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Biomedical subjects

J Drewe

Publications and source records attributed to J Drewe.

At least 91 records · Page 5Linked to original sources
PubMed1996

Permeation enhancement of octreotide by specific bile salts in rats and human subjects: in vitro, in vivo correlations.

1. The potential of bile salts to improve the enteral absorption of octreotide, an orally active somatostatin analogue, was investigated by a combination of in vitro, in situ and in vivo experiments. 2. Incorporation of octreotide into lipid monolayers (as measured by area increase of the monolayer at constant surface pressure using a Langmuir-Blodgett trough set-up) depended on the type of bile salt used for monolayer pre-treatment. Addition of 20 microM octreotide to the subphase containing 20 microM of the dihydroxylated bile salt ursodeoxycholate (UDCA) causes a 9% increase in area, whereas addition of octreotide to the subphase containing the 7 alpha-enantiomer of UDCA, chenodeoxycholate (CDCA), resulted in an area increase of the lipid monolayer of 20%. Area increase by octreotide alone was not significantly different from the increase of octreotide and UDCA in combination. 3. CDCA and UDCA in combination with octreotide increased the permeability of liposomal membranes for rubidium ions, whereas octreotide alone did not significantly change the permeability. This indicates membrane distortion as a possible cause for the enhanced absorption of octreotide by bile salts. 4. In polarized Caco-2 cell monolayers octreotide exhibited a permeation coefficient of 0.008 +/- 0.004 cm h-1. Addition of 0.2-1% of UDCA to the apical incubation medium had no significant effect upon the permeation coefficient. In contrast, 0.2-1% CDCA in the incubation medium resulted in a significant increase (P < 0.05) of the monolayer permeability of octreotide (0.015-0.037 cm h-1). 5. Octreotide was absorbed as the intact peptide from the gastrointestinal tract in rats with an absorption efficiency of 0.26%. Coadministration of bile salt resulted in a dose-dependent increase in absorption efficiency of the peptide up to 20.2%. The observed effect was more pronounced for CDCA than for UDCA. 6. The effect of CDCA and UDCA on octreotide absorption in vivo was assessed in a pharmacokinetic study with healthy volunteers. After oral administration of 4 mg octreotide in the presence of 100 mg bile salt, an average bioavailability of the peptide of 1.26% was achieved in the presence of CDCA, whereas in the presence of UDCA a bioavailability of only 0.13% was reached. This difference was statistically significant (P < 0.01). 7. In conclusion, the co-administration of CDCA is able to enhance the enteral absorption of octreotide. The in vitro and in situ experiments were predictive for the observed effect in human subjects.

Adult↗
PubMed1996

Relevance of p-glycoprotein for the enteral absorption of cyclosporin A: in vitro-in vivo correlation.

1. The interaction of cyclosporin A (CyA) with p-glycoprotein during intestinal uptake was investigated by a combination of in vitro experiments with human Caco-2 cells and an intubation study in healthy volunteers. 2. CyA uptake into the cells was not saturable and exhibited only a low temperature sensitivity, suggesting passive diffusion. When the permeation of CyA across Caco-2 monolayers from the apical to the basolateral side was determined, overall transport had an apparently saturable component up to a concentration of 1 microM. At higher concentrations permeation increased over-proportionally. Calculation of the kinetic parameters of apical to basolateral permeation suggested a diffusional process with a KD of 0.5 microliter min-1 per filter, which was overlayed by an active system in basolateral to apical direction with a KM of 3.8 microM and a Jmax of 6.5 picomol min-1 per filter. 3. CyA permeation was significantly higher when the drug was given from the basolateral side as compared to the permeation from the apical side. Apical to basolateral transport of CyA was increased in the presence of vinblastine, daunomycin and a non-immunosuppressive CyA-derivative. All compounds inhibit p-glycoprotein-mediated transport processes. Basolateral to apical permeation of CyA showed a dose-dependent decrease in the presence of vinblastine. Permeation of daunomycin across Caco-2 cell monolayers was also higher from the basolateral to the apical side than vice versa. Basolateral to apical permeation was decreased in the presence of SDZ PSC 833 and cyclosporin A. 4. Western blot analysis of Caco-2 cells with the monoclonal antibody C219 confirmed the presence of p-glycoprotein in the used cell system. 5. When the absorption of CyA in the gastrointestinal (GI)-tract of healthy volunteers was determined, a remarkable decrease of the plasma AUC could be observed dependent on the location of absorption in the rank order stomach > jejunum/ileum > colon. The decrease in absorption exhibited a marked correlation (r = 0.994) to the expression of mRNA for p-glycoprotein over the GI-tract (stomach < jejunum < colon). 6. All data provide evidence that CyA is a substrate of p-glycoprotein in the GI-tract, which might explain the local differences and the high variability in cyclosporin absorption found in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Evidence for P-glycoprotein-modulated penetration of morphine-6-glucuronide into brain capillary endothelium.

1. Morphine-6-glucuronide is one of the major metabolites of morphine. The potent analgesic action of this compound together with its potential lower apparent toxicity in man, when compared with morphine, indicated its clinical importance. 2. Primary cultures of porcine brain capillary endothelial cells were used to study brain penetration of morphine-6-glucuronide. Biochemical characterization of the cell cultures revealed a marked enrichment in enzymatic activity of alkaline phosphatase (56 fold) and angiotensin converting enzyme (230 fold) as compared to whole brain tissue. By immunostaining the presence of vimentin, factor VIII, the tight junction associated protein ZO-1, and P-glycoprotein was shown. Functional characterization revealed that the carrier system responsible for transport of neutral amino acids was intact. 3. Uptake and transport of morphine-6-glucuronide was marginal and in the range of the extracellular marker sucrose. However, uptake of morphine-6-glucuronide was enhanced significantly (P < 0.0001) in presence of the inhibitors of P-glycoprotein, verapamil or vincristine. The finding that morphine-6-glucuronide may serve as a substrate for P-glycoprotein was confirmed in multidrug-resistant P388 tumour cells. 4. We conclude that penetration of the blood-brain barrier by morphine-6-glucuronide may depend on the expression of the product of the multidrug-resistance (MDR) gene in brain capillary endothelial cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Rapid and highly automated determination of morphine and morphine glucuronides in plasma by on-line solid-phase extraction and column liquid chromatography.

A high-performance liquid chromatography (HPLC) method has been developed for the determination of morphine and its main metabolites, morphine-6-glucuronide (M-6-G) and morphine-3-glucuronide (M-3-G), in plasma or cerebrospinal fluid. Samples were extracted using on-line solid-phase extraction followed by reversed-phase HPLC with fluorescence detection. Recoveries of 20 ng morphine and morphine glucuronides in plasma were over 95%. The limit of detection using 400 microliters of a biological matrix was 0.85, 3.4 and 1.0 ng/ml of M-3-G, M-6-G and morphine, respectively. Inter- and intra-day assay precision was better than 10%. The main advantages of the present described method are increased recoveries (> 95%) and a high degree of automation allowing a high speed in routine analysis. The time required for the fully automated analysis of one sample was less than 26 min.

Automation↗
PubMed1995

Perioperative administration of caffeine tablets for prevention of postoperative headaches.

Interruption of daily caffeine consumption can cause caffeine withdrawal headache. As headache ranks among the most frequent minor postoperative sequelae, the impact of perioperative substitution of caffeine on the incidence of postoperative headache was evaluated. Forty patients undergoing minor surgical procedures with general anaesthesia were randomly allocated to receive either placebo or caffeine tablets at a dosage equal to their individual average daily caffeine consumption. Daily dietary intake was calculated based on an average week-day consumption using conversion factor from previously published sources. The patients were instructed at the preoperative visit to abstain from all external sources of caffeine. Compliance with these dietary restrictions was verified by blood samples obtained immediately before the surgical procedure and on postoperative day 1. The patients were assessed for headache using a standardised checklist immediately before induction of anaesthesia, on the evening of the day of surgery and on the morning of postoperative day 1. Ten patients (50%) who received placebo reported headaches, which persisted in seven patients (35%) until the next day. No patient receiving caffeine substitution therapy reported headache following surgery, and only one complained of headache on postoperative day 1. We suggest that the prophylactic administration of caffeine tablets might be considered for surgical patients who are accustomed to a high daily intake of caffeine.

Adult↗
PubMed1995

Conservative therapy of female genuine stress incontinence with vaginal cones.

OBJECTIVE: The objective was to analyse urodynamic data before and after conservative treatment with vaginal cones. STUDY DESIGN: The design was an open clinical study and was carried out at the Urogynaecology Unit of the University women's hospital. Eighteen women with genuine urinary stress incontinence were treated with vaginal cones for 6 weeks. Cystometry was performed before and after conservative therapy. The patients' subjective improvement and the urodynamic data have been compared. The Mann-Whitney U-test was used for statistical analysis. RESULTS: Of eighteen women with cone therapy, eight were continent after 6 weeks and showed a significant increase of the dynamic urethral closure pressure. Seven patients reported a subjective improvement, and in three women no change of stress incontinence was observed Colposuspension was performed at a later date in these three cases. CONCLUSION: Vaginal cone therapy is a successful method to cure mild female stress incontinence and has the advantage of avoiding incontinence operation. Therapeutic success can be assessed by urodynamic evaluation.

Adult↗
PubMed1995

Transient neurologic symptoms after spinal anesthesia.

We recently reported several cases consistent with transient radicular irritation after spinal anesthesia with hyperbaric 5% lidocaine. The present prospective, blind, nonrandomized study was performed to determine the incidence of these transient neurologic symptoms and to identify factors that might be associated with their occurrence. We studied 270 patients scheduled for gynecologic or obstetric procedures under spinal anesthesia. For spinal anesthesia, either 5% lidocaine in 7.5% glucose or 0.5% bupivacaine in 8.5% glucose was used. Patients were evaluated on postoperative day 3 by a quality assurance nurse who was unaware of the drug given or details of the anesthetic technique. Transient neurologic symptoms were observed in 37% of patients receiving 5% lidocaine, whereas only one patient receiving 0.5% bupivacaine had transient hypesthesia of the lateral aspect of the right foot. These results suggest that symptoms were the result of a specific drug effect. However, because of the limitations of the study one cannot conclude that lidocaine per se was the cause.

Adolescent↗
PubMed1995

Enteral absorption of octreotide: modulation of intestinal permeability by distinct carbohydrates.

Distinct carbohydrates influenced the in vitro permeation of the somatostatin analogue octapeptide octreotide through Caco-2 cell monolayers. Apical addition of 20 mM D-glucose or D-xylose resulted in a 2.3- or 3.4-fold increased octreotide permeation, respectively. However, supplementation with 20 mM L-glucose or 20 mM D-fructose showed no permeation enhancement. Basolateral addition of D-glucose or D-xylose had no significant effect on octreotide permeation. Apical medium supplementation with D-glucose or D-xylose increased permeation of the extracellular marker [14C]polyethylene glycol 4000, indicating that both carbohydrates directly affected the paracellular route of octreotide absorption. Presence of 1 mM phlorizin decreased octreotide permeation through monolayers in the presence of glucose on average by 12.8%, suggesting that the Na(+)-dependent glucose cotransporter might be partially involved in the enhancement of the absorption process of octreotide. Octreotide was absorbed from ligated jejunal loops of rat small intestine with an absolute absorption efficiency of about 0.3%. Coadministration of D-glucose of D-xylose resulted in a 2.2- or 1.9-fold increased absorption of octreotide, whereas D-fructose showed no effect. When the peptide was given in the presence of glucose and 1 mM phlorizin, a significant reduction of absorption enhancement could be observed. Phlorizin did not inhibit octreotide absorption, when the peptide was given in the absence of glucose. The data suggest that in vivo the active transepithelial flux of solutes such as glucose contributes to the enhancement of peptide absorption.

Animals↗
PubMed1994

Effect of intravenous human gastrin-releasing peptide on food intake in humans.

BACKGROUND/AIMS: Bombesin and gastrin-releasing peptide (GRP) are closely related peptides. Both have been proposed to serve as a satiety signal in animals. METHODS: To explore further the role of GRP in humans, its effects on satiety and eating behavior were investigated by infusion of GRP into healthy men at three dosages (10, 40, and 160 pmol/kg per hour) and compared with saline infusions. RESULTS: GRP produced a significant reduction in calorie intake (P < 0.05) but only a 19% (nonsignificant) reduction in food intake. Fluid ingestion was not affected by GRP. No overt side effects were produced by GRP, but subjects experienced d less hunger and early fullness in the premeal period during GRP infusion but not when receiving saline (P < 0.05-0.01). CONCLUSIONS: This study shows that intravenous infusions of GRP can decrease spontaneous food intake at concentrations that produce physiological effects, such as stimulation of acid or pancreatic secretion or gallbladder contraction. The data imply that GRP-like peptides can act as satiety signals in humans, confirming data previously reported in animals.

Adult↗
PubMed1994

Are laboratory values in bone marrow aspirate predictable for venous blood in paediatric patients?

In an emergency situation, early laboratory results are important, but often difficult to obtain. If venous access cannot be established, the intraosseous route may be used as an alternative. This study investigated the predictive value of bone marrow aspirate in performing laboratory studies. Thirty children underwent general anaesthesia for bone marrow aspiration (iliac crest) for oncologic or haematologic reasons. The aspirate and a peripheral venous blood sample, which was obtained simultaneously, were subjected to different laboratory tests and the results were compared by means of confidence interval analyses of the individual ratios of venous/bone marrow values. Based on these analyses, a high predictability of bone marrow values were found for haemoglobin, sodium, chloride, glucose, bilirubin, urea, creatinine, pH, and standard bicarbonate. Moderate, but clinically useful predictability was found for haematocrit, potassium, and total protein, while bone marrow values of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, PCO2, PO2, thrombocytes and leukocytes were systematically different from values in venous blood. Our data suggest that the intraosseous route is not only an important emergency alternative to intravenous access for administering fluids and drugs but may also serve as a reliable alternative for obtaining initial diagnostic laboratory studies when intravascular access is not obtainable.

Analysis of Variance↗
PubMed1994

Genetic effects on the variability of the halothane and caffeine muscle contracture tests.

BACKGROUND: The spectrum of the clinical presentation of malignant hyperthermia (MH) and the results of recent linkage studies suggest that there is a degree of heterogeneity in MH susceptibility. In the current study, we analyzed in vitro muscle contracture tests from members of large families with MH to evaluate if the results of these tests could be related to genetic influences. METHODS: Forty-seven subjects from four families with an MH-related death and with at least five clinically MH-susceptible individuals per family, as diagnosed by an in vitro muscle contracture test according to the protocol of the European MH Group, were included in the current analysis. We compared the strength of muscle contractures to challenges of halothane, caffeine, or both and the effect of these two drugs on twitch potentiation in response to supramaximal electrical stimulation among the families. RESULTS: Clinical MH susceptibility was confirmed in 36 individuals, and 11 individuals were diagnosed as MH-negative. In MH-susceptible individuals, muscle contractures to the 2% halothane challenge were significantly higher in family 1 (n = 15; 16.2 +/- 2.9 mN, mean +/- standard error of the mean) and in family 4 (n = 5; 16.4 +/- 5 mN) than in family 2 (n = 9; 5.8 +/- 1.5 mN) or family 3 (n = 7; 6.0 +/- 1.1 mN). Muscle contractures to the caffeine challenge (2 mM) were significantly increased in family 1 (7.3 +/- 1.4 mN) compared with those in family 3 (1.3 +/- 1.0 mN). In addition, we found a dose-dependent twitch potentiation to the halothane challenge in family 2 (P < 0.01) and to the caffeine challenge in families 2 (P < 0.001) and 3 (P < 0.01), whereas there was no twitch potentiation in families 1 and 4. CONCLUSIONS: The differences of in vitro muscle contracture tests among several families with MH provide evidence for genetic influences on the variability of this test procedure. However, it is not known if the observed differences are caused by heterogeneity of the MH gene mutation(s) or by other genetic factors that might modify muscle contractures in vitro.

Adult↗
PubMed1994

Effects of ondansetron in the prevention of postoperative nausea and vomiting in children.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a commonly observed adverse effect of general anesthesia. Recently, ondansetron, a new serotonin3 (5-hydroxytryptamine3) receptor antagonist was shown to be effective in the prophylaxis and prevention of chemotherapy-induced nausea and vomiting in children and adults as well as of PONV in adults. The aim of the current study was to evaluate the capacity of ondansetron to prevent PONV in pediatric patients. METHODS: Two hundred children (132 boys and 68 girls) 2-10 yr of age received general inhalational anesthesia for surgical procedures (the extremities; ear, nose, and throat; inguinal hernia and phimosis; and dentistry) of an expected duration of less than 90 min. This study was divided into two phases: prophylaxis and rescue treatment. For prophylaxis, patients were randomly assigned to two groups: one group received an intravenous injection of 0.1 mg/kg ondansetron, and the other group received a placebo before surgical incision under double-blind conditions. For rescue treatment, only placebo patients were included; as a rescue medication they received an intravenous injection of 0.1 mg/kg ondansetron or 0.02 mg/kg droperidol according to a prestudy randomization under double-blind conditions. Incidence and severity of PONV (PONV score 0 = no nausea and no retching; 1 = complaining of sickness and retching; 2 = vomiting one or two time in 30 min; 3 = vomiting more than two times in 30 min) was recorded over a 4-h period in the postanesthesia care unit. Within 72 h of the procedure, a follow-up nurse interviewed the parents for late-onset nausea in the children. RESULTS: With regard to prophylaxis, 10% of patients receiving ondansetron had PONV during the 4-h observation period versus 40% of those receiving placebo (P < 0.001). The incidence of vomiting alone (PONV score > or = 2) was 5% and 25%, respectively (P < 0.001). There were no significant differences between ondansetron and droperidol in the treatment of PONV. However, at the end of the 4-h period, ondansetron patients were less sedated than were patients who had received droperidol (P < 0.01). Interviews with parents could be performed for 143 of 200 children (76 ondansetron and 67 placebo). Twenty-four children (15 ondansetron and 9 placebo) showed late-onset PONV after the 4-h observation period but within 24 h of the procedure (19.7% vs. 13.4%; P not significant). CONCLUSIONS: Ondansetron is effective in the prevention of PONV in pediatric patients for the first 4 h after general anesthesia. Lower sedation scores with ondansetron compared with droperidol may be an advantage, especially in ambulatory surgery. However, the incidence of late-onset PONV (> 4-24 h) was not influenced by prophylactic treatment with one dose of ondansetron preoperatively.

Anesthesia, General↗
PubMed1994

Teaching fibreoptic intubation in anaesthetised patients.

One hundred ASA grade 1 and 2 patients requiring orotracheal intubation for various general surgical procedures were randomly assigned to receive either expert rigid laryngoscopic or novice fibreoptic orotracheal intubation under total intravenous anaesthesia. Five anaesthesia residents in the 4th year, with no prior experience in fibreoptic laryngoscopy, participated in a fibreoptic training course, viewing two instructional videos and practising on the intubation manikin. Each resident intubated 20 patients in a randomised fashion either as an expert laryngoscopist or as a fibreoptic novice. The time (SEM) to achieve successful intubation was statistically different for fibreoptic and rigid intubation (77.2 (5.1) s vs 17.7 (1.6) s, p < 0.01). The time to achieve successful rigid laryngoscopic intubation remained constant over the ten intubations, whereas time required for fibreoptic intubation decreases significantly (p < 0.01). The learning objectives (fibreoptic intubation times in 60 s or less and with 90% or greater success rate on the first intubation attempt) were met by all residents. The haemodynamic profile was similar for fibreoptically intubated and conventionally intubated patients and there was no difference between the first two or the last two fibreoptic or rigid intubations. The study was designed to detect a difference of 10% in means (assuming alpha = 0.05 and beta < or = 0.2). The incidence of postoperative sore throat, dysphagia or hoarseness was similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Circulating somatostatin-28 is not a physiologic regulator of gastric acid production in man.

Studies were designed to establish the acid inhibitory potency and plasma kinetics of somatostatin-28 (S-28) in humans and to determine whether the amount of S-28 released into the circulation after a meal is sufficient to regulate gastric acid secretion. A liquid meal induced a significant increase of S-28 (P < 0.01) whereas S-14 levels did not change. Postprandial S-28 concentrations were then mimicked by exogenous infusions and tested on basal and pentagastrin-stimulated gastric acid secretion. Expressed in terms of circulating plasma concentrations measured by specific radioimmunoassays, S-14 was 10 times more potent than S-28 in inhibiting gastric acid production. The plasma half-life of S-28 (1.86 min) was longer than that of S-14 (1.00 min) due to a slower plasma clearance rate. S-28 did neither affect basal and stimulated gastric acid secretion nor postprandial intragastric acidity. These studies suggest that postprandial plasma concentrations of S-28 are unlikely to regulate gastric acid secretion in man. They also show that S-28 is several times less potent than S-14 with respect to inhibition of gastric acid output.

Adult↗
PubMed1994

Comparison of spinal and epidural anesthesia for patients younger than 50 years of age.

To evaluate the respective clinical value of spinal anesthesia with 24-gauge Sprotte needles and epidural anesthesia for younger subjects, 202 patients younger than 50 yr were assigned randomly to undergo one of these two techniques for orthopedic, vascular, urologic, or plastic surgery. Failed blocks occurred in 5% in each group. Spinal anesthesia resulted in significantly less time to achieve sufficient spread of block; a significantly lower incidence of incomplete sensory block at level L5/S1, incomplete motor block, and pain during surgery; and a significantly lower incidence of postlumbar puncture backache (11% vs 30% after epidural anesthesia). The incidence of postdural puncture headache (PDPH) in the spinal and epidural groups was 7% and 4%, respectively (P = not significant), and patient satisfaction was 97% and 93% (P = not significant). Our results demonstrate the effectiveness of both techniques in younger patients, but show that the spinal technique is associated with fewer limitations, suggesting that factors other than PDPH should be considered when choosing between these two techniques.

Adolescent↗
PubMed1994

Assessment of gastric acid output by H2 breath test.

BACKGROUND: The standard method to measure gastric acid secretion is the aspiration of gastric juice. A noninvasive breath test after application of magnesium has been proposed. The aim of this study was to modify the method, to possibly improve the discriminatory value of the test in comparison with intubation tests. METHODS: We measured the time course of the reaction of magnesium and gastric acid in vitro and determined the gastric hydrogen kinetics in humans by insufflation of hydrogen into the stomach and measuring its reappearance in the exhaled air. Thereafter, a comparison of the breath test and the intubation test was done in 10 healthy volunteers in different secretory states. RESULTS: After hydrogen insufflation 31.4% reappeared in 90 min (16.3% exhaled, rest belched). Discriminant analysis showed that the intubation test had a good discriminatory power. On the other hand, the breath test failed to distinguish between different secretory states (stimulation, inhibition, and intermediate). CONCLUSION: Whereas the intubation test discriminated between high and low acid secretion, the breath test did not. This test therefore seems, at least as performed here, unsuitable as a diagnostic test of gastric acid secretion.

Adult↗
PubMed1993

In vitro-in vivo correlation for modified-release formulations.

A correlation of in vitro dissolution rate measurements with in vivo pharmacokinetic results in a human study was obtained for a sustained-release formulation of bromocriptine. Different methods were applied to reach this correlation, and the various outcomes were compared.

Adult↗