Model averaging for robust assessment of QT prolongation by concentration-response analysis.

Assessing the QT prolongation potential of a drug is typically done based on pivotal safety studies called thorough QT studies. Model-based estimation of the drug-induced QT prolongation at the estimated mean maximum drug concentration could increase efficiency over the currently used intersection-union test. However, robustness against model misspecification needs to be guaranteed in pivotal settings. The objective of this work was to develop an efficient, fully prespecified model-based inference method for thorough QT studies, which controls the type I error and provides satisfactory test power. This is achieved by model averaging: The proposed estimator of the concentration-response relationship is a weighted average of a parametric (linear) and a nonparametric (monotonic I-splines) estimator, with weights based on mean integrated square error. The desired properties of the method were confirmed in an extensive simulation study, which demonstrated that the proposed method controlled the type I error adequately, and that its power was higher than the power of the nonparametric method alone. The method can be extended from thorough QT studies to the analysis of QT data from pooled phase I studies.

Estimating the contribution of everolimus to immunosuppressive efficacy when combined with tacrolimus in liver transplantation: a model-based approach.

Determining the efficacy contribution of an investigational drug as part of a novel combination regimen that also includes a previously untested dose of a standard treatment is challenging, particularly when "placebo control" data (combination regimen minus the investigational drug) is not available for comparison. This situation was encountered in a phase III trial that tested the combination of the investigational drug everolimus with a dose of tacrolimus lower than used in standard liver transplantation therapy. The challenge was addressed by predicting the efficacy of the placebo control from the study data using a pharmacometric-based exposure-response analysis, selected to account for features specific to the transplant setting: systematic change in drug exposure over time and sparse pharmacokinetic sampling. The efficacy contribution of everolimus was then demonstrated by comparing this prediction to the efficacy of the combination regimen. This pharmacometrics-based approach may contribute to characterization of therapeutic agents in real-world settings.

Neonatal diabetes mellitus with hypergalactosemia.

We report the case of a male, small-for-gestational-age newborn who presented with failure to thrive, severe fluctuation of blood glucose concentrations, and increased serum concentrations of galactose. The infant responded well to a lactose-free diet supplemented with fructose, inulin and corn starch. The metabolic disorder disappeared within 6 months. The transient course, and results of a molecular analysis of the glucose transporter 2 (Glut2) gene seem to rule out Fanconi-Bickel syndrome.

Physicochemical parameters of x-ray contrast media.

RATIONALE AND OBJECTIVES: Osmolality, including "dynamic osmolality," which is observed during dilution in the plasma, viscosity, density, and partition coefficient of 11 commercially available contrast media and two new nonionic monomers were determined. METHODS: Osmolality was measured by vapor pressure osmometry, viscosity by determining flow in microcapillaries, and partition coefficient in n-octanol or n-butanol/water mixtures by inductively coupled plasma mass spectroscopy or x-ray fluorescence analysis of iodine concentrations. RESULTS: For the commercially available contrast media, the following statistically significant ranking of osmolality was obtained at 300 mg iodine/mL: iotrolan << ioxaglate < iopromide < iopamidol < ioversol = iohexol < iopentol << meglumine diatrizoate. The novel nonionic monomers, ZK 119095 and ZK 139129, had very low osmolalities, and ZK 139129 was isotonic to blood. The partition coefficient for the system n-octanol/water was lowest for the ionic compounds ioxaglate and diatrizoate followed by the nonionic dimer iotrolan. In n-butanol, iotrolan showed the lowest partition coefficient. CONCLUSION: "Dynamic osmolalities" of contrast media may differ from static values possibly because of the formation of "quasi-oligomers." Especially for ZK 139129, disaggregation occurred during dilution and the osmolality increased slightly. However, osmolality was lower than for any other monomer during the whole dilution process.

Increased physiological dead space during exercise after bronchodilation in cystic fibrosis.

Bicycle ergospirometry was performed on 14 patients with cystic fibrosis (CF), for evaluating the effects of salbutamol and theophylline on the ventilatory response to exercise. After 1 week without bronchodilator therapy the patients cycled at 1/3 and 2/3 of their individual maximal working capacity (Wmax). The test was repeated three times after treatment with salbutamol, theophylline, or both drugs, respectively. After the combined therapy, physiological deadspace, ventilation, ventilatory equivalent of oxygen, and end-expiratory oxygen pressure increased significantly during steady state exercise at 1/3 Wmax. Similar, although not statistically significant changes, were observed after monotherapy with salbutamol or theophylline and during exercise at 2/3 Wmax. These effects could not be predicted by any lung function tests at rest or by the Shwachman-Kulczycki score. The results indicate that in some patients with CF bronchodilators can impair lung function during exercise. In conclusion, the effects of medication on exercise performance of patients with CF have to be considered. Especially, the use of bronchodilators requires a careful evaluation of their real benefit in each individual patient.

Association of apnea and nonacid gastroesophageal reflux in infants: Investigations with the intraluminal impedance technique.

An association of apnea and gastroesophageal reflux (GER) was proposed previously. However, pH metry as the standard diagnostic tool for GER only measures acid reflux (pH < 4). It is difficult to interpret studies in infants with a presumed association between apnea and GER based on pH metry because the buffering effect of feeding may result in predominantly nonacid GER. The aim of this study was to investigate the temporal association of apnea and GER with the pH-independent intraluminal impedance technique (IMP). Infants with recurrent regurgitation or respiratory symptoms suggestive of apnea were investigated simultaneously with IMP, pH monitoring, and polygraphy. IMP patterns, pH, oronasal flow, and chest wall movement were recorded and analyzed. In 22 infants, 364 GER episodes were recorded by IMP. One hundred and sixty five apneas were documented by visual validation of polygraph records. Forty-nine apneas (29.7%) were associated with GER; 11 (22.4%) of these showed acid reflux (pH < 4). A significant correlation between the time spent apneic and GER was found (P < 0.001). There is marked association between apnea and gastroesophageal reflux in infants. Patients potentially at risk cannot be reliably identified by pH metry. Its exclusive use is therefore not suitable for the detection of all GER-associated apneas in infants. The pH-independent intraluminal impedance technique has proven to be a sensitive diagnostic tool for this approach.

GH and TSH deficiency.

Hypothyroidism is a recognised complication of GH therapy in GH deficient children. The mechanisms involved include direct effects on thyroid function but also result from the close interrelationship of pituitary cell-lines that differentiate during embryonic development of the anterior pituitary gland. Among numerous pituitary transcriptionfactors that orchestrate pituitary organogenesis Pit-1 was the first to be recognised and is the most extensively studied. Mutations in the Pit-1 gene account for a form of combined pituitary hormone deficiency for GH, Prolactin (Prl) and TSH (CPHD). Despite the variability of the clinical presentation of this syndrome at the time of initial diagnosis, all forms finally result in severe retardation of growth and development due to GH-deficiency and hypothyroidism. More than half of the families with a combined pituitary hormone deficiency have not disclosed any Pit-1 abnormalities. Evidence is accumulating that Prop-1, a transcriptionfactor expressed temporarily in the fetal anterior pituitary, could be a candidate for patients with a Pit-1 phenotype without any Pit-1 gene abnormalities.

Peripheral decrease and pulmonary homing of CD4+CD45RO+ helper memory T cells in cystic fibrosis.

Interstitial lung disease, although of prognostic impact for patients with cystic fibrosis (CF), remains difficult to assess without histopathologic investigations. As changes of peripheral blood lymphocyte subsets (LS) may accompany severe systemic lymphocyte immune responses, we compared peripheral LS of 44 patients with CF, 23 non-CF patients with recurrent pulmonary infections and 83 healthy controls (flow cytometry; CD3, CD19, CD16, CD56, CD4, CD8, CD11b, CD45RA, CD45RO, HLA-DR and CD25 antigens). Additional immunohistochemistry was performed on lung tissue of four CF patients aged 0.5, 12, 17 and 20 years, respectively. Patients with CF showed low absolute counts of CD4+CD45RO+ memory helperT cells, CD16+CD56+ NK cells, CD8+ and interleukin-2 receptor-positive T cells in peripheral blood (P < 0.001). Similar changes were registered in the non-CF patients with pulmonary infections, indicating that those were not specific for CF. Immunohistochemistry showed activation of bronchus-associated lymphoid tissue with interstitial accumulation of CD4+CD45 RO+ T cells in the three older patients. Patients with CF show marked changes of peripheral blood LS which are presumably not CF-specific and may mirror homing to lung tissue in the course of interstitial lung disease. Further research should evaluate its usefulness in monitoring progression of lung disease in CF.

Steady state pharmacokinetics, metabolism and pharmacodynamics of theophylline in children after unequal twice-daily dosing of a new sustained-release formulation.

This was an open-label study in 19 children aged 9-13 years, weighing 27-44 kg, with bronchial asthma. Twenty-four-hour steady-state concentrations of theophylline and its metabolites 1,3-dimethyl uric acid, 3-methyl xanthine and 1-methyl uric acid were assessed after daily dosing of 600 mg (ca 18 mg/kg/day) of the sustained-release theophylline micro-pellet sprinkle system BY158K, for 4 days. The dosing regimen used was an unequal twice-daily dose of 200 mg in the morning after breakfast and 400 mg in the evening after dinner. Twenty-four-hour peak expiratory flow (PEF) profiles were compared before treatment and at steady-state, along with lung function parameters after bronchial provocation. Mean values +/- SD (n = 16) of the steady-state characteristics were Cmin 6.8 +/- 2.1 mg/l, Cmax 14.5 +/- 4.8 mg/l and Cav 10.5 +/- 2.9 mg/l, the plateau time was 11.7 +/- 4.8 hr and peak-trough fluctuation and swing were 72 +/- 21 and 118 +/- 52%, respectively. There was an excellent reproducibility of theophylline pre-dose levels at corresponding time points of the 24-hr sampling period [r = 0.864 (p less than 0.001)]. Mean values +/- SD of the 24 hr average serum metabolite levels were 0.9 +/- 0.2 mg/1 for 1,3-dimethyl uric acid, 0.6 +/- 0.1 mg/1 for 3-methyl xanthine and 0.4 +/- 0.1 mg/1 for l-methyl uric acid. Lung function (n = 17) following bronchial provocation, improved in 10 children after theophylline treatment of 4 days, remained stable in 2 patients and deteriorated in 5 patients. Serum theophylline profiles and PEF profiles ran largely in parallel over the 24-hr period. Six children exhibited typical theophylline induced side-effects, headache (n = 3), nausea (n = 4), dizziness (n = 1), vomiting (n = 4), sleep disturbances (n = 1), pallor (n = 1) and tremor (n = 1), necessitating in 3 children one dose omission/reduction (n = 2) or subsequent dose reduction (n = 1). It has been shown that a twice daily dosing regimen with unequal doses of anhydrous theophylline (BY158K) is well suited to this population of fast metabolisers. The patients were well protected throughout the day, including the critical early morning hours.

Midazolam and ketamine as premedication in colonoscopies: a pharmacodynamic study.

As colonoscopy is often painful, a premedication appears to be indispensable. Commonly, benzodiazepines, i.e. midazolam, alone or in combination with analgesic drugs are used. Besides all advantages, midazolam especially is known to have the risk of oversedation and respiratory depression. Therefore it should be used at minimal dose. In a double-blind, randomized study, three premedication-schedules of midazolam (mid) plus ketamine (ket) were compared in 33 patients, aged between 8 and 60 years, with regard to safety and acceptance by patients and endoscopist. I: ket 1 mg/kg+mid 0.1 mg/kg, max. 5 mg II: ket 1 mg/kg+mid 0.05 mg/kg, max. 2.5 mg III: ket 0.75 mg/kg+mid 0.1 mg/kg, max. 5 mg Oxygen-saturation, heart rate and blood pressure were recorded as well as the evaluations of sedation, cooperation and complaint of pain. To assess the recovery-time of the patients, the reaction time and the attention were evaluated by "Wiener's determination apparatus" and "test d2", respectively, before and at 1, 2, 3 and 4 hours after premedication. Medication I resulted in heavy sedation, good cooperation and amnesia but had the strongest tendency towards hypoxemia. Under schedule III, reduced cooperation and acceptance were seen due to a strong experience of pain. The best conditions during the examination with regard to cooperation, experience of pain and acceptance were found after premedication II without relevant depression of vital parameters. It can be concluded that midazolam can be used at minimal recommended doses as premedication for colonoscopy if combined with ketamine in a sufficient analgesic dosage.

Procedure for the semi-automatic detection of gastro-oesophageal reflux patterns in intraluminal impedance measurements in infants.

The diagnosis of gastro-oesophageal reflux (GOR) is of great interest for paediatric gastroenterologists. pH monitoring is the commonly used procedure for GOR diagnosis but a major amount of postprandial GOR is missed due to the mostly non-acidic gastric contents in infants. The multiple intraluminal impedance technique is based on the recording of the impedance changes during bolus transport inside the oesophagus. It is the first method which allows the pH-independent, long-term registration of GOR. The use of the impedance technology in clinical practice has been limited so far by the time-consuming, visual evaluation of the impedance traces. The new approach of a semi-automatic analysis of the impedance measurements allows the automated detection of reflux patterns. It is based on event marking and an optimised feature description of the impedance traces combined with a fuzzy system for pattern recognition. The classifier is developed and tested on 50 investigations in infants. Compared to the comprehensive, multiple visual evaluation the achieved precision is 75% sensitivity and 48% positive prediction. In comparison to a single visual evaluation the analysis of the automatically proposed patterns corresponds to a 96% reduction of the evaluation time with no loss of precision. Thus the applicability of the impedance technology is enhanced significantly. A combined measurement of pH and impedance gives evidence about the occurrence of GOR, its pH and the acidic exposure of the oesophagus.

[Peculiarities of the pharmacokinetics and pharmacodynamics of theophylline in children]. / Besonderheiten der Pharmakokinetik und Pharmakodynamik des Theophyllins im Kindesalter.

Pharmacologically relevant factors such as enteral absorption, distribution, metabolism and excretion are age-dependent. The absorption of theophylline given in aqueous solution to prenatal infants with apnoea is markedly reduced when administered along with the infant's feed. The metabolic pathway of theophylline depends on the age group. Newborn and older infants form the pharmacodynamically active metabolite, caffeine. The main metabolites 1.3-dimethyl-uric acid and 3-methylxanthine are detectable, as in adults, but 1-methyl-uric acid remains below the demonstrable serum concentration level in infants of our study. The elimination velocity of theophylline is also dependent on the age. In order to achieve effective theophylline concentrations in the serum with oral preparations the galenic properties of the sustained-release products are decisive. By contrast, there was no difference between intravenous administration as permanent infusion or bolus injection. The data presented underline that in the treatment of apnea in premature infants as well as in the treatment of asthma in older children individual controls of serum concentrations are required to achieve further improvement of therapeutic success.

Drug disposition during the perinatal period.

During the perinatal period the problems of drug disposition are pronounced. The adaptation from the maternal-fetal unit to extrauterine life leads to alterations in drug absorption, distribution, metabolism, and renal elimination. Since both morphology and function of the alimentary tract changes, drugs are absorbed more slowly in the neonate than in older infants. Moreover, the serum protein binding of drugs is reduced in neonates. Consequently a measured plasma concentration may reflect a higher plasma/tissue level in the newborn as compared with adults. If the distribution volume of a drug corresponds to the total body water or extracellular water space, the dosage may be calculated in relation to the individual variations in the body surface area. But this procedure is not applicable for the newborn infant due to impaired metabolic functions of the liver and renal elimination mechanisms. The capacity of drug oxidation and glucuronidation is not fully developed in the neonate. Also glomerular filtration and tubular secretion are reduced during the first weeks of life. Therefore the elimination half-lives of many drugs are considerably prolonged in the newborn compared with that in older infants. As a consequence, individual therapeutic drug monitoring based on pharmacokinetic concepts and assisted by computer programs is becoming increasingly important.

Pharmacokinetics and clinical aspects of azlocillin in paediatrics.

A pharmacokinetic and clinical study was done in 25 newborn infants suffering predominantly from pseudomonas infections treated with azlocillin. After a single iv dose of 50 mg azlocillin per kg bodyweight in biphasic concentration time course suggested an open two compartment body model. There was a rapid diffusion between the peripheral and the central compartment. The elimination half life calculated from the beta-slope was 2.5-2.6 h, and differences between premature neonates with more than 2000 g body weight and mature neonates were absent. To maintain a median steady state concentration of 50-80 mg/l in the serum 100-200 mg azlocillin/kg body weight per day must be given. Using this dosage non-linear kinetics and an accumulation of the drug would not occur. Bacteriological and clinical results confirm that in neonatal reinfection, and bronchopulmonary and local infection caused by pseudomonas strains, azlocillin has favourable properties.

Renal toxicity of aminoglycosides in the neonatal period.

Renal toxicity of aminoglycosides seems to be less frequent in newborn infants compared to adults even though glomerular filtration rate and tubular secretion and reabsorption mechanisms are subjected to adaptive processes during the neonatal period. In 14 infants, kinetic parameters of gentamicin were determined using an open three-compartment body model. According to the lower glomerular filtration rate, the beta-elimination phase is longer in the newborn infant compared to adults, while the gamma-elimination phase is quite similar to adult values. The calculated drug accumulation in the deep compartment (kidney) under steady-state conditions is lower in newborns compared to infants. The excretion of urinary enzymes of tubular origin, that is the lysosomal NAG (N-acetyl-beta-D-glucosaminidase), beta-glucuronidase, and the brush-border-associated AAP (alanine-aminopeptidase), GGT (gamma-glutamyl-transpeptidase), are lower in healthy newborn infants compared to older ones. The increase of AAP, for instance, during aminoglycoside therapy is less pronounced in newborn infants, especially in prematures, if compared to adult values. After end of therapy the AAP excretion decreases to normal. The calculated rate of this decrease takes place in a fashion similar to the release of drugs from the kidney (gamma-elimination phase). The data indicate that there may be a lower renal accumulation of aminoglycosides in newborn infants, which can be explained by the morphometric and functional characteristics of the newborn kidney.

[Pharmacotherapy of acute infant enteritis]. / Pharmakotherapie der akuten Säuglingsenteritis.

The management of acute diarrhea in infants with drugs is justified only where these drugs have specific interactions with the pathophysiologic mechanisms involved. Most of the infectious diarrheas are self-limited, many patients recover spontaneously. Antimicrobial drugs are only indicated if mucosal destruction takes place and symptoms of dysentery respectively inflammation are observed. Some authors propose to treat newborn and young infants in case of doubt. If antimicrobial drugs are given uncritically a selection of not obligatory microorganisms can occur, or the number of asymptomatic carriers increases. There is no confirmation that drugs like adsorbents (kaolin, pectin, charcoal) or lyophilized microorganisms have a therapeutic effect. In contrast morphine derivatives like loperamide act not only by slowing the intestinal motility but also by inhibiting the secretion mechanisms of the enterocyts. Nevertheless these drugs can not be recommended for infants since ileus symptoms have been observed.