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H Hummler

Publications and source records attributed to H Hummler.

At least 37 records · Page 2Linked to original sources
PubMed1995

Mechanisms for episodes of hypoxemia in preterm infants undergoing mechanical ventilation.

OBJECTIVE: To ascertain possible mechanisms implicated in the development of transient episodes of hypoxemia (oxygen saturation < 85%) frequently observed in preterm infants undergoing mechanical ventilation, even after the acute phase of respiratory failure has passed. STUDY DESIGN: Tidal flow, airway and esophageal pressure, and oxygen saturation were continuously recorded in 10 infants (mean +/- SD, birth weight 733 +/- 149 gm, gestational age 25.5 +/- 2.2 weeks, age 26.3 +/- 11.9 days) who had repeated episodes of hypoxemia without any evident cause. Measurements of minute ventilation (VE) inspiratory compliance (Ci), and inspiratory resistance (Ri) were compared before and during episodes of hypoxemia. RESULTS: All episodes of hypoxemia were preceded by an active exhalation that produced a mean decrease in end-expiratory lung volume of 6.4 +/- 2.8 ml/kg. The reduction in lung volume was immediately followed by a sudden decrease in tidal flow and volume, despite continuation of mechanical ventilation at the same rate and peak pressure. The resulting hypoventilation was associated with a drop in Ci to approximately one half and an increase in Ri to more than double the baseline values. Approximately 30 seconds after the beginning of hypoventilation, the arterial oxygen saturation reached a hypoxemic level (oxygen saturation < 85%)> CONCLUSION: Most hypoxemic episodes were triggered by an expiratory effort that produced a large decrease in lung volume. This reduction in lung volume probably leads to closure of small airways and the development of intrapulmonary shunts, which would explain the rapid development of hypoxemia.

Analysis of Variance↗
PubMed1994

Maternal toxicokinetics, metabolism, and embryo exposure following a teratogenic dosing regimen with 13-cis-retinoic acid (isotretinoin) in the cynomolgus monkey.

The maternal pharmacokinetics, metabolism, and placental transfer of 13-cis-retinoic acid (isotretinoin) have been determined in the cynomolgus monkey using a dosing regimen which had been previously shown to result in retinoid-specific teratogenic effects [Hummler et al. (1990) Teratology 42:263-272]. The drug (2.5 mg/kg body weight) was administered by nasogastric intubation once a day between gestational days (GD) 16-26, and twice a day between GD 27-31. Maternal plasma kinetics were determined following dosing on GD 26 and GD 31, and placental transfer was studied following the last dose on GD 31. The plasma half life of 13-cis-retinoic acid in the monkey (13.2 h) was comparable to that in the human. The main plasma metabolite in the monkey was the 13-cis-4-oxo-retinoic acid which occurred at levels lower or comparable to those of the administered drug. During multiple dosing, this metabolite accumulated to the same degree as the parent drug. All-trans-retinoic acid was present in maternal plasma in very low concentrations (2% of 13-cis-retinoic acid). The beta-glucuronides of all-trans- and 13-cis-retinoic acid were further minor plasma metabolites. 13-cis-retinoic acid and its 4-oxo-metabolite reached the monkey embryo slowly but extensively during organogenesis and reached 24 h-AUC values of 956 and 590 ng.h/g embryo wet weight, resulting in embryo/maternal plasma concentration ratios of 0.41 and 0.33, respectively. The AUC value of all-trans-retinoic acid (316 ng.h/g) was only raised approximately 40% above the endogenous AUC level (225 ng.h/g); only at two time periods examined were the embryonic all-trans-retinoic acid concentrations above endogenous levels (at 4 h and 8 h; P < 0.01 and < 0.05, respectively; Student's t-test). The beta-glucuronides of all-trans- and 13-cis-retinoic acid were not detected in the embryo. Accumulation of 13-cis-retinoic acid and the 4-oxo-metabolite during the twice-per-day dosing regimen was apparent both in maternal plasma and embryo. An interspecies comparison suggests that the half life as well as the metabolic pattern of 13-cis-retinoic acid in plasma were similar in monkey and human: 13-cis-4-oxo-retinoic acid was the main metabolite in both species and the beta-glucoronides as well as all-trans-retinoic acid were minor metabolites. However, the plasma AUC values of the administered drug and particularly the 4-oxo-metabolite were found to be lower in the monkey as compared to the human.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Comparative teratology and transplacental pharmacokinetics of all-trans-retinoic acid, 13-cis-retinoic acid, and retinyl palmitate following daily administrations in rats.

The retinoids are teratogenic in a wide variety of species. In the rat, 13-cis-retinoic acid and retinyl palmitate are significantly less potent teratogens than all-trans-retinoic acid. This investigation questioned whether differing teratogenic potencies of these moieties can be correlated with the concentrations of these drugs and/or metabolites in the embryonic compartment. Approximately equipotent teratogenic doses of these three retinoids were administered and the pharmacokinetics in maternal plasma and embryo of the most prevalent vitamin A metabolites were measured. The glucuronides of the respective retinoids were the predominant metabolites in the maternal plasma, but were not detected in the embryo. Also, the transport of 13-cis-retinoic acid across the placenta occurred to a much lesser extent than the transport of all-trans-retinoic acid. Administration of either all-trans- or 13-cis-retinoic acid causes a depression in the endogenous retinol concentration. This depression is more pronounced in the maternal plasma than in the embryo. The depression of the retinol level in both plasma and embryo after 13-cis-retinoic acid administration (75 mg/kg/day) was greater than the depression after all-trans-retinoic acid (6 mg/kg/day), corroborating the inferential teratological data that the 13-cis-retinoic acid dose was more embryotoxic than the all-trans-retinoic acid dose. Although the dose of all-trans-retinoic acid was less embryotoxic than that of either 13-cis-retinoic acid or retinyl palmitate, the embryonic exposure to all-trans-retinoic acid was considerably larger, as determined by maximum concentration or area under the concentration-versus-time curve, after administration of all-trans-retinoic acid than after either retinyl palmitate or 13-cis-retinoic acid application. These results suggest that embryonic retinoids other than all-trans-retinoic acid--including the administered substances themselves--are important in the teratogenic process induced by 13-cis-retinoic acid and retinyl palmitate.

Animals↗
PubMed1994

The high sensitivity of the rabbit to the teratogenic effects of 13-cis-retinoic acid (isotretinoin) is a consequence of prolonged exposure of the embryo to 13-cis-retinoic acid and 13-cis-4-oxo-retinoic acid, and not of isomerization to all-trans-retinoic acid.

Previous studies suggested that the rabbit is much more susceptible to the teratogenic action of 13-cis-retinoic acid (13-cis-RA) than the mouse or the rat, while the teratogenicity of all-trans-RA was comparable in these species. In the present study we investigated if pharmacokinetics can explain these species- and structure-related differences. The embryotoxic and teratogenic potential of all-trans-retinoic acid (all-trans-RA) and 13-cis-RA were evaluated in the Swiss hare rabbit after oral administration of daily doses of the two drugs throughout organogenesis, from gestation day (GD) 6 to 18 (plug day = GD 0). All-trans-RA was given at dose levels of 0.7, 2 or 6 mg/kg body weight per day and 13-cis-RA at 3, 7.5 or 10 mg/kg per day. The doses needed to elicit a minimum teratogenic response were found to be 6 mg/kg per day for all-trans-RA and 10 mg/kg per day for 13-cis-RA. Using these doses, transplacental pharmacokinetics of all-trans- and 13-cis-RA were performed. Pregnant rabbits were treated once daily from GD 7 to 12 and plasma and embryo samples were collected for HPLC analysis at various time intervals after the final dose. The main plasma metabolites of all-trans- and 13-cis-RA were all-trans-beta-glucuronide (all-trans-RAG) and 13-cis-4-oxo-RA, respectively. The elimination of 13-cis-RA and its metabolites from maternal plasma were much slower than of all-trans-RA resulting in accumulation of the 13-cis-isomers in plasma. Marked differences in the placental transfer of the two drugs and their metabolites were observed. All-trans-RA and all-trans-4-oxo-RA were efficiently transferred to the rabbit embryo, reaching concentrations similar to the plasma levels. On the contrary, the 13-cis-isomers reached the embryo to a lesser extent. Despite its limited placental transfer, a considerable embryonic exposure to 13-cis-RA and 13-cis-4-oxo-RA was noticed after treatment with isotretinoin, as indicated by their area-under-the-concentration-time-curve (AUC) values in the embryo, which were in the same range as the corresponding AUC value of all-trans-RA after treatment with the all-trans-isomer.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Importance of early exposure to 13-cis retinoic acid to induce teratogenicity in the cynomolgus monkey.

The teratogenic potential of 13-cis retinoic acid (13-cis RA) was further assessed in cynomolgus macaques (Macaca fascicularis) following exposure to two different regimens during the preorganogenic period to determine the influence of time of treatment on the 13-cis RA malformation syndrome established previously (Hummler et al., Teratology, 42:263-272, 1990). In experiment (Exp) 1, 13-cis RA was orally administered once daily (2.5 mg/kg) on gestational day (GD) 16-25 and twice daily (2 x 2.5 mg/kg) on GD 26-27. In Exp 2, the same oral dose was administered once daily on GD 10-20 and twice daily on GD 21-24. Although the ear was affected at about the same incidence (6/9, 67%) in Exp 1 as previously reported, the defects were less severe. Except for hypoplastic vermis of the cerebellum (2/9, 22%), no other defects were seen. In Exp 2, the teratogenic effects of 13-cis RA on the craniofacial skeleton (1/9, 11%), external ear (5/9, 56%), and heart (2/9, 22%) were similar to that reported by Hummler et al.; however, no thymus or cerebellar malformations were observed. Analysis of the three different treatments (GD 16-27 in Exp 1, GD 10-24 in Exp 2, and GD 10-27 in Hummler et al.) suggests that the sensitive periods in the macaque are 1) craniofacial skeleton and heart GD 10-24, 2) thymus and cerebellum > GD 24, and 3) external ear GD 16-24, although the defects are less severe following the shorter exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1993

Developmental toxicity of fleroxacin and comparative pharmacokinetics of four fluoroquinolones in the cynomolgus macaque (Macaca fascicularis).

The potential developmental toxicity of fleroxacin was studied (Phase I) and its pharmacokinetics was compared to ciprofloxacin, temafloxacin, and norfloxacin (Phase II) in the cynomolgus macaque (Macaca fascicularis). Phase I studies involved oral administration of fleroxacin (35 and 70 mg/kg-day) during Gestational Days (GD) 20-34 or 35-49 (N = 10/group); controls received vehicle only. Increased maternal toxicity (weight loss, anorexia, emesis) and embryolethality (4/10, 40%; GD 20-34) were observed at 70 mg/kg-day. Urinary excretion of estrogen conjugates was reduced for females with nonviable pregnancies during both treatment periods (GD 20-34 and 35-49), although steroid hormone levels in serum remained unchanged during treatment; no malformations or growth retardation were observed at gross examination. For Phase II studies, the pharmacokinetics of fleroxacin (70 mg/kg), ciprofloxacin (100 mg/kg), temafloxacin (100 mg/kg), and norfloxacin (150 mg/kg) were studied during a 3-day oral treatment regimen in the nonpregnant (N = 12; 3/quinolone) and pregnant (N = 3; fleroxacin only) macaque. Serial blood samples were collected on the first and third days of treatment in all animals; for pregnant females, the conceptus was removed on GD 31 for analysis of fleroxacin levels. Marked differences between the quinolones were noted in the AUC0-24 hr for nonpregnant females. Based on AUC0-24 hr on the first day of treatment, the rank order was fleroxacin > temafloxacin > ciprofloxacin > norfloxacin. On the third of treatment, the rank order for exposure was temafloxacin > fleroxacin > ciprofloxacin > norfloxacin. Overall, results indicated (1) no marked differences in pharmacokinetic parameters in pregnant versus nonpregnant females, (2) fleroxacin levels in embryonic tissues were similar to maternal plasma levels, and (3) there was a correlation between exposure and embryolethal doses for all fluoroquinolones which resulted in embryolethality except norfloxacin.

Administration, Oral↗
PubMed1992

Teratogenicity of all-trans retinoic acid during early embryonic development in the cynomolgus monkey (Macaca fascicularis).

The embryotoxic and teratogenic potential of all-trans retinoic acid was assessed following exposure prior to and during early organogenesis in the cynomolgus monkey (Macaca fascicularis). Sixteen pregnant females were orally administered all-trans retinoic acid (Tretinoin, Hoffmann-La Roche) once daily from GD 10-20 and twice daily from GD 21-24 at three different dosages, 5 (n = 9), 10 (n = 6) and 20 mg/kg (n = 1). Adverse clinical signs resembling hypervitaminosis A were observed in one animal at 5 mg/kg, in three animals at 10 mg/kg, and in the animal treated with 20 mg/kg all-trans retinoic acid. Maternal weight loss was observed in the 10- and 20-mg/kg groups. A dose-dependent increase in embryolethality was observed, with 22% (2/9), 50% (3/6), and 100% (1/1) occurring at 5, 10, and 20 mg/kg, respectively. The majority of embryonic deaths occurred between GD 16 and 20; the incidence of these early losses was higher than in historical and concurrent controls. No malformations, but a single growth-retarded fetus, was observed in the 5-mg/kg group. Craniofacial malformations, consisting of external ear defects, mandibular hypoplasia, cleft palate, and temporal bone abnormalities, were seen in three viable fetuses in the 10-mg/kg group. Skeletal variations were common to the majority (70%, 7/10) of viable fetuses in both dose groups and were increased relative to historical controls (32%, 25/77). Unlike previous studies with 13-cis-retinoic acid during the pre- and early organogenic stages of development (Hummler et al., Teratology 42:263-272, 1990), no thymic hypo- or aplasia or heart anomalies were observed, which may be attributable to the slightly longer 13-cis retinoic acid treatment period, i.e., GD 10-27. However, external ear and temporal bone defects were common to both all-trans and 13-cis retinoic acid. The similarity observed in the malformation syndrome induced by both all-trans and 13-cis retinoic acid in the cynomolgus monkey and 13-cis retinoic acid embryopathy in humans supports this macaque species as a model for further developmental toxicity studies of vitamin A-related compounds.

Abnormalities, Drug-Induced↗
PubMed1992

[Neonatal heart tumor. Early symptom of tuberous sclerosis].

Congenital heart tumors are rare. About 60% of them are intramurally growing rhabdomyomas. They represent an early symptom of tumerous sclerosis in about 50% of patients. The following report shows that fetal brady arrhythmia led towards the correct diagnosis.

Echocardiography↗
PubMed1990

Induction of malformations in the cynomolgus monkey with 13-cis retinoic acid.

The embryotoxic and teratogenic potential of 13-cis retinoic acid was assessed in the cynomolgus macaque (Macaca fascicularis). A total of 41 animals was orally administered 13-cis retinoic acid in four sequential experiments. In Exp. 1 three dose levels, 2, 10, and 25 mg/kg, were administered on gestational day (GD) 18-28; 5 mg/kg was administered as an equally divided dose twice daily in Exp. 2 and 3 on GD 21-24 and on GD 25-27, respectively; in Exp. 4 the drug was administered at 2.5 mg/kg once daily from GD 10 to 25 and twice daily (2 x 2.5 mg/kg) on GD 26 and 27. Maternal death and toxicity, manifested as reduction in maternal weight and food consumption, and diarrhea, was observed in Exp. 1 in all three dose groups. No significant maternal toxicity was observed in the treatment groups in Exp. 2, 3, and 4 or in the control group. The primary manifestation of developmental toxicity was embryolethality in Exp. 1 and 2. The incidence of embryonic deaths in Exp. 3 was comparable to the historical controls. No malformations in GD 100 fetuses were observed in Exp. 1, 2, and 3. In Exp. 4, five of seven fetuses (71%) had malformations of both external ears, four of seven fetuses (57%) exhibited hypo- or aplasia of the thymus, and two of seven (29%) had malformations (transposition of the great vessels, ventricular septal defect) of the heart. The teratogenic dose for the cynomolgus monkey in the present study was lower than that reported for all other experimental species. Although central nervous system and craniofacial defects were not observed, the incidence of ear and thymus defects was similar to that reported for the human. The cardiovascular defects resembled those reported clinically, but the incidence was lower in the cynomolgus monkey. The similarity in teratogenic sensitivity to humans supports the use of the monkey as a model for developmental toxicity studies of vitamin A-related compounds.

Abnormalities, Drug-Induced↗
PubMed1985

Teratogenesis and reproductive safety evaluation of the retinoid etretin (Ro 10-1670).

Reproduction and teratology studies were performed with etretin, the free acid analog of the retinoid etretinate. The lowest teratogenic dose of etretin in mice, rats and rabbits was 3, 15 and 0.6 mg/kg, respectively. In all three species, the lowest dose which was embryolethal, fetolethal or reduced the survivability of the pups during lactation was 2-3 times higher than the above doses. In rats, the lowest effective dose of etretin was 3 mg/kg in both the study for fertility and general reproductive performance and the peri- and postnatal study. The main adverse effect in these two experiments was a reduced survival of the F1-generation.

Abnormalities, Drug-Induced↗
PubMed1985

Identification and assessment of the effects of chemicals on reproduction and development (reproductive toxicology).

Most studies for determining the reproductive toxicity of a chemical have to be conducted with whole animals. Test procedures used to investigate parts or the whole of the reproductive cycle are described in current guidelines. Other techniques, such as in vitro methods, and those for investigating specific events in the cycle, are under development. Epidemiological studies can give valuable information, although they are difficult to perform and interpret in practice. There is a need for more epidemiological studies of exposed populations and for recording and quantifying the concentrations of chemicals to which such populations are exposed. It is suggested that animal experiments should be programmed in a stepwise manner, and should take into account effects seen in previous toxicity studies. The programme of tests for determining reproductive toxic potential should be established on a case-by-case basis, since many factors will influence the choice of studies and the sequence in which they should be performed.

Animals↗
PubMed1985

The toxicity of beta-carotene.

The safety of beta-carotene, a widely distributed food colorant was assessed in tests with cells and in sub-chronic and chronic experiments with animals. Mutagenicity evaluations which included the standard Ames test and the micro-nucleus test of bone marrow cells from mice showed that beta-carotene exerted no mutagenic properties. Embryotoxicity studies in rats and rabbits showed that there was no evidence of embryotoxicity and a multiple generation study in rats showed that there was no interference with the reproductive function in rats given oral doses of up to 1000 mg/kg/day. Chronic toxicity was studied in a 2-year study with dogs in a toxicity/tumorigenicity study in rats and in a mouse carcinogenicity study. Histological findings in the livers of treated dogs and mice, but not in rats, included vacuolated cells with eccentric nuclei which were distributed in periportal areas and which were frequently associated with minimal lipid deposition. There was no evidence that the vacuolisation was dose-related. It was considered that the vacuolated cells were fat storage cells. There was no effect on the tumor profiles in the rat and the mouse studies.

Abnormalities, Drug-Induced↗
PubMed1983

d,1-alpha-Tocopheryl acetate (vitamin E): a long term toxicity and carcinogenicity study in rats.

Rats were fed vitamin E at various dietary concentrations providing dosages of up to 2000 mg/kg bodyweight/day for 104 weeks. Vitamin K supplementation suppressed the induced hypoprothrombinaemia. Growth rate and survival were unaltered by treatment, and, apart from a trend towards fewer mammary tumours in females, the tumour profile was unaffected. Changes in serum liver enzyme activity and in the appearance of the hepatic macrophages suggested a limited hepatic response to vitamin E overload.

Animals↗
PubMed1978

Collection of control data from teratological experiments on mice, rats, and rabbits. A group study.

A joint study was undertaken in the laboratories of five pharmaceutical companies to evaluate accumulated data on the progeny of mice, rats and rabbits of various strains or breeds. The recorded morphological deviations from normal were classified according to the time of their occurrence during embryonic and foetal development, and three categories were differentiated. Comparison of the data from the various laboratories in general revealed similar results, and the variations observed are presumed to be due to differences in experimental conditions.

Animals↗
PubMedDate not supplied

Vitamin A teratogenicity and risk assessment in the macaque retinoid model.

Studies were performed in the cynomolgus monkey (Macaca fascicularis) to provide risk assessment information on safe dose levels of Vitamin A during human pregnancy. Vitamin A palmitate was orally administered at 7500 IU/kg (2.25 mg/kg) to 80 000 IU/kg (24 mg/kg) body weight during early pregnancy (gestation day [GD] 16-27). The results indicated a dose-related increase in exposure (AUC) to retinyl esters and retinoic acids (RA) (all-trans-RA, all-trans-4-oxo-RA, 13-cis-RA, 13-cis-4-oxo-RA). There was also a dose-related increase in abortion and malformation that affected typical retinoid target tissues in the embryo, including the craniofacial region, heart, and thymus. The NOAEL and LOAEL for structural malformations were 7500 IU/kg and 20 000 IU/kg (6 mg/kg), respectively. A companion study involving oral administration of 13-cis-RA during the same gestational period established the NOAEL for malformations at 0.5 mg/kg/day, which is close to the human therapeutic dose range (0.5 to 1.5 mg/kg/day) associated with retinoid embryopathy. Based on the known similarities in teratogenic susceptibility to 13-cis-RA, the monkey NOAEL for Vitamin A (7500 IU/kg) was used to estimate safe levels of this nutrient in humans applying a safety factor of 10. This approach yielded safe levels of Vitamin A during human pregnancy in the range of approximately 25 000 to 37 000 IU/day.

Abnormalities, Drug-Induced↗