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Biomedical subjects

D K Stevenson

Publications and source records attributed to D K Stevenson.

At least 199 records · Page 11Linked to original sources
PubMed1990

Mortality of metalloporphyrin-treated neonatal rats after light exposure.

Tin protoporphyrin (SnPP) has been used to suppress hyperbilirubinemia in human neonates through inhibition of heme oxygenase. Some of the subjects exhibited mild erythema upon receiving phototherapy. SnPP and three proposed alternatives, tin mesoporphyrin (SnMP), zinc protoporphyrin (ZnPP) and zinc mesoporphyrin (ZnMP) are potential photosensitizers. We therefore studied the phototoxic effects of these compounds in the neonatal rat model. Fed Wistar rats (24-36 h old) were injected intraperitoneally with up to 40 mumol SnPP/kg body weight, 30 mumol SnMP/kg body weight, 60 mumol ZnPP/kg body weight, or 45 mumol ZnMP/kg body weight. The animals were placed over cool white light (20 microW/cm2/nm) for 12 h. Light exposure resulted in SnPP dose-dependent mortality, and the LD50 was determined to be 11.7 mumol/kg body weight. No deaths were observed in pups treated with up to 20 mumol SnMP/kg; treatment with 30 mumol SnMP/kg resulted in a 40% mortality rate. No fatalities were observed among the light-exposed ZnPP- or ZnMP-treated pups. No deaths were observed among control pups treated with the highest metalloporphyrin doses and kept in the dark; similarly, no mortality was observed in untreated light-exposed control animals. We conclude that (1) SnPP and SnMP are potentially fatal phototoxic substances in the neonatal rat; (2) ZnPP and ZnMP may be safer drugs for neonatal rats receiving light exposure, and (3) further studies are needed to fully assess the photobiological hazards of metalloporphyrin administration to humans.

Animals↗
PubMed1990

Heme catabolism in rhesus neonates inhibited by zinc protoporphyrin.

The effect of zinc (II) protoporphyrin IX (ZnPP) administration (40 mumol/kg, i.v.) on neonatal heme catabolism and the associated bilirubin production was investigated in rhesus (Macaca mulatta) neonates. Carbon monoxide excretion rates (VECO), tissue heme oxygenase activity, and plasma bilirubin concentrations were measured during a 26-hour postnatal period. In ZnPP-treated neonates (n = 4), VECO values were significantly (p = 0.002) diminished by 24% within 24 h. When compared to controls (n = 3), tissue heme oxygenase activity in ZnPP-treated neonates was greatly reduced in both liver (94% inhibition, p = 0.047) and spleen (48% inhibition, p = 0.077), but essentially unaffected in the kidney and brain. Although not statistically significant, peak (24-hour) neonatal plasma bilirubin concentrations tended to be lower (23%). These results suggest ZnPP may be efficacious in reducing heme catabolism associated with neonatal jaundice.

Animals↗
PubMed1989

The use of metalloporphyrins for the chemoprevention of neonatal jaundice.

Decreasing bilirubin formation is an important strategy for the prevention of neonatal jaundice. The stannic porphyrins, in particular tin protoporphyrin and tin mesoporphyrin, have been proposed for this purpose because these compounds competitively inhibit heme oxygenase, the rate-limiting enzyme in the heme-degrading pathway. However, these compounds are not only potent inhibitors of heme oxygenase but are also photosensitizers, which can generate cytotoxic oxygen species, such as singlet oxygen. Therapeutic regimens designed to avoid the phototoxicity caused by these and other metalloporphyrins have been suggested. An alternative approach would be the development of derivatives of tin protoporphyrin or other heme analogs that are less phototoxic and are stronger inhibitors of heme oxygenase. However, our understanding of the molecular basis of heme oxygenase inhibition is still limited. The response of heme oxygenase to specific inhibitors varies a great deal and depends on the organ and stage of development. This may be a result of the differing proportions of heme oxygenase isoenzymes in different organs. These questions and others need to be systematically answered so we may better understand and treat disturbances in heme homeostasis. In addition, administration of these compounds may have other metabolic consequences directly and indirectly related to their potent, long-lasting inhibition of heme oxygenase. The significance of such effects, whether transient or permanent, needs to be elucidated.

Bilirubin↗
PubMed1989

Cardiovascular and metabolic effects associated with nifedipine and ritodrine tocolysis.

Recent investigations have indicated that nifedipine, a calcium channel entry blocker, may be useful in the treatment of preterm labor. This prospective, randomized study compares cardiovascular and metabolic effects measured in association with sublingual and oral administration of nifedipine with those noted with the intravenous and oral administration of the beta-adrenergic agent ritodrine. Serial measurements of cardiovascular parameters, hematocrit, electrolytes, glucose, blood urea nitrogen, creatinine, calcium, and serum glutamic-oxaloacetic and glutamic-pyruvic transaminase were compared between groups. Sublingual and oral nifedipine caused minimal cardiovascular alterations. At doses sufficient to achieve tocolysis, ritodrine caused more pronounced cardiovascular changes than nifedipine. Both agents had a hemodilutional effect, but nifedipine was not associated with alterations in serum electrolytes or a dramatic hyperglycemia. On the basis of this study, it appears that the use of nifedipine for preterm labor management is associated with hemodilutional changes but not the adverse cardiovascular or metabolic effects often associated with ritodrine tocolysis.

Blood Glucose↗
PubMed1989

Nifedipine pharmacokinetics during preterm labor tocolysis.

Nifedipine, a calcium entry blocker, has known relaxing effects on the myometrium. Thirteen women in preterm labor received nifedipine for tocolysis. Blood samples obtained serially during treatment and at the time of delivery were assayed for maternal and neonatal nifedipine concentrations. The peak concentration of nifedipine during sublingual therapy ranged from 23.4 to 197.9 ng/ml and reflected substantial interpatient variability. The mean (+/- SD) measurable trough value in patients who received 20 mg of nifedipine orally every 6 hours was 7.2 +/- 5.5 ng/ml. The maternal mean half-life of nifedipine was 81 minutes (range 49 to 137 minutes). At delivery, neonatal nifedipine levels were nondetectable in 6 of the 11 neonates available for study; in 5, values ranged from 29.5 to 1.8 ng/ml. From these results we conclude that both sublingual and oral nifedipine treatment results in variable but usually measurable maternal plasma concentrations and that placental transfer of nifedipine occurs.

Adult↗
PubMed1989

The effect of abortion on the incidence of pre-eclampsia.

The incidence of pre-eclampsia was studied in 9771 women that were pregnant for the first or second time. The protection offered by a previous pregnancy which ended in abortion was compared to that provided by a first pregnancy that proceeded to term. The rate of pre-eclampsia was 2.9% for primigravid women and was significantly lower (1.5%, p less than 0.001) for women giving birth for the second time. Adjusting by multiple regression for confounding factors (e.g., maternal age, social class, ethnic origin and smoking), the incidence of pre-eclampsia was also significantly lower (p = 0.038) following an induced abortion, but not following a spontaneous abortion.

Abortion, Induced↗
PubMed1989

Is teenage pregnancy a neonatal risk factor?

Maternal characteristics and neonatal outcome of 421 primiparas aged 15-19 years who delivered at Bikur Cholim Hospital in Jerusalem were examined. The study group included 190 teenage mothers from the Mea Shearim community who marry young and who receive extensive social and economic support. The control group included 231 teenage mothers from other areas of Jerusalem, characterized by a predominantly low social class, Oriental ethnic origin, and a high rate of out-of-wedlock births (28.6%). The Mea Shearim mothers had a significantly lower incidence of low birth weight (less than 2500 g) infants compared to the control group (6.3% vs. 14.7%, p less than 0.01). The differences could not be explained by maternal age distribution, ethnicity, smoking, or marital status. These results suggest that in a community that provides extensive social and economic support and good access to free prenatal care of high standard, teenage pregnancy is not a neonatal risk factor.

Adolescent↗
PubMed1989

Zinc protoporphyrin inhibits CO production in rats.

We studied the effect of zinc protoporphyrin (ZnPP) on in vivo total bilirubin production, as measured by the excretion rate of carbon monoxide (VeCO), in adult rats. A single subcutaneous dose of ZnPP (40 mumol/kg) suppressed the VeCO between 2-12 h posttreatment, with maximum suppression of approximately 20% by 4 h. The heme oxygenase activity in the liver and spleen of the ZnPP-treated rats was significantly inhibited at 12 h compared with that of the controls. The in vitro inhibition of heme oxygenase activity by the addition of exogenous ZnPP to native rat liver and spleen tissue preparations was observed, as evidenced by suppressed CO production. This in vitro inhibition of heme oxygenase activity by ZnPP was further confirmed by finding decreased bilirubin formation, as measured directly by high-performance liquid chromatography. This study demonstrates that ZnPP can inhibit in vivo liver and spleen heme oxygenase activity and suppress CO production in the rat, as well as inhibit in vitro heme oxygenase activity in native rat tissues.

Animals↗
PubMed1989

A concurrent epidemic of respiratory syncytial virus and echovirus 7 infections in an intensive care nursery.

We describe concurrent outbreaks of respiratory syncytial virus (RSV) and Echovirus 7 (Echo 7) infections in a neonatal intensive care unit, including infants who had dual infections. Seventy-three infants were identified as having RSV from January through June, 1984. During the same surveillance period Echo 7 was cultured from 20 infants, and 6 infants had concurrent RSV and Echo 7 and RSV were isolated, but not concurrently. This dual outbreak of RSV and Echo 7 infections persisted for months despite infection control measures. Control procedures were complicated by: (1) cases of RSV infection at less than 72 hours of age, which had not previously been reported and which led to the reintroduction of RSV into "clean" areas; (2) the lack of a rapid diagnostic test for enterovirus infection; (3) the number of infants who were asymptomatic with each infection; and (4) the logistical problems of handling a dual pathogen outbreak in a confined setting. These problems were compounded by the many risk factors associated with nosocomial infections found in neonatal intensive care settings such as prolonged hospitalizations, endotracheal or nasogastric tubes and contact with many ancillary care personnel.

Age Factors↗
PubMed1989

Carboxyhemoglobin measurements in the diagnosis of ABO hemolytic disease.

To assess hemolysis in hyperbilirubinemic infants with ABO isoimmunization, we measured the carboxyhemoglobin (HbCO) concentrations in full-term infants with ABO isoimmunization during the first week of life. Two groups of infants, ABO compatible (n = 34) and ABO incompatible (n = 30), were further divided into two groups with and without hyperbilirubinemia. All the infants from ABO incompatible pregnancies showed a positive indirect Coombs' test. The groups with hyperbilirubinemia included infants with maximum serum total bilirubin levels about 15 mg/dL and infants treated by phototherapy or exchange transfusion. In the ABO incompatible infants, the HbCO levels in those with hyperbilirubinemia were significantly higher than in infants without hyperbilirubinemia during the first week after birth (p less than 0.01 at 24, 72, 120 hours after birth, respectively). The levels of HbCO in the ABO incompatible infants with hyperbilirubinemia were significantly higher compared with the levels in the ABO compatible infants with hyperbilirubinemia (p less than 0.05 at 24 hours, p less than 0.01 at 72 and 120 hours after birth, respectively). HbCO measurement may facilitate the early diagnosis of hemolytic disease and the prediction of jaundice caused by ABO isoimmunization.

ABO Blood-Group System↗
PubMed1989

Continuous parenteral infusion of vitamin E pharmacokinetics and bilirubin production in premature neonates.

We conclude that 5 mg/kg of vitamin E, administered intra-arterially as an 8-hour continuous infusion, significantly and predictably raises serum vitamin E levels into the supraphysiologic range with no apparent side effects. In a group of premature infants whose initial serum vitamin E levels were generally greater than or equal to 0.5 mg/dL, no decrease in bilirubin production was observed. Thus, vitamin E deficiency probably does not play a prominent role in jaundice of prematurity.

Bilirubin↗
PubMed1989

In vitro inhibition of adult rat intestinal heme oxygenase by metalloporphyrins.

We determined the inhibitory effects of concentrations of tin- and zinc protoporphyrin (1-100 microM) and mesoporphyrin (0.1-10 microM) on the in vitro heme oxygenase (HO) (E.C.1.14.99.3) activity in liver, spleen, and intestine 13,000 x g tissue supernatants from fasted adult male Wistar rats through measurement of carbon monoxide by gas chromatography. All four metalloporphyrins inhibited intestinal HO, under the light-limited conditions of these experiments. The zinc porphyrins showed a clear concentration dependency over the entire range, reducing activity to near zero levels at their highest concentrations. The tin porphyrins reduced HO activity to 26% of initial levels, but the inhibition was not clearly concentration dependent. Liver and spleen supernatants exhibited concentration dependent inhibition by all four metalloporphyrins. We also assessed the effect of light on HO activity measurements. HO determinations in the light (8 microW/cm2/nm) yielded higher HO activity than for reactions performed in the dark. The presence of light and SnPP appeared to stimulate the HO activity of intestinal preparations thus overcoming the observed inhibition. Light and SnPP also decreased to a lesser degree the inhibition for the spleen preparation, but not for the liver. We conclude that heme oxygenase activity measurements via CO determination need to be conducted in the absence of light, in particular when photosensitizers are present. Furthermore, it appears that intestinal HO behaves in a quantitatively different way from other tissues, under varying conditions of metalloporphyrin inhibition and light exposure.

Animals↗
PubMed1989

Carbon monoxide excretion as an index of bilirubin production in rhesus monkeys.

The role of increased heme catabolism in neonatal hyperbilirubinemia was investigated in rhesus (Macaca mulatta) neonates through the measurement of carbon monoxide excretion rates (VECO), blood carboxyhemoglobin content (HbCO), and plasma bilirubin concentrations. Neonatal values were compared to those of adult rhesus monkeys. These indices of bilirubin production responded appropriately to administration of NEM-damaged erythrocytes and tin protoporphyrin. Our results indicate that VECO measurements are a valid index of changes in bilirubin production in the newborn rhesus monkey.

Animals↗
PubMed1989

Vancomycin pharmacokinetics in very low birth weight neonates.

The pharmacokinetics of vancomycin hydrochloride was studied in 12 very low birth weight infants. The gestational age (mean +/- SD) was 25.9 +/- 1.3 weeks and body weight was 769.2 +/- 151.5 g at the time of initiation of the study. Vancomycin was infused over a period of 60 minutes in a dosage of 14.2 +/- 3.2 mg/kg once daily in 10 patients, twice daily in 1 patient and every 36 hours in 1 patient for a mean of 10.5 +/- 4.9 days. Serial blood samples were obtained and the concentration time data were fitted to a one-compartment open model using the ADAPT computer program. A significant positive correlation was found between postconceptional age and vancomycin clearance (P less than 0.005) and between vancomycin elimination half-life and plasma creatinine (P less than 0.01). A negative correlation existed between plasma creatinine and vancomycin clearance (P less than 0.005), between postconceptional age and plasma creatinine (P less than 0.005) and between vancomycin half-life and postconceptional age (P less than 0.01). On the basis of these findings a vancomycin dosage of 15 mg/kg every 24 hours for infants less than 1000 g should yield concentrations within the accepted therapeutic range. This susceptible population requires frequent monitoring of vancomycin concentrations because of the high degree of interpatient variability and the continuous maturation of renal function.

Bacterial Infections↗