion during the first 3 days. Serum Mg in these hypomagnesemic infants did not demonstrate the normal increase with postnatal age that was present in normomagnesemic infants. Decreased neonatal serum Mg was related to increased severity of maternal diabetes, young mothers, mothers for lower gravidity, and prematurity. Decreased serum Mg, alone or with decreased ionized or total Ca, did not correlate with neuromuscular irritability in the infants. Decreased serum Mg in IDM was associated with decreased maternal serum Mg, decreased neonatal ionized and total Ca, increased serum P, and decreased parathyroid function. Serum Mg was not related to dietary P intake, or urinary Ca or P excretion. Thus, transitory neonatal hypomagnesemia occurs in IDM; it is speculated that factors causing HM might include maternal HM or neonatal hyperphosphatemia, and that the HM is related to the hypocalcemia and functional hypoparathyroidism of IDM.

The absolute and relative bioavailability of levothyroxine was determined in young, healthy male subjects after administration of i.v. solution, p.o. solution, or one of two brand-name, commercially available tablets. The mean dose size was about 0.18 mg. Serum concentration-time data were obtained over a period of 50 h. The absolute bioavailabilities of the two tablet preparations were 66% and 72%, respectively.

Elevations of serum thyroxine without thyrotoxicosis or binding protein abnormalities have been documented in 8 of 13 family members, representing 4 generations. This syndrome appears to represent an elevated threshold for the amount of free thyroxine substrate required to maintain adequate T3 production form the peripheral monodeiodination of T4. It reiterates the need for a prudent re-evaluation of all clinically euthyroid patients with elevated serum thyroxine concentrations before concluding that they are indeed thyrotoxic.

Twenty pre-eclamptic mothers treated with MgSO4 and their newborn infants were studied prospectively to determine the clinical and biochemical effects of hypermagnesemia. Maternal serum magnesium concentration rose to 4.4 mg/dl at delivery and was accompanied by a fall in maternal serum calcium concentration during labor. Neonatal serum Mg concentration remained elevated for the first 72 hours of life (mean at 72 hours = 3.0 mg/dl). Serum Mg concentration was higher in premature infants and in babies with birth asphyxia and/or hypotonia. Serum Ca concentration was higher and serum PTH was lower in hypermagnesemic study infants when compared to a retrospectively selected, matched froup of control infants. We speculate that elevated serum Mg values in these infants result in a shift of Ca from bone to plasma, and that elevated Mg and Ca concentrations further suppress neonatal parathyroid function.

Sixty-nine out of a kindred of 100 members covering five generations were examined and studied, and 34 were hypercalcemic. Sixteen subjects were believed, on the basis of laboratory and clinical observations, to have primary hyperparathyroidism. Eight patients were subjected to exhaustive study to identify polyendocrine involvement before neck exploration. No coexisting endocrine abnormalities were found; operation showed multiparathyroid gland involvement in most instances. Measurement of immunoassayable calcitonin and assessment of renal and gut function were carried out in 37 subjects to search out possible causes of "reactive" parathyroid gland hyperfunction. While no such cause-effect relationship was noted for this kindred, 16 of the subjects so tested had serum calcitonin content below the assay limits of sensitivity. What role this apparent lack of calcitonin played in the development of hyperparathyroidism (or vis versa) needs clarification.