Jürgen Drewe

Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2

Glucagon-like peptide-1-(7-36) amide (GLP-1) is an incretin hormone of the enteroinsular axis. Recent experimental evidence in animals and healthy subjects suggests that GLP-1 has a role in controlling appetite and energy intake in humans. We have therefore examined in a double-blind, placebo-controlled, crossover study in 12 patients with diabetes type 2 the effect of intravenously infused GLP-1 on appetite sensations and energy intake. On 2 days, either saline or GLP-1 (1.5 pmol. kg-1. min-1) was given throughout the experiment. Visual analog scales were used to assess appetite sensations; furthermore, food and fluid intake of a test meal were recorded, and blood was sampled for analysis of plasma glucose and hormone levels. GLP-1 infusion enhanced satiety and fullness compared with placebo (P = 0.028 for fullness and P = 0.026 for hunger feelings). Energy intake was reduced by 27% by GLP-1 (P = 0.034) compared with saline. The results demonstrate a marked effect of GLP-1 on appetite by showing enhanced satiety and reduced energy intake in patients with diabetes type 2.Glucagon-like peptide-1-(7-36) amide (GLP-1) is an incretin hormone of the enteroinsular axis. Recent experimental evidence in animals and healthy subjects suggests that GLP-1 has a role in controlling appetite and energy intake in humans. We have therefore examined in a double-blind, placebo-controlled, crossover study in 12 patients with diabetes type 2 the effect of intravenously infused GLP-1 on appetite sensations and energy intake. On 2 days, either saline or GLP-1 (1.5 pmol ⋅ kg-1 ⋅ min-1) was given throughout the experiment. Visual analog scales were used to assess appetite sensations; furthermore, food and fluid intake of a test meal were recorded, and blood was sampled for analysis of plasma glucose and hormone levels. GLP-1 infusion enhanced satiety and fullness compared with placebo ( P = 0.028 for fullness and P = 0.026 for hunger feelings). Energy intake was reduced by 27% by GLP-1 ( P = 0.034) compared with saline. The results demonstrate a marked effect of GLP-1 on appetite by showing enhanced satiety and reduced energy intake in patients with diabetes type 2.

Drug-related problems in hospitals: a review of the recent literature.

Problems associated with pharmacotherapy (in particular, medication errors and adverse drug events) are frequent and are associated with increased costs for treatment.Analysis of original publications published between 1990 and 2005 on the topics of medication errors and/or adverse drug events in hospitalised patients, focusing on the frequency of, risk factors for and avoidance of such problems associated with pharmacotherapy, indicated that medication errors occurred in a mean of 5.7% of all episodes of drug administration, but with a high variability among the 35 studies retrieved. This variability was explained by the methods by which medication errors were detected (systematic screening of patients versus chart review or spontaneous reporting) and by the way drugs were administered (intravenously administered drugs are associated with the highest error frequencies). Errors occurred throughout the whole medication process, with administration errors accounting for more than half of all errors. Important risk factors included insufficient pharmacological knowledge of health professionals, errors in the patient charts or documentation by nurses and inadequate pharmacy services.Adverse events or reactions, on the other hand, affected 6.1 patients per 100 hospitalised and also showed a high variability among the 46 studies retrieved. This variability could also be explained by the different methods of assessment of the frequency of adverse drug events or reactions, as well as by the different wards on which the studies were performed. Important risk factors for adverse drug events or reactions included polypharmacy, female sex, drugs with a narrow therapeutic range, renal elimination of drugs, age >65 years and use of anticoagulants or diuretics.Since medication errors are strong risk factors for preventable adverse drug events or reactions, strategies have to be put in place for their reduction. Such strategies include ensuring that all persons involved in the medication process (nurses, pharmacists and physicians) have good pharmacological knowledge, computerisation of the entire medication process, and the engagement of a sufficient number of clinical pharmacists on the wards.

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. (Anesth Analg 1995;81:1148-53)

Neuroimaging predictors of transition to psychosis : a systematic review and meta-analysis

OBJECTIVES In early stage psychosis research the identification of neurobiological correlates of vulnerability to schizophrenia is an important hurdle. METHODS We systematically reviewed the neuroimaging publications on high-risk subjects with subsequent transition to psychosis (HR-T) and conducted a meta-analysis calculating the effect size Cohens d. RESULTS Out of 30 identified studies 25 met the inclusion criteria. Structural (s)MRI studies showed small to medium effect sizes of decreased prefrontal, cingulate, insular and cerebellar gray matter volume in HR-T compared to high-risk subjects without transition (HR-NT). Meta-analysis revealed relatively larger whole brain volumes in HR-T compared to HR-NT subjects (mean Cohens d 0.36, 95% CI 0.27-0. 46). Compared to HR-NT, HR-T subjects showed in functional imaging studies reduced brain activation in prefrontal cortex, reduced neuronal density, and increased membrane turnover in frontal and cingulate cortex with medium to large effect sizes. CONCLUSIONS Despite methodological differences between studies, structural and neurochemical abnormalities in prefrontal, anterior cingulate, medial temporal and cerebellar cortex might be predictive for development of psychosis within HR subjects.

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 μm. 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 μl min−1 per filter, which was overlayed by an active system in basolateral to apical direction with a KM of 3.8 μm 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, daunomcyin 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 (G***I)‐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 G**I‐tract (stomach < jejunum < colon). 6 . All data provide evidence that CyA is a substrate of p‐glycoprotein in the G***I‐tract, which might explain the local differences and the high variability in cyclosporin absorption found in vivo.

The human brain endothelial cell line hCMEC/D3 as a human blood-brain barrier model for drug transport studies

The human brain endothelial capillary cell line hCMEC/D3 has been developed recently as a model for the human blood‐brain barrier. In this study a further characterization of this model was performed with special emphasis on permeability properties and active drug transport. Para‐ or transcellular permeabilities (Pe) of inulin (0.74 × 10−3 cm/min), sucrose (1.60 × 10−3 cm/min), lucifer yellow (1.33 × 10−3 cm/min), morphine (5.36 × 10−3 cm/min), propranolol (4.49 × 10−3 cm/min) and midazolam (5.13 × 10−3 cm/min) were measured. By addition of human serum the passive permeability of sucrose could be reduced significantly by up to 39%. Furthermore, the expression of a variety of drug transporters (ABCB1, ABCG2, ABCC1–5) as well as the human transferrin receptor was demonstrated on the mRNA level. ABCB1, ABCG2 and transferrin receptor proteins were detected and functional activity of ABCB1, ABCG2 and the ABCC family was quantified in efflux experiments. Furthermore, ABCB1‐mediated bidirectional transport of rhodamine 123 was studied. The transport rate from the apical to the basolateral compartment was significantly lower than that in the inverse direction, indicating directed p‐glycoprotein transport. The results of this study demonstrate the usefulness of the hCMEC/D3 cell line as an in vitro model to study drug transport at the level of the human blood‐brain barrier.

HMG-CoA reductase inhibitors and P-glycoprotein modulation

Five 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitors (statins), (e.g. atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin), were investigated for their ability to reverse P‐glycoprotein (P‐gp) mediated rhodamine 123 (R123) transport in a murine monocytic leukaemia cell line that over‐expresses the multi‐drug resistance protein 1a/b (mdr1a/1b). P‐gp modulation was studied by a fluorimetric assay and confocal microscopy by means of R123 efflux and uptake experiments, respectively. Atorvastatin acid, methyl ester and lactone, lovastatin lactone and simvastatin lactone inhibited R123 transport in a concentration‐dependent manner. Lovastatin acid, simvastatin acid, fluvastatin and pravastatin did not show a significant inhibition of the R123 transport in our cell system. Atorvastatin methyl ester and lactone showed the highest affinities for P‐gp and results were comparable for both methods. In conclusion, monitoring of R123 transport in living cells by confocal microscopy in addition to fluorimetric assay is a sensitive tool to study P‐gp affinity in drug screening that is especially useful for early phases of drug development.

The Effects of Antipsychotics on the Brain: What Have We Learnt from Structural Imaging of Schizophrenia? – A Systematic Review

Despite a large number of neuroimaging studies in schizophrenia reporting subtle brain abnormalities, we do not know to what extent such abnormalities reflect the effects of antipsychotic treatment on brain structure. We therefore systematically reviewed cross-sectional and follow-up structural brain imaging studies of patients with schizophrenia treated with antipsychotics. 30 magnetic resonance imaging (MRI) studies were identified, 24 of them being longitudinal and six cross-sectional structural imaging studies. In patients with schizophrenia treated with antipsychotics, reduced gray matter volume was described, particularly in the frontal and temporal lobes. Structural neuroimaging studies indicate that treatment with typical as well as atypical antipsychotics may affect regional gray matter (GM) volume. In particular, typical antipsychotics led to increased gray matter volume of the basal ganglia, while atypical antipsychotics reversed this effect after switching. Atypical antipsychotics, however, seem to have no effect on basal ganglia structure.

HIV protease inhibitor ritonavir: a more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833

The effect of P-glycoprotein inhibition on the uptake of the HIV type 1 protease inhibitor saquinavir into brain capillary endothelial cells was studied using porcine primary brain capillary endothelial cell monolayers as an in vitro test system. As confirmed by polymerase chain reaction and Western blot analysis, this system functionally expressed class I P-glycoprotein (pgp1A). P-Glycoprotein isoforms pgp1B or pgp1D could not be detected. The uptake of saquinavir into endothelial cells could be described as the result of a diffusional term of uptake and an oppositely directed saturable extrusion process. Net uptake of saquinavir into cultured brain endothelial cells could be increased significantly up to 2-fold by SDZ PSC 833 in a dose-dependent manner, with an IC(50) of 1.13 microM. In addition, the HIV protease inhibitor ritonavir inhibited p-glycoprotein-mediated extrusion of saquinavir with an IC(50) of 0.2 microM, indicating a high affinity of ritonavir for p-glycoprotein. In conclusion, we showed that the HIV protease inhibitor ritonavir is a more potent inhibitor of P-glycoprotein than the multidrug resistance (MDR)-reversing agent SDZ PSC 833. The inclusion of this drug in combination regimens may greatly facilitate brain uptake of HIV protease inhibitors, which is especially important in patients suffering from AIDS dementia complex.

Dose adjustment in patients with liver disease.

Unfortunately, there is no endogenous marker for hepatic clearance that can be used as a guide for drug dosing. In order to predict the kinetic behaviour of drugs in cirrhotic patients, agents can be grouped according to their extent of hepatic extraction. For drugs with a high hepatic extraction (low bioavailability in healthy subjects), bioavailability increases and hepatic clearance decreases in cirrhotic patients. If such drugs are administered orally to cirrhotic patients, their initial dose has to be reduced according to hepatic extraction. Furthermore, their maintenance dose has to be adapted irrespective of the route of administration, if possible, according to kinetic studies in cirrhotic patients. For drugs with a low hepatic extraction, bioavailability is not affected by liver disease, but hepatic clearance may be affected. For such drugs, only the maintenance dose has to be reduced, according to the estimated decrease in hepatic drug metabolism. For drugs with an intermediate hepatic extraction, initial oral doses should be chosen in the low range of normal in cirrhotic patients and maintenance doses should be reduced as for high extraction drugs. In cholestatic patients, the clearance of drugs with predominant biliary elimination may be impaired. Guidelines for dose reduction in cholestasis exist for many antineoplastic drugs, but are mostly lacking for other drugs with biliary elimination. Dose adaptation of such drugs in cholestatic patients is, therefore, difficult and has to be performed according to pharmacological effect and/or toxicity. Importantly, the dose of drugs with predominant renal elimination may also have to be adapted in patients with liver disease. Cirrhotic patients often have impaired renal function, despite a normal serum creatinine level. In cirrhotic patients, creatinine clearance should, therefore, be measured or estimated to gain a guideline for the dosing of drugs with predominant renal elimination. Since the creatinine clearance tends to overestimate glomerular filtration in cirrhotic patients, the dose of a given drug may still be too high after adaptation to creatinine clearance. Therefore, the clinical monitoring of pharmacological effects and toxicity of such drugs is important. Besides the mentioned kinetic changes, the dynamics of some drugs is also altered in cirrhotic patients. Examples include opiates, benzodiazepines, NSAIDs and diuretics. Such drugs may exhibit unusual adverse effects that clinicians should be aware of for their safe use. However, it is important to realise that the recommendations for dose adaptation remain general and cannot replace accurate clinical monitoring of patients with liver disease treated with critical drugs.