Linker design for the modular assembly of multifunctional and targeted platinum(ii)-containing anticancer agents.

A versatile and efficient modular synthetic platform was developed for assembling multifunctional conjugates and targeted forms of platinum-(benz)acridines, a class of highly cytotoxic DNA-targeted hybrid agents. The synthetic strategy involved amide coupling between succinyl ester-modified platinum compounds (P1, P2) and a set of 11 biologically relevant primary and secondary amines (N1-N11). To demonstrate the feasibility and versatility of the approach, a structurally and functionally diverse range of amines was introduced. These include biologically active molecules, such as rucaparib (a PARP inhibitor), E/Z-endoxifen (an estrogen receptor antagonist), and a quinazoline-based tyrosine kinase inhibitor. Micro-scale reactions in Eppendorf tubes or on 96-well plates were used to screen for optimal coupling conditions in DMF solution with carbodiimide-, uronium-, and phosphonium-based compounds, as well as other common coupling reagents. Reactions with the phosphonium-based coupling reagent PyBOP produced the highest yields and gave the cleanest conversions. Furthermore, it was demonstrated that the chemistry can also be performed in aqueous media and is amenable to parallel synthesis based on multiple consecutive reactions in DMF in a "one-tube" format. In-line LC-MS was used to assess the stability of the conjugates in physiologically relevant buffers. Hydrolysis of the conjugates occurs at the ester moiety and is facilitated by the aquated metal moiety under low-chloride ion conditions. The rate of ester cleavage greatly depends on the nature of the amine component. Potential applications of the linker technology are discussed.

[Psammomatous tenosynovialitis of hand and forearm - three new cases]. / Psammomatöse Tenosynovialitis an Hand und Unterarm - drei neue Fälle.

We report about three new observations of psammomatous tenosynovialitis on hand and forearm and performed a review of literature. To the best of our knowledge cases 7, 8 and 9 in the medical literature are now published.

Transient hyperammonemia due to L-asparaginase therapy in children with acute lymphoblastic leukemia or non-Hodgkin lymphoma.

The standard treatment protocol for acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) in childhood includes intravenous therapy with asparaginase (Asp), which may cause hyperammonemia. In this study, all patients receiving asparaginase therapy at the Hospital for Children and Adolescents of the University of Leipzig between January 2002 and December 2007 were reviewed for the occurrence of hyperammonemia. Fifty-four patients were identified (22 girls, 32 boys; mean age 5.8 years). Blood ammonia concentrations were determined in 4 patients due to suspicious clinical signs. All showed hyperammonemia with NH(3) concentrations between 260 and 700 µmol/L. They received specific acute detoxification therapy consisting in protein restriction, administration of benzoic acid, glucose/insulin. All 4 recovered completely. All patients receiving therapeutic regimes that include asparaginase (Asp) should be monitored for the development of transient hyperammonemia.

Coincidence of immune thrombocytopenia, intracranial hemorrhage and graft-versus-host disease in an 11-year-old girl.

Primary immune thrombocytopenia (ITP) in children is usually self-limiting and harmless but can, rarely, result in life-threatening complications. The case of an 11-year-old girl with ITP is presented who developed recurrent intracranial hemorrhages followed by cerebral infarctions. The clinical course was complicated by a graft-versus-host disease involving several organs. Treatment was performed according to the current international consensus report of 2010 with glucocorticoids, immunoglobulin G, anti-D-immunoglobulin and additionally embolisation of the splenic artery. The girl survived. Reliable predictors, preventive measures for life-threatening complications in ITP and more information about the effectiveness and side-effects of the recommended treatment are urgently needed.

Whole-body MRI for primary evaluation of malignant disease in children.

OBJECTIVE: The aim of this study was to compare diagnostic accuracy of whole-body (WB) MRI to a combined reference standard of conventional cross-sectional imaging methods and FDG-PET in the detection of malignant disease spread in children. MATERIALS AND METHODS: 24 children (age between 5 and 18 years) with malignant diseases (mainly Hodgkin's lymphoma and different types of sarcoma) initially examined with conventional cross-sectional imaging methods (ultrasound, computed tomography, or magnetic resonance imaging) were examined prospectively with whole-body MRI (1.5T) and FDG-PET. Studies were read by two nuclear medicine physicians (FDG-PET) and two radiologists (WB-MRI) independently in a blinded manner and each study type was evaluated in consensus. The reference standard was defined as pathological lesions detected in the same location both in FDG-PET and another conventional cross-sectional imaging method. RESULTS: Overall 190 lesions were detected by WB-MRI and 155 lesion were found by FDG-PET. 106 lesions fulfilled the criteria of the reference standard (42 osseous and 64 extraosseous lesions) from which 102 were detected by WB-MRI (sensitivity of 96%). All bone lesions were detected and extra-skeletal lesions were identified with a sensitivity of 93.8%. Overall 88 lesions detected by WB-MRI were not part of the reference standard from which 33 were lesions of the peripheral skeleton not imaged by conventional cross-sectional imaging studies. 4 lesions of the reference standard were not identified by WB-MRI which were all lymph nodes. CONCLUSION: WB-MRI is a radiation free imaging technique with high sensitivity for the detection of malignant disease spread in particular beneficial for children. In patients with suspected bone lesions it should be considered for initial disease evaluation prior to specific and regional imaging methods to reduce the overall number of imaging examinations and radiation exposure.

[Treatment strategies and results of orbital malignancies in childhood]. / Therapiekonzepte und Behandlungsergebnisse maligner Orbitatumoren im Kindesalter.

INTRODUCTION: Each year approximately 1,800 children are diagnosed with cancer in Germany. The orbit is a very rare manifestation site for malignancies in childhood. The most common primary malignant orbital tumour is the rhabdomyosarcoma. Secondary orbital tumours are generally metastases of neuroblastomas or haematological diseases. The five-year survival rate of children with rhabdomyosarcomas has increased to 90 % in the past 30 years due to innovations in radiation and chemotherapy. MATERIAL AND METHODS: A paediatric oncological interdisciplinary approach is taken in the diagnostics and therapy for these rare tumours and is based on therapy optimisation studies that include polychemotherapy, radiation therapy, and surgical treatment. RESULTS: We discuss the current multimodal therapy strategies and results, as well as the role of the ophthalmologist, in the medical care of young patients with malignant orbital tumours, with examples of individual courses of rhabdomyosarcoma, non-Hodgkin's lymphoma, and metastases. CONCLUSIONS: Orbital rhabdomyosarcoma is one of the few life-threatening diseases often first seen by an ophthalmologist. The ophthalmologist's prompt diagnosis and initiation of therapy therefore strongly influences the patient's chance of survival. The role of the ophthalmologist in the medical care of children with orbital malignancies includes a timely clinical diagnosis with histological confirmation, close monitoring of visual functions, the management of ocular complications, as well as long-term follow-up care to detect later therapeutic side effects and/or complications. The treatment of children with suspected tumours is best performed in paediatric oncological centres with access to all necessary specialties in order to ensure rapid diagnosis and therapy.

[Results of an endocrinological follow-up of patients with childhood-or adolescent-onset malignancies]. / Ergebnisse einer unizentrischen endokrinologischen Nachsorge onkologischer Patienten im Kindes-und Adoleszentenalter.

BACKGROUND: Established reports about endocrine follow-ups in children and adolescents with cancer were rare. PATIENTS: 53 children were included in the clinical trial. The mean age was 9.6 years (0.5; 17.2 years), 10 patients died within the study period. The mean body length was normal with -0.14 SDS (-2.3; 2.5 SDS), as well as the body weight with 0.01 SDS and BMI with a mean of -0.03 SDS. Children and adolescents with different types of malignant tumors were included. According to the therapy protocol or tumor entity we divided this population in 5 subgroups (group 1 leukemia with 17 patients, group 2 lymphoma with 11 patients, group 3 tumor of CNS with 10 patients, group 4 bone and soft tissue tumors with 8 patients, group 5 different tumors with 7 patients). METHOD: Anthropometrical and laboratory parameters were analyzed in intervals of 6 months over 2 years from the time point of diagnosis. RESULTS: We found differences in body height in children affected by cerebral tumors at the time of diagnosis and therefore before any therapy was started. These patients were significantly shorter (-0.6 SDS) than the other children. The body weight increased within the first year of therapy and was still higher than normal in the second year (comparison at the time point; from start to the first year+0.5 SDS, to second year+0.4 SDS) independently from the cortisone administration. Moreover, significant differences in the growth factor concentrations between the groups and time points were identified. Interestingly, children who survived their malignant disease tended to have higher levels of IGF-I and IGFBP-3 concentration than the patients who died within the study period. Additionally, the thyroid function was affected, shown as an increase of TSH with a concomitant decrease of the free thyroxin in 91% of all patients independent from the diagnosis (start TSH 1.8, fT4 15.6, after first year TSH 2.8, fT4 15.0). Thyroid function was monitored in 12 children, in 5 patients a short- or long-term substitution with thyroid hormone was indicated. Endocrine testing was initiated in 4 children, in 2 patients affection of the adrenal gland could be excluded, a suspected pituitary dysfunction after radiation was confirmed in 2 patients. CONCLUSION: We could represent that children and adolescents with malignant diseases showed affection of the endocrine system due to the tumour and the intensive therapy. The dysregulations in the endocrine system can be diagnosed through closely spaced monitoring and interdisciplinary cooperation.

[Neurofibromatosis type 1 and associated clinical abnormalities in 27 children]. / Neurofibromatose Typ 1 und assoziierte Krankheiten bei 27 Kindern und Jugendlichen.

Neurofibromatosis type 1 is the most common of the phakomatoses and the clinical follow-up is an interdisciplinary challenge. The data of 27 patients with NF1 were systematically reviewed and compared to data from the literature. All of our patients had clinical signs of NF1. Besides the classic criteria café-au-lait spots (100%), freckling (48,1%), positive family history (44,1%), neurofibromas (40,7%), Lisch nodules (22,2%) and optic pathway tumors (22,2%) there were developmental delay (40,7%), macrocephaly (33,3%), strabism (29,6%), scoliosis (18,5%), epilepsy (14,8%), pubertal anomalies (14,8%), short stature (11,1%) and tics. Morphologically, CNS hamartomas (55,5%), astrocytomas (22,2%) and one pheochromocytoma became apparent. Special findings consist of one aneurysm of internal carotic arteria, juvenile xanthogranulomas, a case of pulmonary stenosis and an intracardial tumor. Four new mutations in the NF1 gene were found. Regular screening of optic glioma with MRI had no clinical significance. In contrast to other authors, one of our patients with optic glioma showed clinical progress after twelve years of age. The detection of astrocytomas led only to therapeutic consequences, when clinical signs or symptoms occurred. As with other authors, we found no potential for CNS hamartoma to proliferate. In three cases with pubertal anomalies we found CNS gliomas, which indicates the need for MRI. The expense of screening, apart from clinical surveillance, seems inadequate in relation to clinical relevance and costs. We describe four new mutations in the NF1 gene; there have been no specific genotype-phenotype correlations. Neurofibromatosis type 1 and associated clinical abnormalities in 27 children.

[Early and late complications after implantation of central venous catheters]. / Früh- und Spätkomplikationen nach Anlage implantierbarer zentralvenöser Kathetersysteme.

The use of implantable central venous catheters by the puncture-technique of Nagy is a safe method performed by trained surgeons. Due to the high mobility and then reduction of painful blood samples this method contributes favourably to the improvement of the quality of life of children with chronic diseases. The analysis of 140 catheters implanted in the Department of Pediatric Surgery of the University of Leipzig between 1995 and 2000 showed 11 cases with early complications. As the most frequent late complications were infection and thrombosis in 51 children. Neutropenia is a particular risk factor during polychemotherapy of malignant tumors. Staphylococcus epidermidis was the most frequently isolated bacillus. Catheter associated infections are only partly treatable by antibiotic therapy. In 29 of 44 cases the explantation of the catheter was necessary. Only a strict hygienic regimen would minimize the risk of infection

Design, synthesis, and biological activity of a novel non-cisplatin-type platinum-acridine pharmacophore.

Platinum-acridine conjugates were prepared from [PtCl2(ethane-1,2-diamine)] and the novel acridinylthioureas MeHNC(S)NMeAcr (6) and MeHNC(S)NMe(CH2CH2)NHAcr (15) by replacing one chloro leaving group in the cisplatin analogue with thiourea sulfur. In HL-60 leukemia cells, IC(50) values for 7 (Pt-tethered 6) and 16 (Pt-tethered 15) were 75 and 0.13 microM, respectively. In the ovarian cell lines 2008 and C13, 16 was active at micromolar concentrations and showed only partial cross-resistance with clinical cisplatin. Possible structure-activity relationships are discussed.

Inversion of the cis geometry requirement for cytotoxicity in structurally novel platinum(II) complexes containing the bidentate N,O-donor pyridin-2-yl-acetate.

Water soluble platinum(II) complexes have been synthesized that contain the N,O-chelate pyridin-2-yl acetate (PyAc) as a novel structural motif in platinum antitumor complexes. The trans-platinum complex trans-[PtCl(PyAc-N,O)(NH3)] (2) (N-donors are trans) and its isomer cis-[PtCl(PyAc-N,O)(NH3)] (4) (N trans to Cl) were prepared from trans-[PtCl2((NH3)(PyAcH)].H2O (1.H2O) and cis-[PtCl2(NH3)(PyAcMe) (3), respectively, employing the bidentate ligand as its methylester (PyAcMe). 2 and 4 are readily formed from the respective dichloro species, even at low pH and in the presence of extra chloride, indicating a high thermodynamic stability of the PyAc chelate ring. 1.H2O and 2-4 were characterized by 1H NMR and IR spectroscopy and elemental analyses. The solid-state structure of 2 was determined: triclinic, P1 (no. 2), with a = 8.170(2) A, b = 9.274(3) A, c = 7.374(2) A, alpha = 108.68(2) degrees, beta = 113.27(2) degrees, gamma = 74.40(2) degrees, V = 479.7(6) A3, Z = 2. The six-membered metallacyclus in 2 adopts a "boat" form, allowing a strainless coordination of platinum. The most promising cytotoxic properties in the above series of compounds have been established for 2 (and 1, which rapidly transforms into 2 at 37 degrees C and neutral pH). Preliminary ID50 values were 0.88 and 1.26 microM, respectively, in cisplatin-sensitive L1210 leukemia. Both compounds proved to be cross-resistant to the clinical drug. Reactions of 2 and 4 with 5'-guanosine monophosphate (5'-GMP) under physiological conditions gave the monofunctional adducts trans- and cis-[Pt(5'-GMP-N7)(PyAc-N,O)(NH3)] (I and II). Chelate-bound carboxylate was not replaced by guanine-N7 when an excess of nucleotide was applied (NMR). In an analogous reaction, 2 reacts with the oligonucleotide d(TCGT) [5'-T(1)-C(2)-G(3)-T(4)-3'] to give the adduct d(TCGT)-N7(3)-Pt(PyAc-O,N)(NH3) (III), which was characterized by a combination of total correlation spectroscopy, double-quantum-filtered correlation spectroscopy, nuclear Overhauser effect spectrometry, and rotating-frame Overhauser enhancement spectroscopy experiments. Binding of the [Pt(PyAc-N,O)(NH3)]+ fragment to N7 of G(3) causes an increase of N-type character of the T(4) and G(3) deoxyribose residues relative to the unplatinated sequence, while those of T(1) and C(2) remain S-type. An internucleotide nuclear Overhauser effect between H6(4) and H2'(3) indicates stacking between guanine and the 3'-thymine base. The most striking feature proved to be the pronounced upfield shift and broadening of the 1H NMR signals assigned to the base protons H5 and H6 in III. Magnetization transfer between H5(2) and H3 of pyridine suggests that this effect is caused by base-base interactions involving the planar ligand on platinum, which must be situated on the 5' face of guanine. Possible implications for the DNA binding and cytotoxic effect of the compounds are discussed.

[Clinical aspects and epidemiology of hepatitis C in immunosuppressed children with mostly oncologic diseases]. / Zur Klinik und Epidemiologie der Hepatitis C bei immunsupprimierten Kindern mit vorwiegend onkologischen Erkrankungen.

Between July and October 1996 hepatitis C virus infection was diagnosed in 21 children who underwent immunosuppressive therapy mainly for malignant diseases. We report on the clinical signs and symptoms, diagnostic procedures and the clinical course of the disease in these patients. Epidemiological, diagnostic and clinical aspects of the outbreak are discussed. Analysis of all available data led to the conclusion that these infections were of nosocomial origin. This requires consequences in the hygienic regimen. In addition to the routinely used antibody-test the HCV-PCR should be the diagnostic method of first choice concerning the HCV-diagnostics in immunocompromised patients.

DNA interactions of antitumor trans-[PtCl2(NH3)(quinoline)].

Recent observations that several trans-platinum complexes exhibit antitumor activity including activity in cisplatin-resistant tumor cells, violates the classical structure/activity relationships of platinum(II) complexes. According to these relationships, only bifunctional platinum(II) complexes with cis-oriented leaving ligands should be therapeutically active. In order to contribute to the understanding of mechanisms underlying the antitumor activity of these new trans-platinum analogs, various biochemical and biophysical methods as well as molecular modeling techniques were employed to study the modifications of DNA by antitumor trans-[PtCl2(NH3)(quinoline)]. The results indicated that trans-[PtCl2(NH3)(quinoline)] coordinated monofunctionally to DNA with a similar rate as transplatin. The overall rate of the rearrangement to bifunctional adducts was also similar to that observed in the case of DNA modification by transplatin, i.e. it was relatively slow (after 48 h approximately 34% adducts remained monofunctional). In contrast to transplatin, however, trans-[PtCl2(NH3)(quinoline)] formed considerably more interstrand cross-links after 48 h (approximately 30%) with a much shorter half-time (approximately 5 h) (approximately 12% for transplatin, t1/2 > 11 h). The results also suggested that the quinoline ligand in all or in a significant fraction of DNA adducts of trans-[PtCl2(NH3)(quinoline)], in which platinum is coordinated to base residues, was well positioned to interact with the duplex. The adducts of trans-[PtCl2(NH3)(quinoline)] terminated in vitro RNA synthesis preferentially at guanine residues. Surprisingly, the type and extent of conformational alterations induced in DNA indicates that trans-[PtCl2(NH3)(quinoline)] behaves in some respects like cisplatin, as indicated by the fact that trans-[PtCl2(NH3)(quinoline)]-modified DNA is recognized by cisplatin-specific antibodies. Models for both monofunctional adducts and bifunctional interstrand cross-links are proposed. Computer-generated AMBER models show that the combination of monofunctional covalent binding and a stacking interaction between quinoline and the DNA bases can produce a kink in the duplex which is strongly suggestive of the directed bend produced by the major cisplatin-DNA adduct (1,2 intrastrand cross-link). Unique DNA adducts of this type formed by trans-[PtCl2(NH3)(quinoline)] may contribute to the antitumor efficacy of this agent.

A report on pathological changes of the dipole moment in children suffering from anthracycline cardiomyopathy.

Cardiomyopathy is a severe complication of the tomour therapy with anthracyclines. Since even minor disturbances of myocardial cell membranes could influence the dipole moment of the heart the noninvasive measurements of this parameter might be useful, particularly in the paediatric population. 17 children aged 2-15 years treated clinically for various malign blood diseases were examined repeatedly with a modified Nelson lead-system up to 3 years. The dipole moment was evaluated by visual comparison of the calculated horizontal and frontal VCGs, evaluation of 3 distinctive vectors, as well as of the magnitude curves and the velocity curves, all of them compared with the normal age dependent percentiles of each respective child. Conventional 12-lead ECGs were used to confirm rhythm disturbances and alterations of P-, PQ-, QRS-, and QT-durations. Our results show that damages of the heart are different during the time of the drug administration, then consisting of acute toxic reactions such as sudden dilatation and/or rhythm disturbances, and of long-term disturbances leading to growth retardation of the heart with the danger of chronic congestive heart failure months or years after the end of the anthracycline treatment. Morphological and biochemical damages of myofibrils caused by the toxicity of anthracyclines precede functional restraints of the heart. A noninvasive method for an early and reliable diagnosis of these damages is urgently needed, particularly for children. Measurements of the dipole moment with the Nelson-lead system seem to offer this diagnostic tool which aims possible changes of the drug administration protocol. (Fig. 3, Ref. 15.)

Limited fat digestion in infants with bronchopulmonary dysplasia.

In 10 hyaline membrane disease patients with development of bronchopulmonary dysplasia, 16 hyaline membrane disease patients without development of bronchopulmonary dysplasia, and 12 very-low-birthweight infants without major medical problems, we measured the lipase and trypsin activity as well as the bile acids concentrations in preprandially aspirated duodenal juice. In addition, fat and nitrogen balances were performed during the 5th and 6th weeks of postnatal life. The mean duodenal lipase activity in the patients with bronchopulmonary dysplasia was significantly lower than those of the patients without bronchopulmonary dysplasia (4.41 +/- 3.0 versus 9.95 +/- 3.0 U/ml, p < 0.05) and of the controls (19.94 +/- 6.8 U/ml). The mean total bile acid concentration was below the critical micellar concentration of 4 mmol/L only in the patients with bronchopulmonary dysplasia. The fecal fat excretion rate in the patients with bronchopulmonary dysplasia was significantly higher than in the patients without bronchopulmonary dysplasia (21.4 +/- 4.6% versus 11.3 +/- 3.4% of intake, p < 0.01) as well as that of the controls (7.9 +/- 2.8% of intake). The serum urea concentrations were similar in the patients without bronchopulmonary dysplasia and in the controls (1.97 +/- 0.6 and 1.89 +/- 0.4 mmol/L, respectively) but significantly higher in the patients with bronchopulmonary dysplasia (2.54 +/- 0.5 mmol/L). The lowest weight gain was found in the patients with bronchopulmonary dysplasia (8.2 +/- 4.7 g/kg/day). It was significantly lower than one of the patients without bronchopulmonary dysplasia or the controls (13.5 +/- 4.0 and 16.2 +/- 3.7 g/kg/day, respectively). The data indicate that patients who develop bronchopulmonary dysplasia have a limited fat absorption, which may help to explain the inadequate weight gain.

Activities of trypsin and lipase in duodenal aspirates of healthy preterm infants: effects of gestational and postnatal age.

Lipase and trypsin activities were estimated in preprandially aspirated duodenal juice of preterm infants with gestational ages between 29 and 32 weeks (group I, n = 33) or between 33 and 36 weeks (group II, n = 22) during the first 6 weeks of postnatal life. The results were compared with the enzyme activities measured in 2- to 6-year-old children. There were no significant differences of the mean lipase or trypsin activities between the two groups lipase; group I 13.7 +/- 7.9, group II 15.9 +/- 9.8 U/ml; trypsin: group I 7.9 +/- 4.7, group II 8.5 +/- 5.1 U/ml). The activities of both enzymes increased significantly and similarly in both groups with postnatal age (lipase: group I r = 0.732, p < 0.01, group II r = 0.743, p < 0.01; trypsin: group I r = 0.705, p < 0.01, group II r = 0.669, p < 0.01). At the end of the study the lipase activities of both groups reached approximately 35% of the values found in the older children, whereas the trypsin activities reached the reference values within the 1st month of life. The results indicate an asynchronously age-related development of lipase and trypsin. The development of the lipase activity is delayed in comparison to the trypsin activity which should be considered in the nutritional management of preterm infants.

Activities of lipase and trypsin in duodenal juice of infants small for gestational age.

In 18 low birth weight infants, small for gestational age, with different degrees of intrauterine growth retardation the activities of pancreatic lipase and trypsin and the concentrations of bile acids were measured in preprandially aspirated duodenal juice. The results were compared to those of 24 low birth weight infants, appropriate for gestational age, with comparable birth weights and postnatal ages. The activities of both measured pancreatic enzymes were negatively correlated with the degree of intrauterine growth retardation, expressed as the difference between the individual birth weight and the weight of the 10th percentile of the intrauterine growth curve (lipase: r = -0.697, p less than 0.001; trypsin: r = -0.739, p less than 0.001). The activity of trypsin in the small for gestational age infants was within the range of that found in the infants appropriate for gestational age. However, the lipase activity was decreased in infants who presented with growth retardation of greater than 400 g/kg birthweight. The concentrations of bile acids were similar in both groups (4.60 +/- 2.51 and 4.55 +/- 2.26 mmol/L, respectively) and sufficient for activating the bile salt stimulated lipase in human milk. The data suggest that in intrauterine growth retarded infants the lipase activity in the duodenal juice can be a limiting factor for optimal fat digestion. This should be considered in the nutritional management of such infants.

Postnatal adaptation of lipase- and trypsin-activities in duodenal juice of premature infants appropriate for gestational age.

In 17 very low birth weight and in 13 low birth weight infants appropriate for gestational age the activities of pancreatic lipase and trypsin, the pH value and the concentrations of total bile acids were measured in the preprandially aspirated duodenal juice between the 10th and the 40th day of postnatal life. The activities of both enzymes increased significantly with increasing postnatal age in both study groups but did not correlate with the gestational age between the 28th and 33rd week of gestation. The pH values were on a low but similar level in both study groups (mean for all infants 5.66 +/- 0.07), and there was no influence of the pH value on the activities of either pancreatic enzyme. The concentrations of total bile acids were also not different between the study groups (mean for all infants = 4.55 +/- 2.26 mmol/l) and no correlation could be found between the concentrations of total bile acids and the activities of both measured enzymes. The data suggest that the intrauterine development of the exocrine pancreas reaches a basal level by the 28th week of gestation and remains on this level up to the 33rd week of gestation. After birth there is a significant increase in enzyme activities for both studied enzymes.