Biomedical subjects

J Drewe

Publications and source records attributed to J Drewe.

At least 109 records · Page 6Linked to original sources

PubMed1993

In vitro effect of ephedrine, adrenaline, noradrenaline and isoprenaline on halothane-induced contractures in skeletal muscle from patients potentially susceptible to malignant hyperthermia.

We have measured the effects of ephedrine, adrenaline, noradrenaline and isoprenaline on halothane-induced contractures in muscle biopsies from patients potentially susceptible to malignant hyperthermia (MH). At concentrations of 4-24 mmol litre-1, ephedrine induced in vitro contractures in halothane 0.44 mmol litre-1-prechallenged muscle, whilst adrenaline, noradrenaline and isoprenaline had no effect. There was a shift of the ephedrine concentration-response curve to the left and an increased maximum muscle contracture in the MH susceptible group compared with the MH negative group (P < 0.001). We conclude that ephedrine increased halothane-induced muscle contractures in vitro either by an unknown pharmacological mechanism or by an adrenergic stimulation which was different from those of the other investigated adrenoceptor agonists.

Dose-Response Relationship, Drug↗

PubMed1993

Enteral absorption of octreotide: absorption enhancement by polyoxyethylene-24-cholesterol ether.

1. The somatostatin octapeptide-analogue octreotide was absorbed as an intact peptide from the gastro-intestinal tract with an absolute bioavailability of about 0.3% in rats. Administration of octreotide in the presence of polyoxyethylene (24)-cholesterol-ether (POECE) resulted in an about 23 fold increase of bioavailability. 2. In vitro studies with Caco-2 cells showed a dose-dependent increase in octreotide permeation with increasing doses of coadministered POECE. The use of [3H]-polyethyleneglycol (PEG) 4000 as an extracellular marker also indicated that higher doses of POECE may partly enhance paracellular transport of macromolecules. 3. By means of fluorescence microscopy it was shown that transepithelial transport of the fluorescent octreotide analogue (4-nitrobenzo-2-oxa-1,3-diazol [NBD] labelled octreotide) was enhanced by the addition of POECE. Besides an increased enterocyte uptake, there was evidence of enhanced partition of NBD-octreotide into the intercellular space between enterocytes after co-administration of POECE. In addition, there appeared to be changes in the hepatic topographic disposition of NBD-octreotide when it was given together with POECE compared with its administration alone. 4. In a study in healthy volunteers, 16 mg POECE significantly enhanced by 8 fold the absorption of octreotide after oral administration.

4-Chloro-7-nitrobenzofurazan↗

PubMed1993

Central nervous system symptoms after intravenous lignocaine: dose-response during pregnancy.

There is continuing controversy over what dose of what drug should be used to identify an accidental intravascular or subarachnoid catheter placement in obstetric epidural anaesthesia. The purpose of this randomized, double-blind study was to evaluate the dose-effect relationship for the production of central nervous system (CNS) symptoms by intravenous lignocaine. Sixty first-trimester, pregnant patients divided into groups of 10 received saline or one of five doses of lignocaine (0.39, 0.5, 0.63, 0.79, and 1.0 mg kg-1) i.v. An ED95 of 1.12 mg kg-1 was calculated to produce reliable CNS symptoms when injected intravascularly. Lignocaine is an effective and reliable marker for intravenous injection in pregnant women.

Abortion, Therapeutic↗

PubMed1992

Role of cholecystokinin in mediating GRP-stimulated gastric, biliary and pancreatic functions in man.

To explore the mechanisms of gastrin-releasing peptide (GRP)-induced gut functions in man, we investigated the effect on gallbladder contraction, exocrine pancreatic secretion and gastric acid secretion of a recently developed CCK receptor antagonist, loxiglumide, on GRP-stimulated effects in six healthy human subjects. Intravenous infusion of graded doses of synthetic human GRP (1-27 pmol/kg per h) caused significant and dose-dependent increases in pancreatic enzyme and gastric acid secretions and in gallbladder contraction. Intravenous administration of loxiglumide (10 mg/kg per h) abolished GRP-stimulated gallbladder contraction, augmented gastric acid secretion, but did not affect exocrine pancreatic secretion. The results suggest that endogenously released CCK is (1) responsible for GRP-stimulated gallbladder contraction, and (2) involved in regulating gastric acid secretion. The results further suggest that GRP-stimulated pancreatic secretion is not mediated by CCK, but has a direct response of GRP on the exocrine pancreas.

Adult↗

PubMed1992

Intracolonic bioavailability of human calcitonin in man.

Human calcitonin (hCT) injected into the lumen of the descending colon of normal human subjects was absorbed within minutes and could be recognized intact in plasma as shown by RIA in combination with reverse-phase HPLC. The absorption was low and variable, with bioavailabilities ranging from 0.01% to 2.7% relative to intravenously administered hCT (area under the concentration-time curve). With intravenous hCT serum calcium was lowered and the fractional urinary excretion of calcium, phosphorus, sodium and chloride was significantly stimulated. With the intracolonic hCT, the fractional urinary excretions of calcium, sodium and chloride were also marginally stimulated relative to intracolonic vehicle (placebo). In conclusion, hCT is absorbed intact from the colon, but the bioavailability is low and highly variable.

Adult↗

PubMed1992

Role of circulating cholecystokinin in control of fat-induced inhibition of food intake in humans.

Cholecystokinin (CCK) has been proposed to serve as a satiety signal in animals and humans. To further explore the role of CCK in humans, the effect on satiety and eating behavior of a specific CCK-receptor antagonist, loxiglumide, that preferentially inhibits peripheral (CCK-A) receptors was investigated. In a randomized, blind, four-period latin square design, 10 subjects received intravenous saline (placebo) or loxiglumide (10 mg/kg per hour) with concomitant intrajejunal perfusions of isotonic saline or fat (containing 50% corn oil and 3% albumin). Food intake and plasma CCK concentrations were assessed, and subjects scored their feelings of hunger and fullness in paired experiments. In placebo-treated subjects, the duration of the meal was shorter during fat perfusion (30 +/- 2 minutes vs. 35 +/- 2 minutes; P less than 0.01; mean +/- SEM). The amount of food intake was reduced (361 +/- 31 g vs. 454 +/- 35 g; P less than 0.05), and fluid ingestion was inhibited (490 +/- 31 mL vs. 625 +/- 38 mL; P less than 0.01). Loxiglumide did not affect any parameter and did not change the pattern of responses. In loxiglumide-treated subjects there was a 4-5-fold elevation in plasma CCK levels. These results confirm that jejunal infusion of lipid reduces the size of the meal and stimulates early satiety. The data imply that these effects are not mediated through peripheral endogenous CCK under these conditions.

Adult↗

PubMed1992

Tolerability and absorption enhancement of intranasally administered octreotide by sodium taurodihydrofusidate in healthy subjects.

Nasal sprays containing different concentrations of the somatostatin analogue octreotide and sodium tauro-24,25-dihydrofusidate (STDHF) as an absorption promoter were evaluated in two consecutive pharmacokinetic studies in healthy volunteers to characterize their bioavailability and local tolerability. The concentrations of STDHF were selected on the basis of a phase diagram generated by a dynamic laser light-scattering technique to ensure that the mixture was above the critical micellar concentrations. Compared to a 50-micrograms subcutaneous injection, the nasal spray formulation without STDHF had a mean relative bioavailability of 17.9%. For nasal formulations containing 3 and 1.65% (w/v) of STDHF, the bioavailability increased to 29.0 and 25.7%, respectively. The enhancement of nasal absorption was dependent on the STDHF concentrations as shown by decreasing the amounts to 1.2 and 0.8% (w/v) for tolerability reasons; the bioavailability was reduced to 15.3 and 20.5% in these cases, respectively. The local tolerability of all STDHF-containing sprays was poor, leading to stinging sensations and lacrimation. The poor local tolerability of the octreotide nasal spray containing different concentrations of STDHF required for effective nasal absorption enhancement appears to be impractical for further clinical development. These findings clearly stress the necessity to investigate tolerability and safety issues of new drug delivery systems in early developmental phases.

Administration, Intranasal↗

PubMed1992

Cardiovascular effects of fibreoptic oral intubation. A comparison of a total intravenous and a balanced volatile technique.

The cardiovascular response to fiberoptic oral intubation under total intravenous anaesthesia with propofol or a balanced volatile technique with thiopentone/enflurane was compared in 50 patients of physical status ASA 1 and 2 who were scheduled for elective ear, nose and throat surgery. Patients were randomly assigned to receive propofol or enflurane. There was no significant difference between the two anaesthetic techniques in haemodynamic profile either before, during or after fibreoptic intubation (the study design was adequate to detect a 20% difference with > 90% statistical power), in incidence of postoperative sore throat or in time taken for intubation. In no patient did the oxygen saturation decrease to below 95% or the CO2 tension exceed 5.8 kPa.

Adult↗

PubMed1992

The absorption site of cyclosporin in the human gastrointestinal tract.

1. An emulsion preparation of cyclosporin was administered locally to different parts of the small and large intestine by gavage: to the duodenum (opposite to the papilla of Vater), jejunum (150 cm distal to the teeth), ileum (300 cm distal to the teeth), and to the colon descendens (30 cm proximal to the anus). 2. The bioavailability of cyclosporin after these instillations was compared with that after oral administration of a hard gelatine capsule formulation. 3. Cyclosporin was found to be absorbed predominantly in the small intestine. This may have implications for dosage in patients with reduced absorptive surface area.

Adult↗

PubMed1992

Enhancement of the oral absorption of cyclosporin in man.

1. The oral absorption of cyclosporin from three new semi-solid oral formulations was compared with the standard soft gelatine preparation in twelve healthy male volunteers. One formulation was based on a solid micellar solution, while the other two, with different in vitro release properties, were based on a microemulsion principle. 2. The results showed that the solid micellar solution and the faster releasing microemulsion formulation increased the extent of absorption on average by 45.2 and 49.0%, respectively, compared with the reference soft gelatine capsule.

Administration, Oral↗

PubMed1992

Effect of halothane equilibration kinetics on in vitro muscle contractures for malignant hyperthermia screening.

In vitro muscle contracture tests for malignant hyperthermia screening are routinely performed using standardized protocols. In the present study on-line monitoring of halothane concentrations in the gas phase was demonstrated to be an improved test standard. The kinetics of halothane concentration and their effect on in vitro muscle contracture tests were evaluated in two test baths, I and II, which contained 3 and 18 ml Krebs-Ringer solution, respectively. The equilibration kinetics for halothane was significantly faster in bath I (t1/2 = 8.2 s) compared with bath II (t1/2 = 25.6 s). Twenty-one pairs of muscle bundles from 21 potentially malignant hyperthermia susceptible patients were investigated, each test bath receiving one bundle from each pair. The variance of muscle contractures was significantly increased in test bath I compared with test bath II. However, there was no influence on malignant hyperthermia diagnosis, suggesting that, within the ranges of t1/2 = 8.2 s-25.6 s, the test bath volumes need not be standardized.

Disease Susceptibility↗

PubMed1992

Enteral absorption of octreotide.

1. The somatostatin octapeptide-analogue, octreotide, is absorbed as intact peptide from the gastrointestinal (GI) tract. 2. In situ absorption experiments in rats confirmed our recent intubation studies in human volunteers demonstrating that the peptide has preferential absorption sites in the small intestine. Absorption of octreotide was higher in the jejunum than in the duodenum or the ileum. 3. Experiments with bile-duct cannulated rats demonstrated that the absorption of octreotide decreased in the presence of bile, reflecting a negative influence of biliary components on the absorption of the peptide. 4. Uptake experiments using rat jejunal brush border membranes were performed to analyse the absorption mechanisms. The transport of octreotide into jejunal brush border membranes was significantly higher than the uptake into membrane vesicles isolated from rat ileum. When initial uptake (0-15s) rates into the membrane vesicles were calculated as a function of the peptide concentration, a saturable component could be observed, indicative of transport mechanisms different from simple diffusion.

Animals↗

PubMed1992

Non-invasive assessment of gastrointestinal motility disorders in diabetic patients with and without cardiovascular signs of autonomic neuropathy.

Twenty six patients with insulin dependent diabetes mellitus underwent a gastric emptying test, a gall bladder contraction test, an orocaecal transit study, and a colon transit test. Eleven patients had signs of cardiovascular autonomic neuropathy, 15 patients were without signs of cardiovascular autonomic neuropathy. Mean gastric clearance of radioopaque markers ingested with a meal averaged 29.5 (2.3) markers per six hours in subjects without cardiovascular autonomic neuropathy compared with 17.8 (2.3) markers per six hours in patients with cardiovascular autonomic neuropathy (p < 0.02). Gall bladder emptying in response to graded CCK8 stimulation was impaired in five of 11 patients with cardiovascular autonomic neuropathy, whereas it was normal in the patients without cardiovascular autonomic neuropathy (p < 0.01). Oral caecal transit times were not significantly different in the two patient groups, whereas colonic transit was slower in the patients with cardiovascular autonomic neuropathy compared with the group without cardiovascular autonomic neuropathy (p < 0.02). There was no correlation between disturbed gastric clearance, impaired gall bladder contraction, and prolonged colonic transit time in the patients with cardiovascular autonomic neuropathy nor was there a correlation between any disturbed motor function and age or duration of diabetes. It is concluded that autonomic neuropathy can affect motor functions throughout the gastro-intestinal tract. Any disturbed motor function in the gut could therefore be one of the numerous expressions of diabetic neuropathy affecting the cardiovascular, the endocrine or the gastrointestinal system.

Adult↗

PubMed1991

[Diagnosis of susceptibility for malignant hyperthermia using in-vitro muscle contraction testing in Switzerland].

Malignant hyperthermia is a potentially fatal pharmacogenetic disorder triggered by volatile anesthetics (halothane, enflurane, isoflurane) and/or succinylcholine. The inheritance of malignant hyperthermia susceptibility is thought to be autosomal dominant and the incidence could be as high as 1:10,000. The only generally accepted diagnostic method at present involves a muscle biopsy followed by in-vitro halothane and caffeine contracture tests. 100 individuals from 45 families who were considered to be potentially malignant hyperthermia-susceptible were investigated from 1986 to 1990 by in-vitro muscle contracture tests using the protocol of the European Malignant Hyperthermia Group. Of 45 families analyzed, 28 had at least one person who was susceptible to malignant hyperthermia with a total of 64 malignant hyperthermia-susceptible individuals. 36 subjects in the 45 families were normal. In addition, our study shows that a femoral nerve block can be used in outpatients as a reliable anesthetic technique to perform biopsies from the vastus medialis muscle for malignant hyperthermia screening.

Adolescent↗

PubMed1991

Relevance of pH dependency on in vitro release of bromocriptine from a modified-release formulation.

Since pH profiles of the dissolution rate are thought to be predictive for the in vivo performance of oral modified-release formulations with respect to bioavailability and dose dumping with food, these pH profiles were established for a new modified-release (MR) formulation for bromocriptine (Parlodel SRO). The results show a marked decrease of bromocriptine dissolution with increasing pH of the dissolution medium. However, when measured in native human duodenal juice (pH 8.1), dissolution was significantly higher than when measured in buffer of comparable pH. In a human pharmacokinetic study, this MR formulation showed good bioavailability and no food effect on the pharmacokinetic profile. Therefore, pH profiles alone seem to have only a limited predictive power for the in vivo performance of this MR formulation for bromocriptine.

Bromocriptine↗

PubMed1991

Pharmacokinetics and pharmacodynamics of a new transdermal delivery system for bopindolol.

1. In two separate studies, each with 12 healthy male volunteers, the pharmacokinetic and dynamic properties of a transdermal delivery system for bopindolol were evaluated. 2. In study I it was shown that bopindolol absorption from a 14 mg patch occurred over the whole 7-day application period. No signs of a significant skin depot were found. 3. In study II, a linear pharmacokinetic behaviour but a non-linear kinetic/dynamic relationship was established for the patches over a dose range from 7 to 21 mg. Comparable peak effects of reduction in exercise-induced tachycardia were observed after different patch doses and an i.v. injection. However, the effect was significantly prolonged with the patches compared with the injection and was maintained over 7 days. 4. The patches showed a good local and systemic tolerability in both studies over a dosing interval of up to 7 days.

Administration, Cutaneous↗

PubMed1991

Helicobacter pylori infection in healthy people: a dynamic process?

Epidemiological studies using serological tests have shown that a large proportion of healthy people have antibodies against Helicobacter pylori (anti-Hp). It is uncertain whether the presence of anti-Hp indicates active infection or only past exposure to the micro-organism. In this study we determined anti-Hp with a specific enzyme linked immunosorbent assay in 100 healthy volunteers who were at the same time investigated for active H pylori infection by means of the 13C-urea breath test. Forty nine per cent had a high anti-Hp titre, but only 24% had active H pylori infection. Our study suggests that a considerable number of healthy people previously infected with H pylori have spontaneously eliminated this microorganism. We suggest that the inability of ulcer patients to eliminate H pylori may be important in the pathogenesis of peptic ulcer disease.

Adult↗

PubMed1990

Pancreatic secretory responses to long-term infusions of secretin and cerulein in humans.

We measured pancreatic enzyme and bicarbonate responses to graded doses of intravenous secretin or cerulein alone or together in healthy human subjects. Bicarbonate responses were steady and well maintained during the last 3.5 h of the 4 h of infusions of secretagogues, giving evidence for a constant pancreatic flow rate. Potentiation (more-than-additive response) was observed between secretin and cerulein for bicarbonate secretion, but not for enzyme secretion. Secretin stimulated pancreatic enzyme secretion. The effect was most pronounced with amylase secretion and less prominent with lipase, trypsin, and chymotrypsin secretion. Changes in the proportion of enzymes were seen over time, with trypsin and chymotrypsin output declining towards the end of cerulein infusion. We conclude that in humans the effects of secretin on pancreatic enzyme secretion are complex and include time-dependent changes in the enzyme mixture, but potentiation between secretin and cerulein does not occur for enzyme output.

Adult↗