[Interaction of opioid analgesics at the level of biotransformation]. / Interaktionen der Opioidanalgetika auf Ebene der Biotransformation.

Opioids are an important component of the drug treatment of patients with acute and chronic pain. They differ in effectiveness, side effect profile and the risk of interactions. In this article the pharmacokinetic mechanisms of drug-drug interactions at the level of biotransformation are described and the clinical consequences which can arise are discussed. The relation of the active components to the two isoenzymes CYP2D6 and CYP3A4 is of major importance for assessing the potential drug-drug interactions of opioid analgesics at the level of the cytochrome P450 enzyme.

[Chronic chest pain]. / Chronischer Brustschmerz.

BACKGROUND: Chest pain is a symptom commonly reported by persons in the general population and represents a differential diagnostic challenge. MATERIAL AND METHODS: The paper is based on a narrative review with a selective search of the literature in Medline for reviews and guidelines on the prevalence and treatment of non-malignant diseases with chronic chest pain in gastroenterology, gynecology and cardiology. RESULTS: The prevalence and current treatment recommendations for the different forms of gastroesophageal reflux disease (GERD), erosive and non-erosive types and irritable esophagus, non-cardiac chest pain, refractory angina in coronary heart disease and postmastectomy nand poststernotomy syndromes are presented. In cases of failure of the established therapy of a single medical discipline, an interdisciplinary assessment including psychosocial issues is recommended. Evidence-based guidelines are available for the management of GERD and of refractory angina. Treatment of postmastectomy and poststernotomy syndromes is based on case reports and expert opinion. CONCLUSION: There is a need for controlled studies on the symptomatic treatment of pain in irritable esophagus, non-cardiac chest pain, postmastectomy and poststernotomy syndromes.

[Improving medication safety]. / Verbesserung der Arzneimitteltherapiesicherheit.

Drug treatment is beneficial in most patients but can also cause adverse events and death. Since preventable adverse drug events are a relevant cause of morbidity and mortality, strategies for improving medication safety are warranted. Studies demonstrate that system failure is the most relevant cause of preventable adverse drug events, with prescribing errors being the most relevant. Lack of information either about the patient, the functioning of a patient's organs and concurrent medications, or about the prescribed drug, its correct dosing, contraindications and drug interactions often lead to preventable adverse drug events. International studies show that medication errors result in more people dying than from traffic accidents. Therefore, in addition to the safety of the drug, it is necessary that the safety of the process of drug treatment must be taken care of. This is called medicine safety. In order to improve medicine safety, it is necessary to consider the organization of the medication process, instead of looking for an individual to blame. The goal of the "Action Plan for Medication Safety in Germany" ("Aktionsplan Arzneimitteltherapiesicherheit für Deutschland") from the Federal Ministry of Health is to optimize patient safety in drug treatment by the joint efforts of physicians, pharmacists, patients, and politicians.

Reversal by NPY, PYY and 3-36 molecular forms of NPY and PYY of intracisternal CRF-induced inhibition of gastric acid secretion in rats.

1. The Y receptor subtype involved in the antagonism by neuropeptide Y (NPY) of intracisternal corticotropin-releasing factor (CRF)-induced inhibition of gastric acid secretion was studied in urethane-anaesthetized rats by use of peptides with various selectivity for Y1, Y2 and Y3 subtypes: NPY, a Y1, Y2 and Y3 agonist, peptide YY (PYY), a Y1 and Y2 agonist, [Leu31, Pro34]-NPY, a Y1 and Y3 agonist, NPY(3-36) and PYY(3-36), highly selective Y2 agonists and NPY(13-36) a weak Y2 and Y3 agonist. Peptides were injected intracisternally 10 min before intracisternal injection of CRF (10 micrograms) and gastric acid secretion was measured by the flushed technique for 1 h before and 2 h after pentagastrin-(10 micrograms kg-1 h-1, i.v.) infusion which started 10 min after CRF injection. 2. Intracisternal injection of CRF (10 micrograms) inhibited by 56% gastric acid secretion stimulated by pentagastrin. Intracisternal injection of NPY and PYY (0.1-0.5 microgram) did not influence the acid response to pentagastrin but blocked CRF-induced inhibition of pentagastrin-stimulated acid secretion. NPY(3-36) (0.5 microgram) and PYY(3-36) (0.25 and 0.5 microgram) also completely blocked the inhibitory action of CRF on pentagastrin-stimulated acid secretion. 3. [Leu31, Pro34]-NPY (0.5-5 micrograms) and NPY(13-36) (0.5-5 micrograms) injected intracisternally did not modify gastric acid secretion induced by pentagastrin or CRF inhibitory action. 4. The sigma antagonist, BMY 14802 (1 mg kg-1, s.c.) did not influence the acid response to pentagastrin but prevented the antagonism by PYY(3-36) (0.5 microgram) of the CRF antisecretory effect. 5. These results show that both PYY and NPY and the 3-36 forms of PYY and NPY are equipotent in blocking central CRF-induced inhibition of pentagastrin-stimulated gastric acid secretion. The structure-activity profile suggests a mediation through Y2 receptor subtype and the involvement of sigma binding sites.

Characterization of two forms of peptide YY, PYY(1-36) and PYY(3-36), in the rabbit.

Peptide YY (PYY) has been purified as a 36 amino acid peptide from intestinal extracts of several mammalian species including pig, rat, dog, and man. The primary structure of rabbit PYY is still unknown, although rabbit tissues have extensively been used for characterization of PYY receptor subtypes and receptor subtype-mediated actions. We report the purification and primary structure of PYY(1-36) (PYY-I) from rabbit intestinal mucosa, and the existence of a second endogenous molecular form of PYY, PYY(3-36) (PYY-II). The amino acid sequence of PYY-I is YPSKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY-amide. Rabbit PYY differs from porcine PYY, which is identical to rat and canine PYY, by two amino acid substitutions at positions 3 (Ser instead of Ala) and 18 (Asp instead of Ser), whereas rabbit PYY and human PYY differ by only one residue at position 3 (Ser instead of Ile). The existence of two endogenous forms of PYY in the rabbit, with PYY-II lacking the amino-terminal dipeptide Tyr-Pro of PYY-I, is consistent with previously reported findings, demonstrating the existence of PYY-II in man and dog (9,11). We have previously demonstrated that PYY-I is an unselective Y1/Y2 agonist, whereas PYY-II is a highly selective Y2 agonist. Thus, proteolytic processing of PYY-I controls the peptide's receptor selectivity. The existence of PYY-I and PYY-II in the rabbit supports the assumption of a physiological role of Y receptor heterogeneity for PYY.

A new molecular form of PYY: structural characterization of human PYY(3-36) and PYY(1-36).

A radioimmunoassay was developed using an antibody raised in rabbits against synthetic porcine PYY. This radioimmunoassay was used to detect PYY immunoreactivity in human intestinal extracts. Human colonic mucosa was extracted with acid, centrifuged and the supernatant concentrated by low pressure preparative reverse phase chromatography. A subsequent C-18 reverse phase HPLC step separated two peaks of PYY immunoreactivity. Each peak was purified by sequential steps of ion-exchange FPLC and reverse phase HPLC. In the final purification step single absorbance peaks were associated with PYY immunoreactivity. Microsequence, amino acid, and mass spectral analysis of the intact and tryptic fragments of the two peptides were consistent with the structures: YPIKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY-amide [human PYY(1-36)] and--IKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY-amide [human PYY(3-36)]. Human PYY(1-36) differs from porcine PYY only at position 3, with Ile instead of Ala, and position 18, with Asn instead of Ser. PYY(3-36) may differ in its biological activity from the intact peptide. Its high proportions in the colon suggest that it is released into the circulation where it could act as a partial antagonist of PYY(1-36).

Structural characterization of canine PYY.

PYY was purified from canine colonic mucosa by sequential steps of reverse phase HPLC and ion-exchange FPLC. Microsequence, amino acid and mass spectral analyses of the purified peptide and its tryptic fragments were consistent with the structure: YPAKPEAPGEDASPEELSRYYASLRHYLNLVTRQRY-amide. Canine PYY(1-36) has the identical sequence as porcine and rat PYY but differs from human PYY at position 3, with Ala instead of Ile, and position 18, with Ser instead of Asn. A smaller form, PYY(3-36), was also purified and characterized. It may differ in its biological activity from the intact peptide and could act as a partial antagonist or agonist of PYY(1-36).

Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV.

Neuropeptide Y, peptide YY and pancreatic polypeptide share an evolutionary conserved proline-rich N-terminal sequence, a structure generally known to be inert to the attack of common proteinases, but a potential target for specialized proline-specific aminopeptidases. Purified human dipeptidyl peptidase IV (also termed CD 26) liberated N-terminal Tyr-Pro from both, neuropeptide Y and peptide YY, with very high specific activities and Km values in the micromolar range, but almost no Ala-Pro from pancreatic polypeptide. Other proline-specific aminopeptidases exhibited low (aminopeptidase P, liberation of N-terminal Tyr) or totally no activity (dipeptidyl peptidase II), as was also observed with less-specific aminopeptidases (aminopeptidase M, leucine aminopeptidase). When human serum was incubated with neuropeptide Y or peptide YY at micro- and nanomolar concentrations, Tyr-Pro was detected as a metabolite of both peptides. Formation of Tyr-Pro in serum was blocked in the presence of Lys-pyrrolidine and diprotin A (Ile-Pro-Ile), specific, competitive inhibitors of dipeptidyl peptidase IV. Incubation of neuropeptide Y or peptide YY with immunocytochemically defined, cultivated endothelial cells from human umbilical cord also yielded Tyr-Pro. Dipeptidyl peptidase IV could be immunostained on most endothelial cells by a specific antibody. We suggest that dipeptidyl peptidase IV might be involved in the degradation of neuropeptide Y and peptide YY to N-terminal truncated neuropeptide Y(3-36) and peptide YY(3-36). Since specific binding to Y1, but not to Y2 subtype of neuropeptide Y/peptide YY receptors requires intact N- as well as C-termini of neuropeptide Y and peptide YY, removal of their amino-terminal dipeptides by dipeptidyl peptidase IV inactivates them for binding to one receptor subtype.

Two molecular forms of peptide YY (PYY) are abundant in human blood: characterization of a radioimmunoassay recognizing PYY 1-36 and PYY 3-36.

Two endogenous forms of PYY are abundant in man and dog, PYY 1-36 (PYY-I) and PYY 3-36 (PYY-II). PYY-II is a major molecular form of PYY in human colon, but it is not known, whether PYY-II is also released into the circulating blood. Several radioimmunoassays for measuring PYY-I in plasma have been developed, but it has not been reported, whether they equally detect PYY-II. We characterize a radioimmunoassay for measuring PYY in human plasma which equally recognizes PYY-I and PYY-II. Using this radioimmunoassay and reversed phase HPLC we demonstrate the existence of two forms of PYY in human blood, coeluting with synthetic PYY-I and PYY-II.

Neuropeptide Y 3-36 is an endogenous ligand selective for Y2 receptors.

Neuropeptide Y (NPY 1-36) binds to Y1 and Y2 receptors with similar affinity. No endogenous molecular form of NPY with selectivity for Y1 or Y2 receptors has been described so far. We report the presence of an endogenous fragment of NPY in porcine brain, NPY 3-36, which lacks the amino-terminal dipeptide Tyr-Pro of NPY 1-36. NPY 3-36 accounts for 35% of NPY-like immunoreactivity in porcine brain. We have compared binding of NPY 3-36 and NPY 1-36 in model systems of Y1-like (SK-N-MC cells) and Y2-like receptors (CHP234 cells). NPY 3-36 and NPY 1-36 had similarly high affinity for Y2-like receptors on CHP234 cells, but NPY 3-36 had a 1000-fold lower affinity than NPY 1-36 for Y1-like receptors on SK-N-MC cells. Thus amino-terminal cleavage of NPY 1-36 generating NPY 3-36 converts an unselective Y1/Y2 receptor ligand into a highly Y2 selective ligand. This may be a means of fine tuning NPY biological actions.

Peptide YY inhibits exocrine pancreatic secretion in isolated perfused rat pancreas by Y1 receptors.

Peptide YY (PYY) inhibits exocrine pancreatic secretion in several species. Two receptors, Y1 and Y2, are known to mediate PYY actions. While PYY 1-36 binds equally to both receptor subtypes, a second endogenous form of PYY, PYY 3-36, selectively activates Y2 receptors. The importance of Y receptor subtypes for inhibition of exocrine pancreatic secretion by PYY is unknown. We studied the effects of PYY 1-36 on cholecystokinin octapeptide (CCK-8)-stimulated amylase secretion in an isolated perfused rat pancreas model. To characterize functionally the receptors involved we determined the effects of a Y1-selective agonist, [Pro34]PYY; a Y2 selective agonist, PYY 3-36; and neuropeptide Y (NPY) in this model. PYY 1-36 significantly inhibited stimulated amylase secretion in the denervated rat pancreas. [Pro34]PYY and NPY both inhibited exocrine pancreatic secretion as potently as PYY 1-36. Contrary to that, the Y2 selective agonist, PYY 3-36, was inactive. We conclude that PYY inhibits exocrine pancreatic secretion in this extrinsically denervated rat pancreas model by Y1 receptors.

Inhibition of canine exocrine pancreatic secretion by peptide YY is mediated by PYY-preferring Y2 receptors.

It is still unclear, which receptor subtype, Y1 and/or Y2, mediates the inhibitory action of PYY on exocrine pancreatic secretion. The present study was undertaken to characterize functionally the Y receptor subtype that mediates the inhibition of exocrine pancreatic secretion by peptide YY (PYY). In eight conscious dogs with chronic gastric and pancreatic fistulas, we compared the action of intravenous infusion of 200 and 400 pmol/kg/h of the Y receptor agonists PYY 1-36, PYY 3-36, PYY 13-36, Pro34PYY 1-36, and NPY 1-36 on the pancreatic secretory response to secretin (20.5 pmol/kg/h) and cerulein (29.6 pmol/kg/h). PYY 13-36, Pro34PYY 1-36, and NPY 1-36 were also studied by giving a fivefold dose (1,000 and 2,000 pmol/kg/h). PYY 1-36 and the Y2 receptor agonist PYY 3-36 significantly inhibited pancreatic secretory responses to secretin and cerulein, whereas inhibition by NPY 1-36 and the Y2 receptor agonist PYY 13-36 was attainable only at doses of 1,000 and 2,000 pmol/kg/h. The Y1 receptor agonist Pro34PYY 1-36 was without effect on pancreatic secretion. We conclude that in dogs the inhibition of exocrine pancreatic secretion by PYY is mediated via Y2 receptors of a PYY-preferring subtype.

[Pro34]peptide YY is a Y1-selective agonist at peptide YY/neuropeptide Y receptors.

We have investigated binding and functional effects of a new peptide YY analogue, [Pro34]peptide YY, at Y1 and Y2-like subtypes of receptors for peptide YY and neuropeptide Y. In binding studies [Pro34]peptide YY had a similarly high affinity as peptide YY to human Y1-like receptors in SK-N-MC cells, a human neuroblastoma cell line of presumed neurogenic origin, and HEL cells, a human cell line derived from a patient with Hodgkin's disease. In functional studies [Pro34]peptide YY stimulated Ca2+ elevations in both Y1-like receptor cell lines with similar potency and efficacy as peptide YY. In contrast to peptide YY [Pro34]peptide YY was 1000-fold less potent in binding to Y2-like receptors in porcine splenic membranes and lacked agonistic effects in another Y2-like receptor-mediated model system, i.e. inhibition of [3H]serotonin release from rat cerebral cortical slices. Thus, [Pro34]peptide YY is a highly Y1-selective full agonist of peptide YY/neuropeptide Y receptors. [Pro34]peptide YY could be useful for studying the importance of Y receptor subtypes in mediating peptide YY physiological actions.

[The terminal ileum as a co-regulator of cyclic interdigestive pancreatic secretion in man]. / Das terminale Ileum als Koregulator der zyklischen interdigestiven Pankreassekretion beim Menschen.

Nutrients present in the ileum of humans can modulate endogenously stimulated pancreatic secretion. To determine whether cyclic interdigestive pancreatic secretion can also be influenced by nutrients in the ileum, six fasting volunteers were intubated with an oro-ileal multi-lumen tube for perfusing test and marker solutions, aspiration of duodenal contents and recording of motility. At the beginning of the interdigestive cycle, the ileum was perfused intermittently with solutions of carbohydrates, proteins or lipids in the physiological amounts observed in the ileum after a meal; saline solution was perfused as a control. After saline, protein and calcium perfusion, the expected periodic increase in chymotrypsin secretion was observed during phase II of the interdigestive cycle (p < 0.05 vs phase I). In contrast, carbohydrates and lipids inhibited the phase-II-associated increase in pancreatic secretion. These findings indicate that the ileum may be involved in the regulation of human interdigestive pancreatic secretion.

[Proteolytic processing by dipeptidyl aminopeptidase IV generates receptor selectivity for peptide YY (PYY)]. / Proteolytisches Processing durch Dipeptidyl-Aminopeptidase IV generiert Rezeptorselektivität für Peptid YY (PYY).

Two receptor subtypes, Y1 and Y2, are known to mediate PYY biological activity. PYY 1-36 binds to Y1 and Y2 receptors with equal affinity, whereas the second endogenous form of PYY, PYY 3-36, selectively binds to Y2 receptors. Dipeptidyl cleavage thus transforms an unselective Y agonist into a highly selective Y2 agonist, PYY 3-36. The enzyme responsible for this processing is unknown. Since PYY has a proline in the penultimate position it is protected from the attack of most unspecific exopeptidases. Only a few exopeptidases are theoretically capable of generating PYY 3-36 from PYY 1-36. Of the enzymes tested only the dipeptidyl aminopeptidase IV (DPP IV, E.C. 3.4.14.5) cleaved Tyr-Pro from PYY 1-36 with high activity. Since DPP IV is found on the endothelial surface and brush border membranes it can be considered a candidate enzyme for generating PYY 3-36 in vivo, thereby regulating the ratio of Y1/Y2 receptor stimulation by PYY.

[Y1 receptors mediate inhibitory and stimulatory effects of peptide YY in isolated small intestine and large intestine muscles of the rabbit]. / Y1-Rezeptoren vermitteln inhibitorische und stimulatorische Effekte von Peptid YY an der isolierten Dünndarm- und Dickdarmmuskulatur des Kaninchens.

Peptide YY has been shown to have stimulatory and inhibitory effects on gastrointestinal motility. However, the receptors mediating these effects are unknown. To determine if specific YY receptor agonists can mediate the effects on gastrointestinal motility we studied the effects of peptide YY (PYY), of Pro34PYY, a selective Y1 agonist, and of PYY 3-36, a selective Y2 agonist, on the motility in isolated smooth muscle strips from rabbit small and large intestine. In strips from distal colon, PYY stimulated spontaneous motility whereas it inhibited spontaneous contractions in circular strips from distal ileum. In distal circular colon maximal inotropic response (10.1 +/- 2.1% of a maximal response to carbachol 10(-5) M) was found at PYY 10(-8) M; (ED50 3.1 +/- 1.2 x 10(-9) M). In distal circular ileum maximal inhibition (by 39 +/- 20% of basal motility index) was found at 10(-7) M; (ID50 6.2 +/- 1.4 x 10(-9) M). PYY caused a dose-dependent inhibition of the on-contraction induced by electrical field stimulation. This inhibition could not be reversed by alpha- or beta-adrenergic blockade. PYY had no influence on the inotropic response evoked by carbachol. Both the stimulatory effect of PYY observed in distal colon and the inhibitory effect in distal ileum could be reproduced by the Y1 agonist Pro34PYY, but not by the Y2 agonist PYY 3-36. In distal circular colon the maximal inotropic response evoked by the Y1 agonist was 10 +/- 1.4%; (ED50 1.2 +/- 0.5 x 10(-8) M).(ABSTRACT TRUNCATED AT 250 WORDS)

[Chronic abdominal pain--internistic-psychosomatic aspects]. / Bauchschmerz aus internistisch-psychosomatischer Sicht. Gestresster Magen--gereizter Darm?

Abdominal pain is considered to be chronic when it persists for at least three months or when a patient experiences such pain for a total of three months during the course of a year. Pathophysiologically, nociceptive/neuropathic functional pain syndrome, mental disorders with the cardinal symptom of chronic pain, and mixed forms can be distinguished. In 50% of the patients, the cause of chronic abdominal pain is a functional gastrointestinal disorder e.g. functional dyspepsia irritable bowel syndrome. On the basis of a structured pain history, a physical examination and a basic "technical" diagnostic program (laboratory investigations, abdominal ultrasonography, Esophagogastroduodenoscopy, colonoscopy), correct assignment to one of the above-mentioned can be achieved in most of the cases.

[Smoking cessation. A physician's responsibility]. / Raucherentwöhnung. Eine ärztliche Aufgabe.

Giving up smoking is a cost-effective measure in the secondary prevention of chronic arterial disease and chronic obstructive pulmonary disease. The involvement of the physician in the primary prevention of smoking and kicking the habit in the case of tobacco-related disease, must receive greater emphasis than has so far been the case in Germany. Weaning smokers suffering from tobacco-related disease from their habit is a task for the physician, and may take the form either of a single minimal intervention, or successive consultations that can be integrated in every medical activity. The concept of stepwise smoking dishabituation is supported by evidence-based consensus recommendations on the part of relevant national and international medical societies and public institutions.