Pharmacokinetics and short-term metabolic effects of mammalian cell-derived biosynthetic human growth hormone in man.

The pharmacokinetics and acute effects of an authentic recombinant DNA-derived human growth hormone (rhGH) produced by genetically engineered mammalian cells were determined in 12 healthy volunteers following intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) administration of 4 IU (1.3 mg) hGH/m2 body surface area. Following i.v. administration, apparent elimination half-life of rhGH was 18 min. Following i.m. administration, a mean peak serum concentration of 36.9 ng/ml (range 13-61 ng/ml) occurred at 3 h, and following s.c. administration, more sustained but lower serum concentrations occurred, with mean peak concentrations of 16.4 and 16.3 ng/ml at 4 and 6 h (ranges 9.0-27.5 ng/ml and 6.5-35.5 ng/ml at 4 and 6 h, respectively). The mean area under the curves was lower after s.c. (134 +/- 48 ng.h.ml-1) than after i.m. (194 +/- 48 ng.h.ml-1) injections (p < 0.03). Comparable results were obtained for the same dose of rhGH given subcutaneously in concentrations of either 4 IU/ml or 10 IU/ml. Both i.m. and s.c. administrations caused similar increases in free fatty acids at 4 h and insulin-like growth factor I at 24 h. Insulin, C-peptide and blood glucose were almost unchanged during the first 4 h after administration, whereas leukocytes increased significantly (p < 0.0001). Local and systemic tolerance were good, and no adverse reactions were observed. In a GH-deficient child, hGH serum levels between 10 and 20 ng/ml were demonstrated for a period of 8 h after s.c. administration of 0.07 IU rhGH/kg body weight.

[Atopy-suggesting symptoms in the first 2 years of life. Effect of gestational age, nutrition and social class]. / Atopie-verdächtige Symptome in den ersten zwei Lebensjahren. Einfluss von Geburtsreife, Ernährung und Sozialstatus.

In a prospective study on 318 non-selected infants signs of atopy as well as interrelations with feeding regimens and family history of atopic disease were investigated at the age of 1 1/2 year. The study population was recruited from preterm and term babies hospitalized 1985 in the University Children's Hospital Freiburg, Germany. The most common symptom was eczema. In addition, clinical symptoms of atopy in first degree relatives were a significant risk factor. Because the highest incidence of atopic symptoms occurred in preterm born children with allergic background in their families, we therefore consider this population at highest risk to develop atopic disease. On the other hand there was no significant influence of breast feeding, cow's milk formula and the time of intake of allergenic food on the clinical manifestation of atopy in any group. Although eczema occurred predominantly in infants with higher social level the respiratory tract symptoms were reported more frequently in children from working class families. We therefore regard the social status as an important confounding variable in the studies of risk factors for the development of allergy.

Myocardial energetics in patients with dilated cardiomyopathy. Influence of nitroprusside and enoximone.

Cardiotonic agents influence myocardial energy consumption by vasodilation, which may reduce energy demand, and by inotropism, which may increase it. To distinguish between the two effects, myocardial oxygen consumption must be analyzed in relation to its hemodynamic determinants. The coupling of myocardial oxygen consumption with its determinants was investigated in 22 patients with idiopathic dilated cardiomyopathy (NYHA Class II and III). Predicted myocardial oxygen consumption by the pressure-work index, the Bretschneider index, and the pressure-volume area correlated moderately with measured myocardial oxygen consumption (r = 0.57, p less than 0.001; r = 0.52, p less than 0.005; and r = 0.63, p less than 0.001). Multiple regression analysis, including left ventricular peak systolic wall stress, systolic stress-time integral, pressure-volume work, maximum rate of left ventricular pressure rise, and mean velocity of circumferential fiber shortening indicated that systolic stress-time integral is the major determinant of myocardial oxygen consumption (r = 0.75, p less than 0.001) in these patients. Enoximone, a phosphodiesterase inhibitor, has an inotropic and a vasodilating effect. To investigate the inotropic portion of the energy cost of this phosphodiesterase inhibitor, the influence of enoximone on myocardial oxygen consumption and systolic stress-time integral was compared with the effects of nitroprusside, which is a vasodilator only. Nitroprusside (10 patients) and enoximone (12 patients) reduced left ventricular systolic stress-time integral from 109 +/- 22 to 71 +/- 21 (p less than 0.005) and from 104 +/- 23 to 42 +/- 10 (p less than 0.001) 10(3) dynes.sec/cm2, respectively. Myocardial oxygen consumption decreased from 159 +/- 44 to 112 +/- 23 (p less than 0.005) and from 134 +/- 28 to 109 +/- 21 (p less than 0.001) microliters/beat/100 g, respectively. In both groups, there was a significant correlation between the decrease in myocardial oxygen consumption and the decrease in systolic stress-time integral. The slopes of the respective linear regression lines were significantly different (1.27 for nitroprusside and 0.51 nl.cm2/100 g.dynes.sec for enoximone, p less than 0.05), indicating a smaller decrease of myocardial oxygen consumption for a given decrease of stress-time integral with enoximone. Applying the pressure-work index or the pressure-volume area instead of systolic stress-time integral yielded comparable results. Thus, vasodilation reduces myocardial oxygen consumption in proportion to the reduction of stress-time integral. With enoximone, the energy-saving effect of vasodilation is counteracted in part by the increased energy d

[Enzyme diagnosis in progressive muscular dystrophies, especially in the Duchenne type]. / Enzymdiagnostik bei progressiven Muskeldystrophien, insbesondere beim Typ Duchenne.

The serum activities of muscular enzymes are important for the diagnosis and follow-up of muscular diseases. They reflect the degeneration of muscular tissue. The serum enzyme activities (creatine kinase (CK), creatine kinase MB (CKMB), Aldolase (ALD), Lactat-dehydrogenase (LDH), a hydroxy-buty-rat-dehydrogenase (a-HBDH), glutamat-oxalacetat-transaminase (GOT), and glutamat-pyruvat-transaminase (GPT) in Duchenne muscular dystrophy show an increase during the first three years of life, a maximum between the age of 3 and 4 and an asymptotic decline thereafter. Taking the blood samples under non-standardised conditions the coefficients of variation (VK) differed considerably. For a -HBDH the lowest value was obtained (VK = 0.37). The VK-value of ALD was comparatively high (VK = 0.68). The correlation among the enzymes themselves was high and a-HBDH correlated closest to LDH and a-HBDH also to GPT. Thus we conclude that LDH, ALD- and GPT-determinations may be abandoned in Duchenne dystrophy. In Duchenne muscular dystrophy the course of the different enzyme activities can be described by an heuristic mathematical formula (y = Ae-at + bte-ct). With its aid it is possible to calculate the value of the constant c individually for each patient, if at least 4 enzyme values distributed over 3 or more years are available. The evaluation of the enzymes and clinical data of 88 Duchenne patients has shown that the value of constant c is individually correlated to the speed of progression of the disease. This proved most reliable in the case of the CK (r = 0.43 resp. 0.76) and CKMB (r = 0.45). The mean of the constant c in the group of Duchenne patients (n = 88) was -0.29/year, in Beckers dystrophy (n = 7) -0.14/year and in limb girdle dystrophy (n = 12) -0.21/year. In Duchenne muscular dystrophy the calculation of constant c renders it possible to select patients with similar velocity of progression to reinforce the "power of therapeutic studies". The evaluation of pilot studies may be more objective, if the enzyme values actually measured under therapy are compared with those prospectively estimated by mathematical analysis of the course of the enzyme values before treatment.

Age dependence of flow velocities in basal cerebral arteries.

Flow velocities in the basal cerebral arteries were studied by transcranial Doppler sonography. A longitudinal study was undertaken on 25 healthy newborn babies during the first 20 days of life, and a cross sectional study was performed on 112 healthy children between 1 day and 18 years of age. A rapid linear increase of flow velocities was found within the first 20 days with higher velocities in neonates of higher birth weight and gestational age. Maximal values were recorded at the age of 5 to 6 years. After that the velocities decreased linearly to 70% of their maximum at the age of 18 years. Reference values were derived from the data considering age and birth weight. The increasing flow velocities probably reflect the increasing cerebral blood flow during the first years of life. Our results also support the hypothesis of a decrease in cerebrovascular resistance during infancy. With the technique of transcranial Doppler sonography and the introduced reference values normal and abnormal intracranial flow velocities can now be assessed by non-invasive methods in all paediatric age groups.

A mathematical analysis of creatine kinase activity in the course of Duchenne muscular dystrophy.

Recently, clinical follow-up studies have shown that the age of first symptoms and the speed of progress may vary considerably in Duchenne muscular dystrophy (DMD). Prognostic factors would be of interest not only for the patients themselves, but also for the selection of DMD patients for therapeutic studies. Creatine kinase (CK) activity reflects the dystrophic degeneration of the muscle cells. Therefore, the coherence of the course of CK activity and its relationship to the clinical state was investigated with the aid of a heuristic mathematical formula. Two constants were calculated, b and c. The data of 88 DMD patients proved the validity of the mathematical formula. Constant b seemed to be of no clinical relevance. The height of constant c was related to the age at which the ability to walk was lost (r = -0.76). This constant provides an objective individual assessment of the prognosis in DMD. In addition, the mathematical analysis of the CK course opens the way for a prospective CK estimation, which is relevant for the evaluation of therapeutic trials.

[Height and weight of 70 prenatally dystrophic children of ages 5 to 11]. / Grösse und Gewicht 70 pränatal dystropher Kinder im Alter von 5-11 Jahren.

Growth-retarded, markedly slim children with poor appetite are often seen by a pediatric endocrine service without any previous information to their parents about known correlations between their condition and poor intrauterine growth. There are follow-up studies covering the first years of life, but only a few concerning growth prognosis in later years. Therefore, full-term, nonasphyxiated small-for-date children were traced by a questionnaire at ages between 5 to 11 years, and growth data were evaluated using standard deviation scores (x-means/s): for the whole group the height deficit was -0.724 +/- 0.965 SD, whereas normal persons show a deviation from normality of 0.000 +/- 1.000 SD (p less than 0.001); it was -0.823 +/- 0.949 SD and -0.495 +/- 0.927 SD for children with birth weights below and above the 3rd percentile for birth weight resp., and -1.285 +/- 1.031 and -1.261 +/- 1.069 SD for children whose length or length and weight were below the 3rd percentile at birth. The weight deficit (0.048 +/- 0.999 SD) of the whole group was statistically but not medically significant. There was no correlation to the parents or the mothers heights. These data correspond well with those from a review of the literature. Together with an accurate bone age determination our data could help to improve the counselling of involved families about growth prognosis of their originally small for date children.

Evidence for mitochondrial origin of the HCO3(-)-ATPase in brush border membranes of rat proximal tubules.

High HCO3(-)-ATPase activity is known to exist in mitochondria of renal tubular cells. In brush border membrane (BBM) preparations of proximal tubules such an anion-stimulated enzyme was also found. However, these preparations always contained mitochondrial markers. The putative localization and the role of this ATPase in BBM is still controversial. Some authors consider the HCO3(-)-ATPase in the BBM to be a mitochondrial contamination; others attribute to this ATPase a key role in H+ transport in the proximal tubule. To reinvestigate this problem, BBMs from rat kidney cortex were isolated by a simple, rapid (1.5-h) Ca2+-precipitation method, yielding a BBM fraction enriched 12.4-fold with respect to the marker enzyme leucine aminopeptidase (LAP). There was no basolateral Na+-K+-ATPase and no mitochondrial succinate dehydrogenase detectable. Cytochrome c oxidase was drastically reduced to 7 +/- 1% of that observed in the homogenate (TH). The activity of HCO3(-)-ATPase in the BBM fraction was 19 +/- 4 IU/g protein, i.e., 27% that of the homogenate. As sonication of the TH exclusively increases the activity of HCO3(-)-ATPase, its relative activity was 7.5% and thus equal to that of the mitochondrial marker. In many BBM preparations no HCO3(-)-ATPase was detectable. In those BBM preparations in which traces of HCO3(-)-ATPase were found, this activity coincided with that of cytochrome c oxidase in the respective preparation. There was a constant activity ratio of cytochrome c oxidase/HCO3(-)-ATPase in the TH, BBM, and pellet 1. The activity of HCO3(-)-ATPase in BBM did not depend on the activity of LAP.(ABSTRACT TRUNCATED AT 250 WORDS)

[Improved immunocompetence in two children with chronic Epstein-Barr virus infection under treatment with a standardized thymus hormone preparation (thymostimulin)]. / Verbesserte Immunkompetenz bei zwei Kindern mit chronischer Epstein-Barr-Virusinfektion unter der Behandlung mit einem standardisierten Thymushormon-Präparat (Thymostimulin).

Two children with chronic Epstein-Barr virus infection were treated with a standardized thymic hormone preparation (thymostimulin, TP-1 Serono). The treatment was well tolerated. No adverse reactions, no side effects were observed. Results of immunological investigations showed a trend towards normalisation. Additional clinical evidence showed up, which pointed to a response to the therapy.

[Noninvasive intracranial pressure measurement at the anterior fontanelle in the first days of life]. / Nichtinvasive Hirndruckmessung über der vorderen Fontanelle bei gesunden Säuglingen in den ersten Lebenstagen.

A continuous registration of intracranial pressure by aplanation-tonometry on the anterior fontanelle was performed in 12 healthy term newborns during the night hours of the first 3 days. The median intracranial pressure of the first day was 4.01 +/- 2.74 cm H2O. There was a slight increase between the first and the second day of life and a significant increase between second and third day up to 5.84 +/- 2.66 cm H2O. In our interpretation this result is a sign for the active reconfiguration of the skull by increasing intracranial pressure, which may be a consequence of changing tonus of cerebral vessels.

Plasma elimination of antithrombin III (heparin cofactor activity) is accelerated in term newborn infants.

Antithrombin III (AT III) levels are markedly increased in newborn infants following exchange transfusion with adult blood, and subsequently return to pre-exchange values. This transient rise in AT III (heparin cofactor activity), was used to estimate its plasma elimination half-life. AT III activities were measured serially, before and after double-volume exchange transfusions with heparinised blood in newborn infants requiring therapy for severe hyperbilirubinaemia. The plasma elimination half-life of AT III activity was calculated to be 3.9 +/- 1.4 h (mean +/- SEM). Compared with published data on the kinetics of AT III infusions in adults, the neonate has a considerably accelerated turnover. This finding has important implications for the design of future therapeutic trials of AT III concentrates and provides further evidence that plasma proteins, including components of the coagulation system, appear to have different kinetics in the neonatal period.

[Advantages of hyposensitization with a high dose of allergoid in pollen allergy]. / Vorteile einer Hyposensibilisierung mit höher dosiertem Allergoid bei Pollenallergie.

Grass and rye pollen sensitive children were hyposensitized with glutaraldehyde-modified, tyrosine-adsorbed grass and rye allergoid. We evaluated the clinical efficacy and immunological changes associated with the administration of 3100 NOON-Units (NU) with 3 injections in 15 patients (group A) and 9100 NU with 6 injections in 13 patients (group B) preseasonally. No systemic side effects during therapy were observed. In patient's assessments, a clinical improvement was reported; however, group B achieved better symptom and medication scores. The latter group obtained slightly higher specific IgG levels than group A after two seasons of treatment, whereas the co-seasonal increase of specific IgE was higher in group A. Hyposensitization with grass and rye allergoid is a safe therapy, a better clinical and immunological effect being observed in a high dose regimen.

Pharmacokinetics of hydrochlorothiazide in relation to renal function.

The pharmacokinetics of hydrochlorothiazide (HCT) was investigated in 23 subjects with normal renal function or widely varying degrees of renal failure. The half-life of elimination increased from 6.4 h in subjects with normal renal function to 11.5 h in patients with mild renal impairment (endogenous creatinine clearance between 30 and 90 ml/min), and to 20.7 h in patients with an endogenous creatinine clearance below 30 ml/min. The cumulative urinary excretion and the renal HCT clearance were correspondingly reduced in patients with impaired kidney function. In normal subjects HCT was mainly excreted by tubular secretion, but as renal HCT clearance in patients with renal impairment did not differ significantly from endogenous creatinine clearance, it was concluded that the secretory mechanism is most markedly impaired. In patients with an endogenous creatinine clearance of 30 to 90 ml/min, the dosage of HCT should be reduced to 1/2 and in patients with a endogenous creatinine clearance below 30 ml/min to 1/4 of the normal daily dose to avoid dose dependant side-effects.

Arterial occlusion in a preterm infant. Successful non-surgical treatment with urokinase and low-dose heparin.

Neonatal arterial occlusion is a rare condition of obscure aetiology, when not associated with catheterization of the umbilical artery. Embolic occlusion of the left iliac artery was diagnosed in a preterm baby weighing 1000 g, who presented with a cold, pale and pulseless left leg on the 6th day of life. Surgical embolectomy was contraindicated in this very small baby. Fibrinolytic therapy with urokinase and administration of low-dose heparin resulted in a complete recovery of skin colour, skin temperature and blood pressure. After three weeks of urokinase therapy, no pulse differences could be detected between right and left femoral and popliteal arteries by Doppler examination, and only minimal differences were present between right and left tibial arteries.

Decreased production or increased turnover of antithrombin III in severe acquired coagulopathy?

During the course of severe coagulopathy in an infant suffering from septicaemia and shock, antithrombin III levels were determined repeatedly before and during substitution therapy with human antithrombin. By mathematical analysis of these data, using a biexponential function, the plasma elimination half-life of the antithrombin III was estimated to be 7.5-10.5 h. Compared with known plasma half-lives of radioactively labelled antithrombin III in adults the increase was five-to ten-fold. This indicates that the significantly decreased levels of antithrombin III in this case of coagulopathy were at least partly due to an accelerated consumption of antithrombin III. The estimation of the plasma elimination half-life of antithrombin III helps to differentiate decreased production from increased consumption in cases of severe coagulopathy. Thus, a more precise diagnosis of disseminated intravascular coagulation can be made whilst taking advantage of substitution therapy and avoiding the hazards of radioactive tracer proteins.

Independent of etozolin elimination of kidney function. Single dose experiments in patients with renal insufficiency.

Following a single oral dose of the novel diuretic ethyl (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetate (etozolin, Elkapin), the plasma levels of the parent drug and its active metabolite (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetic acid (ozolinone) were determined by means of HPLC. In order to learn whether or not impairment of renal function influences the plasma levels of the diuretics and their elimination rate 19 patients with various degrees of reduced glomerular filtration rate were investigated. The lack of correlation between elimination half-life (HL) and creatinine clearance showed that there is no influence of kidney disease on the pharmacokinetic parameters of etozolin and ozolinone. Even in severe renal insufficiency the HL of etozolin and ozolinone did not differ from normal values, the mean HL of etozolin being 2.8 +/- 0.4 h and of ozolinone being 10.2 +/- 1.5 h. Also impairment of liver function did not signficantly alter the pharmacokinetic parameters of these diuretic agents. It is concluded that in the single dose experiments renal insufficiency does not significantly influence the metabolization of etozolin and ozolinone.

[Distribution volume and elimination of triamterene and its active metabolites in the rabbit (author's transl)]. / Verteilungsvolumen und Elimination von Triamteren und seinen wirksamen Metaboliten beim Kaninchen.

In rabbits the volumes of distribution of triamterene (TA) and its metabolites hydroxytriamterene (OH-TA) and hydroxytriamterene sulfuric acid ester (OH-TA-ester) were determined after i.v. administration of the agents. Both TA as well as its metabolites distribute in at least 2 compartments, OH-TA exhibiting by far the greatest volume of distribution, followed by TA and then by OH-TA-ester. TA and its phase-II-metabolite are eliminated at practically equal rate, whereas the elimination of OH-TA is relatively slow.