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Biomedical subjects

H Hummler

Publications and source records attributed to H Hummler.

At least 19 recordsLinked to original sources
PubMed2005

[Triploidy: prompt diagnosis based on typical clinical signs in a live-born extremely low birth-weight infant].

A child with complete triploidy is rarely born alive. However, owing to the advances in perinatal medicine even extremely immature preterm infants receive full support in the delivery room and are admitted to the neonatal ICU. Consequently, the clinician may also have to consider the diagnosis of triploidy when faced with a dysmorphic extremely preterm infant. We report here the smallest described live born girl of 25 + 5 weeks of gestational age with typical clinical findings of complete triploidy phenotype II. The aim of the case report is to make the neonatologist aware of this syndrome using photographs of this case as well as discussing the literature available. Prompt clinical diagnosis confirmed by chromosome analysis helps doctors and parents with the decision whether to continue promising or to limit futile life support measures.

Chromosome Aberrations↗
PubMed1999

13-cis-Retinoic acid alters neural crest cells expressing Krox-20 and Pax-2 in macaque embryos.

This study investigates hindbrain and associated neural crest (NCC), otocyst, and pharyngeal arch development in monkey embryos following teratogenic exposure to 13-cis-retinoic acid (cRA). cRA was orally administered (5 mg/kg) to pregnant long-tailed macaques (Macaca fascicularis) between gestational days (GD) 12 and 27. Embryos were surgically collected at desired stages during treatment, analyzed for external morphological changes, and processed for immunohistochemistry. Two transiently expressed nuclear proteins, Krox-20 and Pax-2, were used as markers for the target cellular and anatomical structures. Rhombomere (r) expression patterns of Pax-2 (r4/r6) and Krox-20 (r3/r5) were maintained after cRA treatment, but r4 and r5 were substantially reduced in size. In untreated embryos, Krox-20 immunoreactive NCC derived from r5 migrated caudally around the developing otocyst to contribute to the third pharyngeal arch mesenchyme. In cRA-treated embryos, a subpopulation of NCC rostral to the otocyst also showed Krox-20 immunoreactivity, but there was a substantial reduction in Krox-20 post-otic NCC. Pax-2 immunoreactive NCC migrating from r4 to the second pharyngeal arch were substantially reduced in numbers in treated embryos. Alteration in the otic anlage included delayed invagination, abnormal relationship with the adjacent hindbrain epithelium, and altered expression boundaries for Pax-2. cRA-associated changes in the pharyngeal arch region due to cRA included truncation of the distal portion of the first arch and reduction in the size of the second arch. These alterations in hindbrain, neural crest, otic anlage, and pharyngeal arch morphogenesis could contribute to some of the craniofacial malformations in the macaque fetus associated with exposure to cRA.

Animals↗
PubMed1999

Pathogenesis of retinoic acid-induced ear malformations in primate model.

13-cis retinoic acid (RA) is a causative agent for human/monkey retinoic acid embryopathy (RAE), in which the most common type of malformation is microtia or anotia. In the present study, malformed ears of monkey fetuses exposed to RA during early embryogenesis were analyzed and revealed a subtype of defects., i.e., apparent duplication of the external/middle ear. A part of the posterior auricle appeared to be ectopically formed in the anterior auricular region or in the region posterior to the auricle. Additionally, there was duplication of the zygomatic arch, malleus, and incus. In order to characterize possible pathogenetic events underlying these malformations, embryos at selected stages were collected after dosing dams with RA at 5 mg/kg/day during gestational days 12-27. Cellular retinoic acid binding protein I whole-mount immunostaining showed that RA induced specific alterations in the migration of cranial neural crest cells (NCC). NCC en route to the second pharyngeal arch were bifurcated, and some of these NCC migrated abnormally into the first and/or third arches, which may underlie external ear duplication. Scanning electron microscopy and neurofilament immunostaining provided evidence that there was partial duplication of trigeminal nerve/ganglion following RA insult. The duplication of NCC neuronal derivatives in the first pharyngeal arch is consistent with duplication of NCC mesenchymal components (zygomatic arch, malleus, and incus). Therefore, RA-induced alterations in cranial NCC migration patterns are likely to be a pathogenetic event underlying ear malformations (including duplication) of RAE in monkeys.

Animals↗
PubMed1999

Dietary vitamin A and teratogenic risk: European Teratology Society discussion paper.

This review discusses the predictive value of animal models in assessment of possible risk from excess vitamin A consumption during pregnancy and the human evidence concerning risk of congenital malformations from excess vitamin A in the diet, consumed either as a constituent of normal foods or in the form of dietary vitamin supplements. Other sources of exposure to vitamin A include medicines (dermal and oral preparations) and cosmetics, but these are not further considered here. Conservative estimates of the likely safe intake of vitamin A during pregnancy are available, based on results from scientific research to date. However, current uncertainties are such that further research is needed to more clearly define intakes which may be on the borderline between those which are beneficial and those which may pose a risk to the developing embryo and fetus.

Abnormalities, Drug-Induced↗
PubMed1999

Delivery room management of extremely low birth weight infants: spontaneous breathing or intubation?

OBJECTIVE: To study the effect of two different delivery room (DR) policies on the rate of endotracheal intubation and mechanical ventilation (EI/MV) and short term morbidity in extremely low birth weight infants (ELBWI; <1000 g, >/=24 weeks). METHODS: Retrospective cohort study of 123 inborn ELBWIs born in 1994 and in 1996. DR policies have changed. Until 1994, ELBWIs were intubated immediately after delivery when presenting the slightest signs of respiratory distress or asphyxia after initial resuscitation using a face mask and a handbag. During 1995, the guidelines for respiratory support were changed. In 1996, continuous (15 to 20 seconds), pressure controlled (20 to 25 cm H2O) inflation of the lungs using a nasal pharyngeal tube, followed by continuous positive airway pressure (CPAP; 4 to 6 cm H2O) was applied to all ELBWIs immediately after delivery to establish a functional residual capacity and perhaps to avoid EI/MV. In addition to the changes in respiratory support, the prevention of conductive and evaporative heat loss was improved in 1996. For analysis of morbidity and mortality, infants were matched for gestational age and birth weight. RESULTS: The rate of EI/MV in the DR decreased from 84% in 1994 to 40% in 1996. In 1996, 25% of the ELBWIs were never intubated (7% in 1994), but 35% of the ELBWIs needed secondary EI/MV, primarily because of respiratory distress syndrome (RDS). Initial ventilator settings, ventilator days, mortality, and morbidity were not different between ELBWIs with EI/MV in the DR and infants with secondary EI/MV attributable to RDS in the intensive care unit. ELBWIs with no EI/MV that was caused by RDS had a lower morbidity (ie, bronchopulmonary dysplasia, intraventricular hemorrhage >grade 2 and/or periventricular leukomalacia), mortality, and fewer hospital days (mean: 79 vs 105 days). The incidence of gastrointestinal adverse effects like feeding intolerance or necrotizing enterocolitis was not increased in 1996. PaCO2 was significantly higher at admission to the neonatal unit in ELBWIs with CPAP in 1996 (54 +/- 15 mm Hg, 7.2 +/- 2.0 kPa) compared with infants with EI/MV in 1994 (38 +/- 11 mm Hg, 5.1 +/- 1. 5 kPa. A total of 26% of spontaneously breathing infants had hypercapnia (PaCO2 >/=60 mm Hg [8.0 kPa]), compared with 7% of infants with EI/MV in 1994. Within the first few hours of life, PaCO2 decreased to 46 (32 to 57) mm Hg (6.1 [4.3 to 7.6] kPa) in never intubated ELBWIs (n = 17), but increased to 70 (57 to 81) mm Hg (9.3 [7.6 to 10.8] kPa) in ELBWIs (n = 14) with RDS and secondary EI/MV (age 5.5 [1 to 44] hours). CONCLUSIONS: In our setting, the individualized intubation strategy in the DR restricted EI/MV to those ELBWIs who ultimately needed it, without increasing morbidity or mortality in infants with secondary EI/MV attributable to RDS. We speculate that an individualized intubation strategy of the ELBWI is superior to immediate intubation of all ELBWIs with slight signs of respiratory distress after birth.

Cohort Studies↗
PubMed1998

Effects of 13-cis-retinoic acid on hindbrain and craniofacial morphogenesis in long-tailed macaques (Macaca fascicularis).

Hindbrain and craniofacial development during early organogenesis was studied in normal and retinoic acid-exposed Macaca fascicularis embryos. 13-cis-retinoic acid impaired hindbrain segmentation as evidenced by compression of rhombomeres 1 to 5. Immunolocalization with the Hoxb-1 gene product along with quantitative measurements demonstrated that rhombomere 4 was particularly vulnerable to size reduction. Accompanying malformations of cranial neural crest cell migration patterns involved reduction and/or delay in pre- and post-otic placode crest cell populations that contribute to the pharyngeal arches and provide the developmental framework for the craniofacial region. The first and second pharyngeal arches were partially fused and the second arch was markedly reduced in size. The otocyst was delayed in development and shifted rostrolaterally relative to the hindbrain. These combined changes in the hindbrain, neural crest, and pharyngeal arches contribute to the craniofacial malformations observed in the retinoic acid malformation syndrome manifested in the macaque fetus.

Animals↗
PubMed1998

Retinoid teratogenicity in the macaque: verification of dosing regimen.

To further define teratogenicity associated with 13-cis-retinoic acid (13-cis-RA) in the cynomolgus monkey, the drug was orally administered on three different treatment regimens. Experiment (Exp.) 1 (2.5 mg/kg/day, gestational day [GD] 12-27, n = 11) investigated the teratogenicity of a single daily dose of 13-cis-RA administered shortly after embryo implantation. Pharmacokinetic sampling was done to determine retinoid profiles on the first (GD12) and last (GD27) days of treatment. Exposure to 13-cis-RA during early organogenesis in Exp. 2 (2.5 mg/kg/day, GD20-27, and 2 x 2.5 mg/kg/day, GD28-30, n = 5) investigated the potential adverse effects of 13-cis-RA on the developing limb. The use of multiple doses of 13-cis-RA in Exp. 3 (2 x 2.5 mg/kg/day, GD26-27, n = 5) investigated the necessity of double dosing on the induction of retinoid embryopathy in the macaque. Malformations of retinoid target organs as well as embryolethality were most prevalent when single daily doses of 13-cis-RA were administered during pre- and early organogenesis in Exp. 1. Moreover, multiple doses on GD26-27 failed to induce any manifestation of abnormal development in Exp. 3. These results confirm that the lowest observed adverse effect level (LOAEL) in macaques is 2.5 rather than 5.0 times greater than that observed in human pregnancies. Exposure during forelimb development (GD20-30) in Exp. 2 was unsuccessful in inducing defects of this skeletal region, although defects in several retinoid target organs (i.e., cerebellum and internal ear) were present, indicating that a teratogenic threshold was achieved. Pharmacokinetic analysis of 13-cis-RA and its metabolites on GD12 and 27 in Exp. 1 showed considerable exposure to the administered drug and its 4-oxo-metabolite. In contrast, the exposure to all-trans-RA was negligible. The results support the use of a specific treatment schedule in early gestation in the macaque as the most appropriate model for characterizing the teratogenic potential of retinoids in humans.

Abnormalities, Drug-Induced↗
PubMed1998

Safety of vitamin A: recent results.

A still unresolved public health concern is that excessive vitamin A intake, like vitamin A deficiency, possibly causes birth defects not only in animals but also in man. Due to the low incidence of possibly vitamin A-related malformations in man, available data cannot convincingly define the upper safe limit of periconceptional vitamin A intake. Direct human intervention studies are not feasible for ethical reasons. Therefore, a novel approach in addressing this issue was chosen by combining teratogenicity data from a validated animal model with data on systemic exposure to vitamin A and its major metabolites in female volunteers. In a study in pregnant women endogenous plasma concentrations of vitamin A metabolites during early pregnancy ranged from 0.26 to 7.72 ng/ml. Since they did not cause any foetal malformations, retinoid plasma levels in this range can be considered non-teratogenic. Results of a trial in non-pregnant women document that daily oral vitamin A supplements of 4000, 10,000 and 30,000 IU given for 3 weeks were in the range or slightly above the range of endogenous plasma levels seen in early pregnancy. Even after a 3-week treatment with 30,000 IU/day, peak plasma levels of retinoic acid and isotretinoin were within or just slightly above the range of their physiological levels. In cynomolgus monkeys (average weight: 3-4 kg), a NOAEL (no observed adverse effect level) of 7500 IU per kg body weight and a LOAEL (lowest observed adverse effect level) for developmental toxicity of 20,000 IU/kg was found. Considering these results in the cynomolgus monkey, a dose of 30,000 IU/day should also be considered as non-teratogenic in man.

Abnormalities, Drug-Induced↗
PubMed1997

Increased incidence of sighs (augmented inspiratory efforts) during synchronized intermittent mandatory ventilation (SIMV) in preterm neonates.

A reflex resulting in a deep, sigh-like inspiratory effort (augmented breath) is frequently triggered during synchronized mechanical ventilation in preterm infants. We studied the incidence of augmented inspiratory efforts and their effect on ventilation and lung compliance during conventional IMV and synchronized IMV (SIMV) in 15 preterm neonates (GA 26.7 +/- 1.5 wks (mean +/- SD), BW 925 +/- 222 g, age 1-8 days). Augmentation of spontaneous inspiratory effort was defined as an esophageal pressure deflection occurring coincident with a synchronized mechanical breath and exceeding the previous unassisted spontaneous effort by more than 50%. The incidence of augmented breaths was higher during SIMV (11.1 +/- 7.7%; P < 0.01) than during conventional IMV (5.1 +/- 6.1%). However, when the synchronized breaths were triggered late (200-300 msec) after the onset of inspiration, augmented breaths occurred no more frequently than during conventional IMV (6.0 +/- 4.7%). The incidence of augmented breaths correlated inversely with dynamic lung compliance (P = 0.014), but was not significantly influenced by a change in PEEP. Although inspiratory effort increased nearly three times during the augmented breaths, tidal volume increased only 12%. The change in tidal volume was limited because the augmented effort reached its maximal negativity only approximately 500 ms after the beginning of the synchronized, mechanical breath and at a time when the mechanical breath had already ended. For this reason the augmented effort did not contribute significantly to minute ventilation, but only prolonged inspiration. Dynamic lung compliance did not change significantly after an augmented breath. The results indicate that augmented inspiratory efforts are more common in preterm neonates ventilated with SIMV than with conventional IMV, but do not contribute significantly to ventilation.

Cohort Studies↗
PubMed1997

Computer-controlled minute ventilation in preterm infants undergoing mechanical ventilation.

INTRODUCTION: Computer-controlled minute ventilation (CCMV) continuously adjusts the ventilator rate to changes in spontaneous respiratory drive and pulmonary mechanics to maintain a preset total minute ventilation. HYPOTHESIS: We hypothesized that CCMV would maintain ventilation and oxygenation with fewer mechanical breaths than conventional intermittent mandatory ventilation in very low birth weight infants. METHODS: Very low birth weight infants in clinically stable condition who were undergoing mechanical ventilation were enrolled. The number of mechanical breaths, total and mechanical expiratory minute ventilation, mean airway pressure, oxygen hemoglobin saturation by pulse oximetry, and transcutaneous partial carbon dioxide and partial oxygen tensions were obtained during intermittent mandatory ventilation and CCMV (45 to 60 minutes) and compared by paired t test. RESULTS: Fifteen infants were studied. Birth weight (median, range) was 700 gm (550 to 1205 gm), gestational age 26 weeks (23 to 34 weeks), age 21 days (3 to 50 days). When switched from intermittent mandatory ventilation to CCMV, the number of mechanical breaths was reduced (15 +/- 2.8 to 8.6 +/- 2.9 breaths per minute, p < 0.001), leading to lower airway pressure (3.97 +/- 1.00 to 3.45 +/- 1.00 cm H2O, p < 0.001) and lower expiratory minute ventilation generated by the mechanical ventilator (116 +/- 31 to 65 +/- 28 ml/min per kilogram, p < 0.001), while total expiratory minute ventilation remained unchanged. Mean transcutaneous partial carbon dioxide and oxygen tensions, oxygen hemoglobin saturation, and the time spent within different oxygen hemoglobin saturation ranges did not differ between both ventilatory modes. CONCLUSION: CCMV maintained adequate ventilation and oxygenation with lower mechanical ventilatory support than IMV. CCMV may reduce barotrauma and chronic lung disease during long-term use.

Down-Regulation↗
PubMed1996

Retinoid metabolism and transplacental pharmacokinetics in the cynomolgus monkey following a nonteratogenic dosing regimen with all-trans-retinoic acid.

Retinoids often exhibit a complex metabolic pattern and differential transplacental kinetics, which make it difficult to pinpoint the proximate compound responsible for the observed teratogenic effect. We have therefore studied the pharmacokinetics and metabolism of all-trans-retinoic acid (all-trans-RA) in cynomolgus monkeys following application of a nonteratogenic dosing regimen and compared the results with corresponding data from a previous study with a teratogenic dosing regimen with 13-cis-RA [Hummler et al. (1994) Teratology 50:184-193]. All-trans-RA was administered to pregnant cynomolgus monkeys (Macaca fascicularis) by nasogastric intubation at a dose of 5 mg/kg body wt once daily from gestational day (GD) 16 to 26 and twice daily at 8-h intervals from GD 27 to 31. Examination of the fetuses of four dams on GD 100 +/- 2 showed no embryotoxic or teratogenic effects of the applied dosing regimen (Experiment 1). Maternal plasma retinoid pharmacokinetics on GD 16, 26, and 31 as well as embryonic retinoid profiles after the last drug administration on GD 31 were determined in thirteen further dams (Experiment 2). All-trans-RA reached much lower plasma concentrations after the last two treatments on GD 31 than after the first one on GD 16 and the eleventh one on GD 26 (0-24-h area-under-the-concentration-time-curve (AUC) values: 104 +/- 59 ng x h/ml (after the last treatment on GD 31), 189 +/- 110 (GD 16) and 393 +/- 305 ng x h/ml (GD 26). The predominant plasma metabolites of all-trans-RA were its beta-glucuronide and the beta-glucuronide of all-trans-4-oxo-RA. Both of these retinoids accumulated in the plasma during the period of treatment and displayed AUC values 5- to 30-fold higher than those of all-trans-RA. Embryonic concentrations of all-trans-RA were not increased over endogenous levels after the last administration on GD 31 when plasma concentrations were low. To evaluate the placental transport of all-trans-RA in the presence of high plasma concentrations, a further experiment was performed, in which a single dose of all-trans-RA (10 mg/kg body wt) was given to four pregnant monkeys on GD 31, and plasma pharmacokinetics as well as embryonic concentrations of retinoids at 4 h post-treatment were determined (Experiment 3). This dosing schedule yielded high plasma concentrations of all-trans-RA, while embryonic concentrations were about 40% of plasma levels. Based on the plasma AUC values on GDs 16 and 26 obtained in Experiment 2 and the degree of placental transfer, as determined on GD 31 in the presence of high plasma levels in Experiment 3, we estimated embryonic AUC values for the 24-h period following the nonteratogenic doses on GDs 16 and 26 in Experiment 2. These AUC values were similarly high to the embryonic AUC value of all-trans-RA obtained after application of the teratogenic dosing regimen with 13-cis-RA [Hummler et al. (1994) Teratology 50:184-193]. In addition, plasma AUC values of all-trans-RA were 2- to 7-fold higher after all-trans-RA administration (present study) than after dosing with the teratogenic dose of 13-cis-RA. These results strengthen our recent suggestion that the teratogenic effects induced in cynomolgus monkeys by 13-cis-RA treatment cannot solely result from the action of all-trans-RA, but may involve 13-cis-RA and 13-cis-4-oxo-RA, which could act directly or function as transport vehicle.

Animals↗
PubMed1996

Patient-triggered ventilation: a comparison of tidal volume and chestwall and abdominal motion as trigger signals.

Patient-triggered synchronized ventilation requires reliable and early detection of the infant's inspiratory effort. Several trigger methods have been developed that frequently lack the sensitivity to detect inspiration in small preterm infants (trigger failure), or show a high rate of breaths triggered by artifacts in the respiratory signal (autotrigger). The purpose of this study was to determine the effectiveness of the following trigger signals: abdominal movement sensed by a newly developed induction technique, chestwall motion detected by changes in transthoracic impedance, and tidal volume measured by anemometry at the endotracheal tube connector. Ten preterm infants (birth weight, 580-1,424 g; median weight, 943 g; study weight, 535-1,415 g; median weight, 838 g; gestation age, 26-32 weeks, median gestational age, 28 weeks, study age, 1-50 days, median study age, 11 days) were included in the study. A Sechrist SAVI ventilator was triggered by one of three signals: chestwall or abdominal movement, or tidal volume generated by the infants. Response time between beginning of inspiratory flow, the occurrence of the trigger signal (signal delay), and the onset of the triggered breath (trigger delay) were determined for each of the three signals. The signal response time was -13.5 msec (95% CI, -33 to -2 msec) for the abdominal movement signal, indicating that it started before inspiratory flow; 0.0 msec for the volume signal; and 44.0 msec (95% CI, 29-73 msec) for the chestwall signal (P < 0.002); this long delay was secondary to chestwall distortion and a subsequent delay in outward ribcage movement in many infants. The trigger delay for the abdominal signal was 90.0 msec (95% CI, 55-104 msec), 135.5 msec (95% CI: 82-186 msec) for the volume signal, and 176.5 msec (95% CI: 165-232 msec) for the chestwall signal, indicating that there was a difference in the rise time of signal voltage between the three methods (P < 0.01). The rate of autotriggered breaths was 3.2% (95% CI, 0.3-9.3%) when using the abdominal signal, 0.55% (95% CI, 0.0-2.1%) for the tidal volume signal, and 11.25% (95% CI, 0.5-27.8%) for the chestwall signal (P < 0.05). The incidence of trigger failure was low with all three signals and was not significantly different between the techniques. In summary, the chestwall signal had a long trigger delay and was highly susceptible to false triggering. It is, therefore, not a reliable trigger signal for synchronized mechanical ventilation in preterm infants. In contrast, tidal volume and abdominal movement signals had an acceptable trigger delay and a low rate of autotriggering, making them useful clinical trigger signals.

Confidence Intervals↗
PubMed1996

Influence of different methods of synchronized mechanical ventilation on ventilation, gas exchange, patient effort, and blood pressure fluctuations in premature neonates.

We studied the effects of two methods of synchronized mechanical ventilation [synchronized intermittent mandatory ventilation (SIMV) and assist/control (A/C)] on ventilation, gas exchange, patient effort, and arterial blood pressure (ABP) fluctuations. SIMV and A/C were applied in random order in 12 preterm neonates (gestational age, 29.7 +/- 2.3 weeks; birth weight, 1,217 +/- 402 g). We measured total (Vetot) and mechanical (Vemech) minute ventilation, spontaneous (Vtspont) and ventilator supported (Vtmech) tidal volume, transcutaneous oxygen saturation (SpO2), transcutaneous PO2 (TcPO2), and PCO2, (TcPCO2), mean airway pressure (Paw), phasic esophageal pressure deflections (Pe) as an estimate of inspiratory effort, mean arterial blood pressure (ABP), and beat-to-beat ABP fluctuations. The measurements obtained during conventional intermittent mandatory ventilation (IMV) were compared with the recordings during SIMV and A/C. To make the measurement conditions comparable and to prevent hyperventilation, peak inspiratory pressure was reduced during the A/C mode so that Vetot remained in the same range as during the IMV mode. Whereas Vetot was similar in all three conditions by study design, Vemech was larger during SIMV and A/C than during IMV. Vtmech increased during SIMV and by study design was smaller during A/C than during IMV. Pe decreased during SIMV and A/C compared with IMV, and Paw was higher during A/C than during IMV or SIMV. Beat-to-beat ABP fluctuations were reduced during SIMV and A/C compared with IMV and showed a close positive correlation with Pe changes. We conclude that SIMV increases Vemech and reduces Pe compared with IMV, resulting in smaller intrathoracic and ABP fluctuations. During A/C, a substantial portion of the spontaneous respiratory effort is shifted to the ventilator, resulting in a further decrease in Pe and ABP fluctuations.

Blood Pressure↗
PubMed1996

Influence of infection on patent ductus arteriosus and chronic lung disease in premature infants weighing 1000 grams or less.

OBJECTIVES: To test the hypotheses that (1) infection increases ductal dilatory prostaglandins and inflammatory mediators that may influence the closure of a patent ductus arteriosus (PDA), increasing the incidence of late episodes of PDA (after 7 days) and the rate of closure failures, and (2) the concurrence of PDA and infection increases the risk of chronic lung disease (CLD). METHODS: One hundred fourteen premature infants (birth weight, 500 to 1000 gm) were prospectively assessed for PDA and infection. Serum levels of 6-ketoprostaglandin F1 alpha and tumor necrosis factor alpha were measured routinely in all infants and when PDA or infection was present. Multivariate assessment of risk factors for PDA closure failure and for CLD was done by logistic regression, and expressed as an odds ratio and as 95% confidence intervals. RESULTS: Late PDA episodes were more frequent in infants with infection than in those without infection. A temporally related infection (<5 days between both diagnoses) was associated with an increased risk of PDA closure failure (odds ratio, 19.1 (confidence interval, 4 to 90)). In addition to birth weight and the severity of initial respiratory failure, PDA and infection increased the risk of CLD (odds ratio, 11.7 (confidence interval, 1.7 to 81) for PDA; odds ration, 3.1 (confidence interval, 1 to 11) for infection). Furthermore, when both factors were temporally related, they further increased the risk of CLD (odds ratio, 29.6 (confidence interval, 4.5 to >100)). Infants with infection and those with PDA had higher levels of 6-ketoprostaglandin F1 alpha than did control subjects. Levels of tumor necrosis factor alpha were also elevated in infants with infection and in those with late PDA. CONCLUSIONS: Infection adversely influences PDA outcome by increasing the risk of late ductal reopening and PDA closure failures. Increased levels of prostaglandins and tumor necrosis factor alpha in infants with infection may explain the poor PDA outcome. The concurrence of PDA and infection potentiates their negative effects on the risk of CLD.

Chronic Disease↗
PubMed1996

Embryotoxic doses of vitamin A to rabbits result in low plasma but high embryonic concentrations of all-trans-retinoic acid: risk of vitamin A exposure in humans.

Retinoid pharmacokinetics were examined in plasma, placenta and embryos of gestational d 12 rabbits following application of an embryotoxic dosing regimen (10 mg retinyl palmitate/kg body wt per day from gestational d 7 to 12). Vehicle-treated or untreated rabbits served as controls. Physiological concentrations of all-trans-retinoic acid (all-trans-RA) and 13-cis-RA in rabbit plasma (5-8.33 nmol/L) were very close to the endogenous levels in human plasma. In addition, we identified endogenous all-trans-RA, 3,4-didehydroretinol and 3,4-didehydroretinoic acid in rabbit embryo. Following the last retinyl palmitate administration, apparent steady-state concentrations of all retinoids were reached in the examined compartments of rabbits. The major polar retinoid in plasma was 9, 13-di-cis-RA, but its embryonic concentrations were only about 6% of those in plasma. In the embryo, retinol and its esters were found at high concentrations; lower amounts of all-trans-4-oxo-RA and the newly identified 14-hydroxy-4, 14-retro-retinol could also be measured. Embryonic concentrations of all-trans-RA were about 100% higher than endogenous levels. The overall exposure of the embryo to this retinoid was, however, substantial. Embryonic area under the concentration time curve values strongly suggest that the embryotoxicity of the applied dosing regimen is mainly due to the action of all-trans-RA. A very remarkable finding of this study is the marginal increase of plasma concentrations of all-trans-RA over their endogenous levels, which is comparable to the human situation after vitamin A intake. This analogy indicates that high vitamin A intake may be associated with a higher risk for teratogenic effects in humans even in the absence of high elevation of plasma all-trans-RA levels.

Animals↗
PubMed1995

Single versus multiple dose administration of all-trans-retinoic acid during organogenesis: differential metabolism and transplacental kinetics in rat and rabbit.

Standard teratogenicity testing is usually performed by administration of a test compound daily throughout an extended period of organogenesis (e.g., between Days 6 and 15 in rat and 6 and 18 in rabbit). On the other hand, single dose experiments during a specific period were often demonstrated to be more effective in unveiling a particular teratogenic effect. We have assessed here if toxicokinetics is an important factor for the interpretation of the differences between two administration regimens of all-trans-retinoic acid (all-trans-RA) in two species. The transplacental pharmacokinetics of a low teratogenic dose of all-trans-RA administered orally were compared in a single versus multiple dose regimen in both the Wistar rat and the Swiss hare rabbit. In both species, the single dose animals were treated on Gestational Day 12, while the multiple dose animals received daily doses from Gestational Days 7 through 12. Pharmacokinetic profiles were determined for maternal plasma and embryo after dosing on Gestational Day 12 (for both the single and multiple dose regimens) and analyzed by reverse-phase HPLC. The dose used for both species was 6 mg/kg body wt/day which has recently been reported to be a marginal to low teratogenic dose when administered daily throughout organogenesis. In both rat and rabbit, the AUC of all-trans-retinoic acid in maternal plasma was much reduced (factor of 9 in the rat, factor of 2 in the rabbit) after multiple application as compared to the single administration, presumably due to enzyme induction. A similar, but not as pronounced effect was also observed in the embryo of both species. This diminished effect in the embryo indicates a relative increase of placental transfer at the lower maternal plasma concentration observed after multiple dosing, which may possibly be due to an increased availability of binding sites such as cytosolic retinoic acid binding protein and nuclear receptors in the embryo. In the rat, also the metabolite levels were reduced, while in the rabbit, the metabolites of the 13-cis-configuration were concomitantly increased. Our results suggest that multiple administration of a drug such as retinoic acid, which induces its own elimination pathways, results in substantially lowered drug levels in maternal plasma and embryo.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗