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Diabetic Medicine 10/2011; 29(5):692-3. · 2.90 Impact Factor
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ABSTRACT: Diabetic ketoacidosis (DKA) is a frequent acute complication at onset of type 1 diabetes. It is assumed that increased public awareness about diabetes symptoms may reduce DKA rate at diabetes onset. To investigate the time-dependent trend in DKA prevalence we analysed the frequency and determinants of DKA at disease onset over 15 years in pediatric patients.
The prevalence of DKA at disease onset was analysed in individuals aged ≤18 years treated for the first time from 1995-2009 within 7 days after diagnosis in pediatric centers. Simple and multiple logistic regression analysis was performed to investigate influencing factors on DKA prevalence. Change of the probability of ketoacidosis over years were modelled in the logistic regression as linear trend.
16 562 individuals from 170 institutions were studied with a mean age of 9.2 ± 4.2 years. DKA (pH <7.3) was present in 20.8% of patients without a significant trend between 1995 and 2009 (p=0.222). DKA prevalence was higher in children ≤5 years (26.3%) and in the age group 10-15 years (21.7%) than in individuals aged 5-10 years (16.4%) and 15-18 years (16.9%, p<0.001). Girls had DKA more often than boys (21.2% vs. 19.3%, p=0.002). DKA frequency was increased in individuals with migration background (26.5% vs. 19.2%, p<0.001).
DKA prevalence at diabetes onset was constant at about 21% during the last 15 years. Very young children, pubertal adolescents, girls and individuals with migration background are at higher risk for DKA at diagnosis. To prevent DKA earlier diagnosis of type 1 diabetes is warranted especially in these patient groups.
Klinische Pädiatrie 01/2011; 223(2):70-3. · 1.77 Impact Factor
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ABSTRACT: During fetal development of the anterior pituitary gland, a number of sequential processes occur that effect cell differentiation and proliferation. Molecular anlyses have revealed several steps thay are required for pituitry cell line specification and have identified specific factors that control these steps. The gene encoding the pituitary transcription factor 1 (pit-1) is expressed during differentiation steps that take place quite late in the development of the anterior pituitary gland. Clinically, patients with mutations ofthePITIgene are characterized by severe deficiencies in growth hormone (GH) and prolactin (PRL), and often develop secondary hypothyroidism. A second pituitary transcription factor is known as Prophet of Pit-1 (Prop-1), and a mutation of the Prop1 gene has been detected in Ames dwarf mice. Several Prop1 mutations have been identified that structurally affect the ‘paired-like’DNA-binding domain of the Prop-1 protein molecule. Patients with PROPl mutations show combined pituitary hormone deficiency. These patients exhibiy secondary hypogonadism in addition to the deficiencies of Gh, PRL and thyroid-stimulating hormone (TSH) also seen in patients with PITI mutations. Although all are in the subnormal range, the levels of GH, PRL and TSH in patients with PROP 1mutations are on average, slightly higher than in patients with PITI mulations. Some degree of hypocortisolism may necessitate cortisol substitution in patients with PROP1 mutations.
Acta Paediatrica 04/2008; 88(s433):33 - 41. · 2.07 Impact Factor
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S Himpel,
P Panzer,
K Eirmbter,
H Czajkowska,
M Sayed,
L C Packman,
T Blundell, H Kentrup,
J Grötzinger,
H G Joost,
W Becker
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ABSTRACT: Protein kinases of the DYRK ('dual-specificity tyrosine-regulated kinase') family are characterized by a conserved Tyr-Xaa-Tyr motif (Tyr-319-Tyr-321) in a position exactly corresponding to the activation motif of the mitogen-activated protein kinase (MAP kinase) family (Thr-Xaa-Tyr). In a molecular model of the catalytic domain of DYRK1A, the orientation of phosphorylated Tyr-321 is strikingly similar to that of Tyr-185 in the known structure of the activated MAP kinase, extracellular-signal-regulated kinase 2. Consistent with our model, substitution of Tyr-321 but not of Tyr-319 by phenylalanine markedly reduced the enzymic activity of recombinant DYRK1A expressed in either Escherichia coli or mammalian cells. Direct identification of phosphorylated residues by tandem MS confirmed that Tyr-321, but not Tyr-319, was phosphorylated. When expressed in COS-7 cells, DYRK1A was found to be fully phosphorylated on Tyr-321. A catalytically inactive mutant of DYRK1A contained no detectable phosphotyrosine, indicating that Tyr-321 is autophosphorylated by DYRK1A. MS identified Tyr-111 and Ser-97 as additional autophosphorylation sites in the non-catalytic N-terminal domain of bacterially expressed DYRK1A. Enzymic activity was not affected in the DYRK1A-Y111F mutant. The present experimental data and the molecular model indicate that the activity of DYRK1A is dependent on the autophosphorylation of a conserved tyrosine residue in the activation loop.
Biochemical Journal 12/2001; 359(Pt 3):497-505. · 4.90 Impact Factor
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ABSTRACT: Fragestellung. Für viele Patienten mit Mukoviszidose wird mit zunehmenden Lebensalter eine Störung der Glukosetoleranz bis hin zum manifesten
Diabetes mellitus relevant und behandlungswürdig. Der Einfluss einer pseudomonaswirksamen i.-v.-Chemotherapie auf die Glukosehomöostase
bei Zystischer Fibrose wurde untersucht.
Patienten und Methode. Bei 14 Mukoviszidosepatienten im Alter von 7–35 Jahren wurden zu Beginn und am Ende einer 14-tägigen, routinemäßig durchgeführten,
i.-v.-Chemotherapie ein oraler Glukosetoleranztest mit Erfassung des Blutzuckers und des Seruminsulins unternommen.
Ergebnisse. Nach den Kriterien der American Diabetes Association hatten 3 der 14 Patienten eingangs eine gestörte Glukosetoleranz und
weitere 3 einen Diabetes mellitus. Von diesen 6 Patienten hatten 4 zu Ende der Antibiotikatherapie eine normale Glukosetoleranz,
1 eine einschränkte Glukosetoleranz und 1 weiterer einen Diabetes mellitus. Gleichzeitig ging die Gesamtinsulinsekretion leicht
zurück. Die maximale Insulinsekretion wurde im 2. Test früher erreicht, ohne dass eine Beschleunigung der frühen Insulinantwort
festgestellt werden konnte.
Schlussfolgerung. Die Therapie der chronischen bronchopulmonalen Infektion von Mukoviszidosepatienten mit pathologischer Glukosetoleranz oder
Diabetes mellitus führt über eine Verbesserung der Insulinsensitivität, weniger der Dynamik der Insulinsekretion, zu einer
Verbesserung der Glukosehomöostase. Die Erarbeitung diagnostischer Standards zur Früherfassung einer Glukosetoleranzstörung
bei Zystischer Fibrose sollte die Abhängigkeit der Ergebnisse von der begleitenden Therapie berücksichtigen.
Background. For many patients with cystic fibrosis impaired glucose tolerance or even diabetes mellitus is becoming relevant with growing
age. The influence of an anti-Pseudomonas chemotherapy on glucose homeostasis of cystic fibrosis patients was investigated.
Patients and methods. In fourteen cystic fibrosis patients aged between 7 and 35 years glucose tolerance was tested by standard oral glucose tolerance
test in the beginning and at the end of a routine anti-Pseudomonas chemotherapy of fourteen days. Beside the blood glucose serum insulin was determinated.
Results. According to the criteria of the American Diabetes Association three of the fourteen patients had an impaired glucose tolerance
and another three had diabetes mellitus when tested at the beginning of anti-Pseudomonas chemotherapy. In four of these six patients glucose tolerance was normal at the end of the chemotherapy. Of the remaining
two patients one fulfilled the criteria for impaired glucose tolerance and one for diabetes mellitus. In these patients insulin
secretion was lower in the second test. Peak insulin was reached earlier while there was no significant improvement of early
insulin response.
Conclusion. The treatment of chronic airway infection in cystic fibrosis patients with impaired glucose tolerance or diabetes mellitus
results in an improvement of glucose homeostasis by a better insulin sensitivity and less by improvement of early insulin
response. In developing diagnostic protocols for screening of cystic fibrosis-related diabetes mellitus the impact of the
concomitant therapy on glucose homeostasis should be considered.
Monatsschrift Kinderheilkunde 01/2001; 149(2):154-158. · 0.27 Impact Factor
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ABSTRACT: About 50% of preterm infants and neonates receiving methylxanthines for respiratory stimulation will develop a pathological gastro-oesophageal reflux (GOR) pattern. In the face of potential GOR-related complications the effect of a concomitant treatment with a prokinetic agent, such as cisapride, should be evaluated. In this study 32 formerly preterm infants were studied simultaneously by 24-hour oesophageal pH monitoring and cardio-respirogram before the presumed end of caffeine treatment. In 14 of these infants a reflux index (RI; percentage of recording time) of more than 4% could be detected (pH <4). Ten of them were treated orally with cisapride (0. 2 mg/kg t.i.d.). Data of pH monitoring, cardio-respirogram and caffeine serum concentrations were obtained before and 5 days after introducing cisapride. The RI and the frequency of GOR decreased significantly with cisapride. The steady-state serum concentrations of caffeine were not influenced by cisapride and the extent of periodic breathing remained unchanged. In conclusion, cisapride has a positive influence on GOR parameters during caffeine treatment without impairing the oral bioavailability or therapeutic effect of caffeine.
Biology of the Neonate 02/2000; 77(2):92-5. · 1.90 Impact Factor
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ABSTRACT: Organizing pneumonia in cystic fibrosis has hitherto been considered a nonspecific reparative process. We report on an adult patient with cystic fibrosis and histologically proven bronchiolitis obliterans organizing pneumonia, who experienced sustained clinical improvement under corticosteroid therapy. This case suggests that bronchiolitis obliterans organizing pneumonia may be a distinct pulmonary complication in cystic fibrosis and improve with specific therapy.
Respiration 02/2000; 67(3):316-9. · 2.26 Impact Factor
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ABSTRACT: During fetal development of the anterior pituitary gland, a number of sequential processes occur that affect cell differentiation and proliferation. Molecular analyses have revealed several steps that are required for pituitary cell line specification and have identified specific factors that control these steps. The gene encoding the pituitary transcription factor 1 (Pit-1) is expressed during differentiation steps that take place quite late in the development of the anterior pituitary gland. Clinically, patients with mutations of the PIT1 gene are characterized by severe deficiencies in growth hormone (GH) and prolactin (PRL), and often develop secondary hypothyroidism. A second pituitary transcription factor is known as Prophet of Pit-1 (Prop-1), and a mutation of the Prop1 gene has been detected in Ames dwarf mice. Several Prop1 mutations have been identified that structurally affect the 'paired-like' DNA-binding domain of the Prop-1 protein molecule. Patients with PROP1 mutations show combined pituitary hormone deficiency. These patients exhibit secondary hypogonadism in addition to the deficiencies of GH, PRL and thyroid-stimulating hormone (TSH) also seen in patients with PIT1 mutations. Although all are in the subnormal range, the levels of GH, PRL and TSH in patients with PROP1 mutations are, on average, slightly higher than in patients with PIT1 mutations. Some degree of hypocortisolism may necessitate cortisol substitution in patients with PROP1 mutations.
Acta paediatrica (Oslo, Norway: 1992). Supplement 01/2000; 88(433):33-41.
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ABSTRACT: A 17-year-old boy and a 12-year-old girl with cystic fibrosis (forced expiratory volume in 1 sec, 36% and 14% of predicted values, respectively) developed severe right-sided lung infections with abscess formations and complete atelectases unresponsive to medical therapy. In both patients, unilateral emergency pneumonectomy resulted in rapid clinical improvement. Despite her severe underlying lung disease, the girl experienced a remarkable increase in quality of life; 2 years after surgery, she died from respiratory failure. The male patient has now survived for 4 years, and lung transplantation still remains a therapeutic option for him. We believe that pneumonectomy is a valuable rescue therapy for patients with cystic fibrosis and intractable unilateral lung infections who are at high risk of dying while waiting for lung transplantation. Pediatr Pulmonol. 1999; 23:376-379. (C) 1999 Wiley-Liss. Inc.
Pediatric Pulmonology 12/1999; 28(5):376-379. · 2.53 Impact Factor
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ABSTRACT: 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.
European Journal of Endocrinology 11/1999; 141(4):379-81. · 3.42 Impact Factor
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ABSTRACT: Impaired glucose tolerance (IGT) is an increasingly frequent complication of cystic fibrosis (CF). In CF patients, a fast postprandial rise in plasma glucose is typically followed by a delayed but prolonged insulin response. Patients may develop symptoms of both hyper- and hypoglycaemia. The alpha-glucosidase inhibitor, acarbose, delays the hydrolysis and subsequent absorption of ingested carbohydrates. The aim of this study was to investigate the efficacy of acarbose in CF patients with IGT. During a 2-week inpatient period for treatment of Pseudomonas infection, 12 CF patients with IGT were studied in a double-blinded, randomized crossover trial. Each patient received acarbose (50 mg t.i.d.) for 5 days and placebo for 5 days (days 3-8 and days 10-14, respectively). Glucose, insulin and C-peptide responses to a standardized nutritional load were measured at baseline and at the end of each study period (Days 2, 8 and 14). Treatment with acarbose was associated with significant reductions in the mean value, mean peak values and the area under the curve of plasma glucose, insulin and C-peptide, compared to respective baseline values and placebo. Gastro-intestinal disturbances were recorded in 67% of patients during therapy with acarbose. CONCLUSION: Acarbose has a positive therapeutic effect on glucose tolerance in cystic fibrosis patients, as shown by attenuation of postprandial plasma glucose increase and a significant decrease in insulin secretion response. However, acarbose treatment was associated with adverse gastro-intestinal effects that may prevent patients from accepting long-term therapy.
European Journal of Pediatrics 07/1999; 158(6):455-9. · 1.88 Impact Factor
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ABSTRACT: The pituitary transcription factor Pit-1 is expressed during the later differentiation stages of anterior pituitary development and Pit-1 mutations have been identified as the cause of a combined pituitary hormone deficiency (CPHD) for GH, prolactin and TSH. Mutations within the human Pit-1 gene can either impair the DNA binding of this transcription factor, or while leaving DNA binding capabilities unimpaired, decrease its function within the transactivation complex. Approximately half of all patients with this phenotype do not show any defect within the Pit-1 gene. Prop-1, a recently discovered transcription factor of anterior pituitary development, seemed a likely candidate for such mutations. Prop-1 mutations, however, have been found so far to induce a combined pituitary hormone deficiency for GH, prolactin, TSH and gonadotropins. We describe here a group of patients with isolated and combined pituitary hormone deficiencies who were screened for Pit-1 and Prop-1 mutations to characterize the phenotypic spectrum of defects within these two genes.
Journal of pediatric endocrinology & metabolism: JPEM 05/1999; 12 Suppl 1:311-7. · 0.88 Impact Factor
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ABSTRACT: Among the very rare intracerebral lipomas, those of the corpus callosum are the most frequent. Due to the advanced technology and the frequent use of ultrasonography these lesions are diagnosed more and more often. A female neonate was admitted to our hospital because of a progressive thrombocytopenia. Pregnancy was complicated by an autoimmune thrombocytopenia of the mother. While there were no remarkable findings on clinical presentation, a sonogram of the brain revealed an area of increased echogenicity in the midline which was interpreted as an intracerebral hemorrhage. In absence of any respective clinical signs a magnet-resonance-tomography of the brain was performed leading to the hypothesis of a lipoma of the corpus callosum (LCC) that could be verified by a densitometry in a cranial computer tomography (CT). Obviously, the initially performed sonogram was misinterpreted as an intracerebral hemorrhage due to the coincidence with the thrombocytopenia. At last the discrepancy of clinical and ultrasonographical findings led to the diagnosis by magnet-resonance-tomography and CT scan. Knowledge of the typical sonographic appearance of an LCC may be helpful for the differential diagnosis of this rare lesion even in fetal ultrasound.
Zeitschrift für Geburtshilfe und Neonatologie 10/1998; 202(5):217-9.
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Clinical Infectious Diseases 12/1997; 25(5):1245-6. · 9.15 Impact Factor
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ABSTRACT: A cDNA clone of a protein kinase with high similarity to the Clk (Cdc2-like kinases) subfamily was isolated from a rat brain library and characterized. Its deduced amino acid sequence exhibited a 99% identity with human Clk3 and was therefore designated rat Clk3. In addition to the protein kinase domain, the sequence (490 amino acids) comprises an N-terminal domain with a strikingly high portion of basic amino acids. A glutathione S-transferase fusion protein of Clk3 catalyzed autophosphorylation of the kinase but not phosphorylation of the exogenous substrates histone or casein. By Northern blot analysis of different rat tissues, mRNA of Clk3 was detected predominately in testis, suggesting that this kinase regulates a predominately testicular function.
Biochimica et Biophysica Acta 07/1996; 1312(1):63-7. · 4.66 Impact Factor
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ABSTRACT: The cDNA of a novel, ubiquitously expressed protein kinase (Dyrk) was cloned from a rat brain cDNA library. The deduced amino acid sequence (763 amino acids) contains a catalytic domain that is only distantly related to that of other mammalian protein kinases. Its closest relative is the protein kinase Mnb of Drosophila, which is presumably involved in postembryonic neurogenesis (85% identical amino acids within the catalytic domain). Outside the catalytic domain, the sequence comprises several striking structural features: a bipartite nuclear translocation signal, a tyrosine-rich hydrophilic motif flanking the nuclear localization signal, a PEST region, a repeat of 13 histidines, a repeat of 17 serine/threonine residues, and an alternatively spliced insertion of nine codons. A recombinant glutathione S-transferase-Dyrk fusion protein catalyzed autophosphorylation and histone phosphorylation on tyrosine and serine/threonine residues with an apparent Km of approximately 3.4 microM. Exchange of two tyrosine residues in the "activation loop" between subdomains VII and VIII for phenylalanine almost completely suppressed the activity and tyrosine autophosphorylation of Dyrk. Tyrosine autophosphorylation was also reduced by exchange of the tyrosine (Tyr-219) in a tyrosine phosphorylation consensus motif. The data suggest that Dyrk is a dual specificity protein kinase that is regulated by tyrosine phosphorylation in the activation loop and might be a component of a signaling pathway regulating nuclear functions.
Journal of Biological Chemistry 03/1996; 271(7):3488-95. · 4.77 Impact Factor
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ABSTRACT: The cDNA of a novel protein kinase (referred to as SNRK) was isolated from a rat fat cell cDNA library with a probe generated by a cloning approach based on the polymerase chain reaction. The encoded polypeptide (746 amino acids, Mr=81627) contains all conserved subdomains characteristic of the protein serine/threonine kinase family. A recombinant fusion protein with glutathione S-transferase catalysed autophosphorylation as well as phosphorylation of histone, confirming that SNRK has indeed protein kinase activity. By Northern blot hybridization, a 5-kb mRNA was detected in brain, heart, fat cells, intestine, testis, ovary, adrenal gland and thymus. In 3T3-L1 cells. SNRK was specifically expressed in the differentiated, adipocyte-like phenotype, whereas its mRNA was not detected in fibroblasts. Sequence comparisons of its catalytic domain relate SNRK to the SNF1 family of protein kinases. The noncatalytic domain comprises several intriguing structural features, including a glycine-rich region, two PEST sequences, and a bipartite nuclear localization signal which is preceded by a stretch of ten consecutive acidic residues. This part of the sequence exhibits no extended similarity with other proteins. In addition, we detected a high degree of sequence similarity with other SNF1-related proteinases in a small region (30-35 amino acids) flanking the C-terminus of the catalytic domain. This domain (designated the SNH domain) appears to define the subfamily of SNF1-related protein kinases and might represent a new type of regulatory domain of protein kinases.
European Journal of Biochemistry 03/1996; 235(3):736-43. · 3.58 Impact Factor
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ABSTRACT: Two novel protein serine/threonine phosphatases were cloned from a rat fat cell library with probes generated by a polymerase chain reaction-based cloning approach. One of these cDNAs encoded a protein presumably representing the rat homologue of PPV from Drosophila (75% identity of amino acids). The other novel cDNA encoded a protein phosphatase of 499 amino acids and was designated PPT. Its catalytic domain contains motifs typical for protein phosphatases but is only distantly related with PP1, PP2A, and PP2B (38-42% identical amino acids). When expressed in Escherichia coli, the catalytic domain of PPT exhibited protein phosphatase activity (dephosphorylation of phosphorylase a) that was inhibitable by okadaic acid. As a unique feature among other members of this gene family, PPT has an amino-terminal extension of 200 amino acids harboring three tandemly arranged tetratricopeptide repeat (TPR) motifs. This domain has previously been found in other proteins involved in the regulation of RNA synthesis or mitosis. mRNA of PPT was predominantly found in brain and, in lower levels, in testis, but was nearly undetectable in spleen, lung, skeletal muscle, kidney, and liver. It is suggested that the TPR domain of PPT may be involved in the regulation of the function of this novel protein phosphatase.
Journal of Biological Chemistry 10/1994; 269(36):22586-92. · 4.77 Impact Factor
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ABSTRACT: A polymerase chain reaction-based cloning approach was employed in order to identify ADP-ribosylation factors (ARF) in murine 3T3-L1 cells and to study their expression before and after differentiation of cells to the adipocyte-like phenotype. Partial sequences comprising the effector domains of ARF were amplified with degenerate primers and cloned. Five of these sequences were identified as murine homologues of known human ADP-ribosylation factors (ARF 1, 2, 4, 5, and 6). In addition, partial sequences of two previously unknown isoforms were found, and complete cDNA clones were isolated from a rat fat cell library and were sequenced. Both sequences harbor a putative myristoylation site in position 2, the known consensus sequences presumably involved in GTP binding and hydrolysis, and lack cysteine residues in the C terminus. Their amino acid sequences share a 56 and 41% identity, respectively, with human ARF 1. Based on a comparison with the known ARF isoforms, the first clone appears to represent the mammalian homologue of a known sequence from Drosophila (dARL 1, 79% identity) and was therefore designated rARL 1. The second clone resembled none of the known ARF-like proteins and was designated rARL 4. mRNA of ARL 4 was undetectable in the fibroblasts but abundant in the adipocyte-like phenotype, its expression starting on day 6 of the differentiation. In contrast, ARF 1, 2, and 5 were unaltered by differentiation of the 3T3-L1 cells; mRNA levels of ARF 6, and also of ARL 1 and ARF 4, were reduced after differentiation. It is suggested that the function of ARL 4 is related to the adipocyte-like phenotype of 3T3-L1 cells.
Journal of Biological Chemistry 07/1994; 269(22):15683-8. · 4.77 Impact Factor
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ABSTRACT: 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.
International journal of clinical pharmacology and therapeutics 03/1994; 32(2):82-7. · 1.18 Impact Factor
