[Chronic motility disorders of the upper gastrointestinal tract in the elderly. Pharmaceutical, endoscopic and operative therapy]. / Chronische Motilitätsstörungen des oberen Gastrointestinaltrakts im Alter. Medikamentöse, endoskopische und operative Therapien.

Primary motility disorders of the upper gastrointestinal (GI) tract result from an impairment of the motor function of the esophagus, stomach, and duodenum by malfunction of the enteric nervous system or degeneration of the gastrointestinal muscle layer. Other forms of upper GI motility disorders occur secondary to underlying systemic diseases. The exact pathophysiology of the disturbances within the enteric nervous system of the upper GI tract is not yet clearly understood. For motility disorders resulting from systemic diseases the lack of knowledge with respect to the underlying pathomechanism is even greater. The term functional dyspepsia summarizes some symptoms of the upper abdomen, suggesting a disorder of upper GI motility or perception; however, this link to disturbed physiology has never been convincingly demonstrated. This overview describes therapeutic options for motility disorders of the upper GI tract regarding medicinal, endoscopic and surgical targets. The efficacy of medicinal therapy of upper GI motility disorders is low due to the lack of understanding of the pathophysiology. Therefore, endoscopic and other interventional therapies have to be applied also in the elderly patient group. The restrictions for metoclopramide published by the European Medicines Agency (EMA) in July 2013 have limited the armentarium of medicinal therapy of chronic motility disorders of the upper GI tract.

Are marketed topical metronidazole creams bioequivalent? Evaluation by in vivo microdialysis sampling and tape stripping methodology.

AIM: To evaluate the bioequivalence of 3 marketed topical metronidazole formulations by simultaneous dermal microdialysis and stratum corneum sampling by the tape stripping methodology, and to compare the techniques as tools for the determination of bioequivalence. METHODS: Nine microdialysis probes were inserted in the volar aspect of the left forearm of 14 healthy volunteers and, following application of the 3 metronidazole creams, microdialysis samples were collected for 5 h. On the right forearm, tape strip sampling was performed 30 and 120 min after product application. At the end of the experiment, ultrasound scanning measurements confirmed that all probes were placed inside the dermis. RESULTS: There was no statistical difference in penetration of the 3 topicals as determined by microdialysis. However, their bioequivalence could not be determined due to intersubject variability exceeding the criteria for bioequivalence evaluation. Tape strip sampling established a bioequivalence between 2 of the creams, but rejected any bioequivalence between these 2 formulations and the third. The third formulation was a generic formulation approved despite containing a lower concentration of metronidazole (0.75%) than the innovator formulation (1.0%). The result of the bioequivalence evaluation depends on the methodology employed. CONCLUSION: Whenever the dermis is the target tissue, microdialysis provides the most relevant information on drug bioavailability.

Targeted deletion of beta 1 integrins in F9 embryonal carcinoma cells affects morphological differentiation but not tissue-specific gene expression.

The integrin superfamily of heterodimeric transmembrane adhesion receptors mediates many cell-cell and cell-matrix interactions whose functions are believed to be critical for normal morphogenesis and differentiation. By eliminating the beta 1 integrin gene through homologous recombination, we have assessed the role of the beta 1 integrin family in the F9 embryonal carcinoma model for endodermal differentiation. F9 cells were unexpectedly found to maintain three copies of the beta 1 gene and complete elimination required three sequential rounds of targeting to generate triple knockout lines (beta 1 TKO). Elimination of the beta 1 integrin family of adhesion receptors from F9 cells resulted in reduced adhesion to fibronectin, laminin and collagen, but strongly enhanced adhesion to vitronectin. The absence of beta 1 integrins did not promote significant compensatory upregulation of either beta 3 or beta 5 subunits, both of which are known to act as vitronectin receptors when associated with alpha v. The loss of beta 1 integrins severely affected morphological differentiation when the beta 1-deficient cells were induced to differentiate to either parietal or visceral endoderm. Parietal endoderm derived from beta 1-deficient cells retained a rounded morphology and migrated poorly on both fibronectin and vitronectin. Visceral endoderm derived from beta 1-deficient cells were also unable to form a normal, confluent epithelial monolayer; instead, a non-contiguous layer containing clumps of disorganized cells was observed. However, loss of beta 1 integrins did not interfere with induction by differentiating agents of tissue-specific gene products for either visceral or parietal endoderm. These results suggest that beta 1 integrins mediate morphological differentiation (migration and epithelial formation) but not tissue-specific gene expression in induced F9 cells, and that these two processes are not necessarily linked in this system.

Combined intervention programme reduces inappropriate prescribing in elderly patients exposed to polypharmacy in primary care.

PURPOSE: To evaluate the effect of a combined or a single educational intervention on the prescribing behaviour of general practitioners (GPs). The primary endpoint was effect on inappropriate prescribing according to the Medication Appropriateness Index (MAI). METHODS: General practitioners were randomised to either (1) a combined intervention consisting of an interactive educational meeting plus feedback on participating patients' medication, (2) a single intervention with an interactive educational meeting or (3) a control group (no intervention). Elderly (>65 years) patients exposed to polypharmacy (>or=5 medications) were identified and approached for inclusion. Data on medications prescribed over a 3-month period were collected, and the GPs provided detailed information on their patients before and after the intervention. A pre- and post-MAI were scored for all medications. RESULTS: Of the 277 GPs invited to participate; 41 (14.8%) volunteered. Data were obtained from 166 patients before and after the intervention. Medication appropriateness improved in the combined intervention group but not in the single intervention group. The mean change in MAI and number of medications was -5 [95% confidence interval (CI) -7.3 to -2.6] and -1.03 (95% CI -1.7 to -0.30) in the combined intervention group compared with the group with the educational meeting only and the no intervention group. CONCLUSIONS: A combined intervention consisting of an interactive educational meeting plus recommendations given by clinical pharmacologists/pharmacists concerning specific patients can improve the appropriateness of prescribing among elderly patients exposed to polypharmacy. This study adds to the limited number of well-controlled, randomised studies on overall medication appropriateness among elderly patients in primary care. Important limitations to the study include variability in data provided by participating GPs and a low number of GPs volunteering for the study.

Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones secreted in response to meal ingestion, thereby enhancing postprandial insulin secretion. Therefore, an attenuated incretin response could contribute to the impaired insulin responses in patients with diabetes mellitus. The aim of the present investigation was to investigate incretin secretion, in obesity and type 1 and type 2 diabetes mellitus, and its dependence on the magnitude of the meal stimulus. Plasma concentrations of incretin hormones (total, reflecting secretion and intact, reflecting potential action) were measured during two meal tests (260 kcal and 520 kcal) in eight type 1 diabetic patients, eight lean healthy subjects, eight obese type 2 diabetic patients, and eight obese healthy subjects. Both in diabetic patients and in healthy subjects, significant increases in GLP-1 and GIP concentrations were seen after ingestion of both meals. The incretin responses were significantly higher in all groups after the large meal, compared with the small meal, with correspondingly higher C-peptide responses. Both type 1 and type 2 diabetic patients had normal GIP responses, compared with healthy subjects, whereas decreased GLP-1 responses were seen in type 2 diabetic patients, compared with matched obese healthy subjects. Incremental GLP-1 responses were normal in type 1 diabetic patients. Increased fasting concentrations of GIP and an early enhanced postprandial GIP response were seen in obese, compared with lean healthy subjects, whereas GLP-1 responses were the same in the two groups. beta-cell sensitivity to glucose, evaluated as the slope of insulin secretion rates vs. plasma glucose concentration, tended to increase in both type 2 diabetic patients (29%, P = 0.19) and obese healthy subjects (22% P = 0.04) during the large meal, compared with the small meal, perhaps reflecting the increased incretin response. We conclude: 1) that a decreased GLP-1 secretion may contribute to impaired insulin secretion in type 2 diabetes mellitus, whereas GIP and GLP-1 secretion is normal in type 1 diabetic patients; and 2) that it is possible to modulate the beta-cell sensitivity to glucose in obese healthy subjects, and possibly also in type 2 diabetic patients, by giving them a large meal, compared with a small meal.

Metronidazole clearance: a one-sample method and influencing factors.

After 96 administrations of metronidazole to 36 subjects, it was found that the clearance could be determined from one plasma sample, the dose, and a volume of distribution estimated from sex, age, body weight, and height, without loss of precision and accuracy compared with conventional clearance determinations (r greater than 0.97). In 230 sample pairs the plasma and saliva concentrations of metronidazole were identical (r = 0.99). In 119 subjects the one-sample clearance of metronidazole was unimodally distributed. Body weight (r = 0.28) and the alcohol consumption (r = 0.23) correlated with the metronidazole clearance. In the same subjects the consumption of tobacco (r = 0.28), alcohol (r = -0.19), coffee/tea (r = 0.27), age (r = -0.24), and sex (r = 0.28) correlated with the antipyrine clearance. The clearances of metronidazole and antipyrine were correlated (r = 0.34). The differential influence of the environmental factors on the elimination rates supports differential metabolism of metronidazole and antipyrine.

Antipyrine clearance in pneumonia.

Antipyrine clearance was estimated by a one-sample technique in 14 patients with acute fever and clinical pneumonia. Antipyrine clearance during the acute illness was 31.4 +/- 7.6 ml/min (X +/- SD). Fourteen and 28 days later during convalescence, clearance values were higher (47.8 +/- 18.9 and 49.2 +/- 15.0 ml/min, respectively). We conclude that microsomal hepatic drug metabolism in adults is impaired during pneumonia.

Pulmonary disease and antipyrine clearance.

We investigated hepatic microsomal enzyme activity by the one-sample saliva test for antipyrine clearance determination in 35 homozygous, alpha 1-antitrypsin-deficient outpatients with chronic pulmonary disease. Twenty-five outpatients with chronic obstructive lung disease and comparable lung function impairment and 31 healthy volunteers served as controls. Antipyrine clearance did not differ significantly between the two groups of patients with pulmonary disease. However, the clearance was 18% lower in these two groups than in the healthy volunteers (P less than 0.01). Antipyrine clearance was lowest in patients with severe lung function impairment (P less than 0.01).

Cimetidine clearance and bioavailability in hepatic cirrhosis.

Nine patients with compensated alcoholic and nonalcoholic cirrhosis of the liver and 11 patients with peptic ulcer received 200 mg of cimetidine orally and intravenously. No differences were observed in cimetidine clearance between the group with peptic ulcer (556 +/- 44 ml/min, mean +/- SEM) and the group with cirrhosis (606 +/- 64 ml/min). The bioavailability of cimetidine was unchanged (84 +/- 4% and 97 +/- 7%). In the patients with cirrhosis, cimetidine clearance did not correlate with galactose elimination capacity or antipyrine clearance. Cimetidine clearance was related to creatinine clearance only when both groups were considered. A reduction of cimetidine dose in patients with compensated cirrhosis appears unwarranted.

Thiopurine methyltransferase genotype distribution in patients with Crohn's disease.

BACKGROUND: Inter-individual response to azathioprine is partly due to inter-individual variation in the thiopurine methyltransferase (TPMT) activity. The TPMT genotype, which reflects the TPMT activity, has previously been studied in healthy Caucasians, with the most common variant allele being TPMT*3A. TPMT genotyping in adult patients with Crohn's disease has never been performed systematically. AIM: To determine the TPMT genotype distribution in adult patients with Crohn's disease. METHODS: One hundred and twenty randomly selected Danish patients (64 females and 56 males) with azathioprine-dependent Crohn's disease were included, and a polymerase chain reaction assay was used for TPMT genotyping. The patients were genotyped for the low-level genotype G460-->A and A719-->G transitions. RESULTS: One hundred and nine patients (90.3%; 95% confidence interval, 84.1-95.3) had a wild-type/ wild-type genotype, whereas 10 patients (8.3%; 95% confidence interval, 4.1-14.8) had one non-functional mutant allele and one patient (0.8%; 95% confidence interval, 0.02-4.6) had two non-functional mutant alleles. Only the TPMT*3A variant allele was found. CONCLUSIONS: The study showed a TPMT genotype distribution amongst adult Danish patients with Crohn's disease which was similar to the distribution of TPMT variant alleles normally found in healthy Caucasians.

Drug-induced hepatic disorders. Incidence, management and avoidance.

Drug-induced liver injury has been associated with more than 800 different drugs, leading to hospital admission in 1 of 600 to 3500 admissions. This amounts to 2 to 3% of all hospitalisations due to adverse drug reactions, or about 3% of all jaundiced patients. The prognosis of clinically overt drug hepatotoxicity is relatively serious. The clinical picture is essentially nonspecific, with a highly variable latency period from days to years. Drug hepatotoxicity can mimic almost any kind of liver disease. A thorough drug history, a low threshold of suspicion and the exclusion of other causes of liver disease are important for the detection of drug-induced liver disorders. Treatment consists of discontinuation of suspected drug(s), acetylcysteine in the course of paracetamol (acetaminophen) toxicity, and liver transplantation in selected cases of fulminant liver failure. Guidelines regarding the use of selected drugs such as methotrexate and halothane should be followed. Potentially hepatotoxic drugs should be used cautiously in alcoholic patients with or without liver involvement. Patients with uncompensated liver disease should receive a reduced dose of drugs adjusted to the degree of liver function impairment. The general public should be warned against abuse of hepatotoxic drugs such as paracetamol and anabolic steroids.

Beyond posttraumatic stress disorder: object relations and reality testing disturbances in physically and sexually abused adolescents.

OBJECTIVE: To evaluate posttraumatic stress disorder (PTSD) symptom severity, object (interpersonal) relations disturbances, and reality testing disturbances in a sample of physically and sexually abused adolescents. METHOD: Subjects were 37 students, 16 boys and 21 girls, enrolled at a private, residential school for children with various conduct problems. Students completed several psychological tests, including the Child Post-Traumatic Stress Disorder Reaction Index (CPTSD-RI) and the Bell Object Relations and Reality Testing Inventory. RESULTS: Of the 37 students, 22 (59.5%) had CPTSD-RI scores in the severe and the very severe ranges. The most common object relations and reality testing disturbances were insecure attachment and uncertainty of perception, respectively. CPTSD-RI scores were positively correlated with two of the four object relations scores (insecure attachment and egocentricity) and with all three reality testing scores (reality distortion, uncertainty of perception, and hallucinations/delusions). Mean CPTSD-RI scores were higher for students whose abuse had involved sex (sexual and physical abuse, sexual abuse only) than they were for students whose abuse had been physical only. Alienation and social incompetence, the two object relations disturbances not correlated with PTSD symptom severity, were associated with having experienced abuse at an early age and having been abused by a parent or stepparent (versus a nonparent). CONCLUSION: To address more effectively the long-term difficulties associated with child maltreatment, clinicians and clinician-investigators ought to evaluate interpersonal and reality testing disturbances, as well as PTSD symptom severity.

Congenital absence of the oval window: radiologic diagnosis and associated anomalies.

BACKGROUND AND PURPOSE: In most children with conductive hearing loss, acquired otitis media and/or middle ear effusion are ultimately diagnosed. Congenital conductive hearing loss is a rare condition; absence of the oval window is an unusual pathogenesis for this type of hearing impairment and can be associated with an anomalous horizontal facial nerve canal. Our goal was to describe the imaging features of congenital absence of the oval window, to determine the frequency with which anomalous development of the horizontal facial nerve canal occurs, and to review the developmental error responsible for this malformation. METHODS: Nine temporal bones in seven patients (5 to 36 years old) were found to have an inadequately formed oval window on high-resolution CT scans; seven ears showed complete lack of oval window formation, and two showed partial absence of the oval window. Records were reviewed for clinical information, and images were examined for associated anomalies. RESULTS: Six of nine ears with abnormal oval window formation showed malposition of the horizontal facial nerve canal. In each of these, the canal was abnormally low, overlying the expected location of the oval window; three of the canals lacked a visible bony covering. Seven of the nine ears were found to have a dysplastic or absent stapes. CONCLUSION: Congenital absence of the oval window can be diagnosed on CT studies. In the present series, this anomaly was associated with a grossly aberrant horizontal facial nerve canal in six of nine involved ears. Familiarity with the developmental sequence of oval window formation fosters an understanding of these anomalies. Preoperative recognition is important clinically, as a low facial nerve will block surgical access to the oval window and its presence will alter patient management.

Urea synthesis in patients with chronic pancreatitis: relation to glucagon secretion and dietary protein intake.

BACKGROUND & AIMS: Up-regulation of urea synthesis by amino acids and dietary protein intake may be impaired in patients with chronic pancreatitis (CP) due to the reduced glucagon secretion. Conversely, urea synthesis may be increased as a result of the chronic inflammation. The aims of the study were to determine urea synthesis kinetics in CP patients in relation to glucagon secretion (study I) and during an increase in protein intake (study II). METHODS: In study I, urea synthesis rate, calculated as urinary excretion rate corrected for accumulation in total body water and intestinal loss, was measured during infusion of alanine in 7 CP patients and 5 control subjects on spontaneous protein intake. The functional hepatic nitrogen clearance (FHNC), i.e. urea synthesis expressed independent of changes in plasma amino acid concentration, was calculated as the slope of the linear relation between urea synthesis rate and plasma alpha -amino nitrogen concentration. In study II, 6 of the patients of study I had urea synthesis and FHNC determined before and after a period of 14 days of supplementation with a protein-enriched liquid (dietary sequence randomized). RESULTS: Study I: Alanine infusion increased urea synthesis rate by a factor of 10 in the control subjects, and by a factor of 5 in the CP patients (P<0.01). FHNC was 31.9+/-2.4 l/h in the control subjects and 16.5+/-2.0 l/h (P<0.05) in the CP patients. The glucagon response to alanine infusion (AUC) was reduced by 75 % in the CP patients. The reduction in FHNC paralleled the reduced glucagon response (r(2)=0.55, P<0.01). Study II: The spontaneous protein intake was 0.75+/-0.14 g/(kg x day) and increased during the high protein period to 1.77+/-0.12 g/(kg x day). This increased alanine stimulated urea synthesis by a factor of 1.3 (P<0.05), FHNC from 13.5+/-2.6 l/h to 19.4+/-3.1 l/h (P<0.01), and the glucagon response to alanine infusion (AUC) by a factor of 1.8 (P<0.05). CONCLUSIONS: Urea synthesis rate and FHNC are markedly reduced in CP patients. This is associated with, and probably a result of, impaired glucagon secretion, and predicts a lower than normal postprandial hepatic loss of amino nitrogen. An increase in dietary protein intake increases alanine stimulated urea synthesis and FHNC by a mechanism that involves an increase in glucagon. This indicates that the low FHNC during spontaneous protein intake included an adaptation to the low protein intake, effectuated by a further decrease in glucagon secretion.

Harmonic grey scale imaging of the human brain.

Harmonic imaging increases the signal-to-noise ratio in grey-scale imaging. With the use of ultrasound contrast agents (UCA), imaging of brain perfusion seems possible. The authors used an ultrasound system in connection with a 1.8/3.6-MHz harmonic sector transducer and an acoustic densitometry unit for quantification of ultrasound intensity in the thalamus (THAL), the temporoparietal white matter (TPWM), and the lateral fissure (LF). Ten milliliters of BY963, a spherosome-air-based UCA, was injected intravenously in 12 healthy volunteers. Time-intensity curves were calculated. Mean increase of intensity (standard deviation [SD]), mean area under the time-intensity curve (AUC) from baseline (SD), and mean transit time (MTT) (SD) in the region of LF, THAL, and TPWM were 2.2 +/- 1.7, 1.1 +/- 0.6, 0.9 +/- 0.9 dB and 16.7 +/- 22.7, 4.7 +/- 4.7, 3.7 +/- 6.3 as well as 11.1 +/- 3.5, 9.7 +/- 3.1, and 11.9 +/- 8.0, respectively. There was a statistically significant difference for mean AUC (p = 0.02) but none comparing mean intensity increase (p = 0.07) and MTT (p = 0.9). The authors' study indicates that different regions of the human brain show different time-intensity curves. These results suggest that it is possible to measure parameters closely related to perfusion in various regions of the adult human brain.

High serum enalaprilat in chronic renal failure.

BACKGROUND: Most angiotensin-converting enzyme (ACE) inhibitors and their metabolites are excreted renally and doses should hence be reduced in renal insufficiency. We studied whether the dosage of enalapril in daily clinical practice is associated with drug accumulation of enalaprilat in chronic renal failure. METHODS: Fifty nine out-patients with plasma creatinine >150 micromol/L and chronic antihypertensive treatment with enalapril were investigated, in a cross-sectional design. RESULTS: Median glomerular filtration rate (GFR) was 23(range 6-60) ml/minute/1.73 m2. The daily dose of enalapril was 10 (2.5-20) mg and the trough serum concentration of enalaprilat was 31.8 (<2.5-584.7)ng/ml. Ninety percent of the patients had higher serum concentrations of enalaprilat than has been reported in subjects with normal kidney function, and a marked elevation of serum enalaprilat was observed in patients with GFR <30 ml/minute. All but three patients had serum ACE activity below the reference range. The ACE genotype did not influence the results. Additional pharmacokinetic studies were done in nine patients in whom GFR was 23 (10-42)ml/minute/1.73 m2. The median clearance of enalaprilat was 28 (16-68) ml/minute and correlated linearly with GFR (r=0.86, p=0.003). Intra-subject day-to-day variation in trough concentrations was 19.7%. CONCLUSION: Patients with chronic renal failure given small or moderately high doses of enalapril may thus have markedly elevated levels of serum enalaprilat. Whether this affords extra renoprotection, or on the contrary may inappropriately impair renal function, is not known, and should be investigated in prospective, controlled studies.

Tracheal ligation increases cell proliferation but decreases surfactant protein in fetal murine lungs in vitro.

Tracheal occlusion affects both fetal lung growth and maturation. The authors used a murine in vitro whole organ culture model to investigate these effects. The authors hypothesized that tracheal ligation would increase lung growth by increasing cell proliferation and would change surfactant protein synthesis in this system. Lungs were removed from day 14 gestation murine fetuses (term, 21 days). Tracheas were ligated and explants cultured in chemically defined, serum-free media for 1, 3, 4, 5, 7, or 14 days. DNA synthesis and cell division were assessed using a 5-bromo-2'-deoxy-uridine (BrdU) incorporation assay. Surfactant proteins A and B, markers of lung maturity, were detected using immunohistochemistry. Ligated lungs showed more BrdU-labeled cells per 1,000 x field (cells/hpf) at every time point. Ligated lungs on day 1 showed 27% more cells/hpf than unligated, on day 3, 21% more, on day 5, 54% more, on day 7, 60% more, and on day 14, 123% more (P < .05). In contrast, ligated lungs showed significantly less staining for surfactant proteins A and B than did unligated lungs. The authors conclude that tracheal ligation increases cell division but decreases surfactant protein in fetal murine lungs in vitro. These data suggest that although tracheal occlusion increases lung growth, it may decrease or delay lung maturation. This model provides a powerful tool for investigating the mechanisms underlying fetal lung development and tracheal occlusion-induced pulmonary hyperplasia.

Metronidazole elimination is preserved in the elderly.

1 The disposition of metronidazole and its major metabolites was compared in 11 subjects aged 86 +/- 6 years and 8 aged 30 +/- 6 years. 2 The plasma clearance of metronidazole was 1.20 +/- 0.53 and 1.25 +/- 0.22 ml min-1 kg-1, the volume of distribution 0.77 +/- 0.27 and 0.77 +/- 0.09 1 kg-1 and the half-life 7.8 +/- 1.9 and 7.2 +/- 0.9 h in elderly and young subjects, respectively (P less than 0.05). 3 The area under the plasma concentration-time curve of the hydroxy metabolite was 32 +/- 14 and 21 +/- 3 mM min-1 (P less than 0.05) whereas its half-life was 21 +/- 14 and 12 +/- 2 h (P less than 0.05) in the elderly and young subjects, respectively. 4 The recovery in the urine of metronidazole and its metabolites was 42 +/- 21% and 87 +/- 6% of dose in elderly and young subjects, respectively (P less than 0.05). With this reservation the only elimination pathways of metronidazole affected by old age were the renal excretion of unchanged compound and the hydroxy metabolite. 5 It is concluded that the ability to eliminate metronidazole is preserved in old age and that age-related dose adjustments are not necessary.

Multiple relationships: does the new ethics code answer the right questions?

The new "Ethical Principles of Psychologists and Code of Conduct" (American Psychological Association, 1992) presented expanded attempts to clarify the ethical issues regarding multiple relationships and to provide useful guidance for psychologists. This article proposes that the new code fails to address adequately two basic questions necessary to provide psychologists with clear guidance: (a) What are multiple relationships? and (b) When do multiple relationships constitute unethical conduct? The article offers a definition of multiple relationships and identifies several dynamics operating within a professional relationship that are likely to be adversely affected by the imposition of a secondary relationship. Unethical multiple relationships are defined. Finally, the article suggests additions to the new code that would enhance its utility for psychologists.

[Drug metabolism in the small intestine--the significance for biological availability]. / Tyndtarmens laegemiddelomsaetning--betydning for biotilgaengelighed.

The gut contains drug metabolizing enzymes and drug export proteins, of which the most important are CYP3A4 and P-glycoprotein. P-glycoprotein is localised to the apical membrane and CYP3A4 in the subapical cytoplasmic membranes in the enterocytes. The substrate and modulator specificity overlap between the two systems. The function of the two systems may be integrated. The intestinal first pass effect is the fraction of a drug which is metabolised or excreted during the absorption from the lumen. The significance of the intestinal first pass effect for the bioavailability of the three model drugs, midazolam, cyclosporin and digoxin, has been reviewed. The impact of different disease states in the gastrointestinal tract on the function of intestinal drug metabolising enzymes and P-glycoprotein is far from elucidated. Further insight into the function of these systems may lead to optimisation of drug therapy.