Katalin Müllner

Update on the pharmacogenomics of proton pump inhibitors

Proton pump inhibitors (PPIs) are widely used for the treatment of gastroesophageal reflux disease as well as other acid-related disorders. PPIs are metabolized primarily via the CYP2C19 and CYP3A4 isoenzymes; their activity is influenced both by exogenous and endogenous (pharmacogenetic) factors. The CYP2C19 polymorphism affects the metabolism of PPIs, causing large individual pharmacokinetic variations. Differences in the CYP2C19-mediated metabolism can produce marked interpatient variability in acid suppression, in drug-interaction potential and in clinical efficacy. Understanding the pharmacokinetic properties of PPIs and examining the pharmacogenetic alterations may help clinicians optimize PPI therapy and administer individual treatment, especially to nonresponder patients with gastroesophageal reflux disease or ulcer or after failed eradication therapy.

Alpha-2 adrenergic and opioid receptor-mediated gastroprotection

Clonidine inhibited the development of gastric mucosal lesions induced by either acidified ethanol or indomethacin. The ED50 values were: 7.1 and 5.2 microg x kg(-1) orally, respectively. The gastroprotective effect was antagonised by the pre-synaptic alpha-2 antagonist yohimbine, the more selective alpha-2 antagonist Ch-38083 and the pre-synaptic alpha-2B antagonist prazosin. Moreover, the non-selective opioid receptor antagonist naloxone, the delta receptor selective naltrindole also reversed the clonidine-induced mucosal protective action. Clonidine was also effective following intracerebroventricular administration with the ED50 of 37 ng/rat against ethanol-induced mucosal damage. Our results suggest that: 1) the gastroprotective effect of clonidine is likely to be mediated by alpha-2B adrenoceptor subtype; 2) there is an interaction between pre-synaptic alpha-2 adrenoceptors and opioid system; and 3) clonidine can induce gastroprotection by central mechanism.

Intracerebroventricular injection of clonidine releases β-endorphin to induce mucosal protection in the rat

The possibility that the endogenous opioid system could be involved in the central nervous system (CNS)-mediated gastroprotective effect of clonidine was investigated. Intracerebroventricularly (i.c.v.) injected clonidine (470 pmol/rat) inhibited the gastric mucosal lesions induced by (orally administered) acidified ethanol in a significant manner in the rat. The gastroprotective effect of the centrally administered clonidine was antagonised by i.c.v. or intracisternally (i.c.) administered presynaptic alpha-2 adrenoceptor antagonist, yohimbine; the non-selective opioid receptor antagonist, naloxone; and the delta opioid receptor antagonist naltrindole. These results suggest that an interaction between central alpha-2 adrenoceptors and endogenous opioid systems is involved in mediating the mucosal protective effect. beta-endorphin antiserum (i.c.) also antagonised the gastroprotection induced by intracerebroventricularly injected clonidine indicating that beta-endorphin release is likely to be a key factor in the gastroprotective effect of clonidine. Furthermore, the i.c.v. or i.c. injection of beta-endorphin produced a potent gastroprotection in the picomolar range. The mucosal protective effect of clonidine was abolished after vagotomy indicating that the central effect may be conveyed to the periphery by vagal efferents. Since atropine (1 mg/kg i.v.) failed to modify, but hexamethonium (10 mg/kg i.v.) antagonised the gastroprotective effect of clonidine, it would appear that in the periphery nicotinic, but not muscarinic, cholinergic receptors are likely to be involved in the mucosal protective effect of clonidine. In conclusion, clonidine (i.c.v.) induces gastroprotective action by releasing an endogenous opioid substance - most likely beta-endorphin - in the rat. The clonidine-induced central gastroprotection requires the integrity of vagal pathway; cholinergic nicotinic - but not muscarinic - receptors might mediate the effect in the periphery.

Have Biologics Changed the Natural History of Crohn's Disease?

Crohns disease (CD) is a progressive condition, with most patients developing a penetrating or stricturing phenotype over time. The introduction of anti-tumor necrosis factor (TNF) therapies over the past 10-15 years, which was supported by accumulating evidence both from trials and clinical practice, has led to a significant change in patient management, monitoring, and treatment algorithms. Anti-TNF therapy was demonstrated to be effective for both luminal and fistulizing disease. Regular therapy with both infliximab and adalimumab was shown to increase the likelihood of clinical remission and mucosal healing, as well as to reduce the need for surgery and hospitalization in both clinical trials and clinical practice, especially in patients with pediatric-onset CD, shorter disease duration, and when used in combination with immunosuppressives. This has led to new treatment goals and to the use of early aggressive medical therapy in a selected group of patients with a worse prognosis. Exploratory clinical trials are underway to determine if further optimization of therapies and treatment beyond clinical remission leads to superior disease outcomes. However, more long-term clinical data are needed to assess whether an early, aggressive therapeutic strategy employing anti-TNF, alone or in combination with biologicals, can further improve long-term disease outcomes in both pediatric patients and young adults.

Functional evidence that gastroprotection can be induced by activation of central α2B-adrenoceptor subtypes in the rat

Clonidine injected intracerebroventricularly (i.c.v.) (0.47 nmol/rat) exerted gastric mucosal protective effect against acidified ethanol. Evidence was obtained that the gastroprotective effect of clonidine was blocked by i.c.v. injected alpha(2)-adrenoceptor antagonists yohimbine (non-subtype selective antagonist), prazosin and 2-[2-(4-(O-methoxyphenyl)piperazin-1-yl)ethyl]-4,4-dimethyl-1,3-(2 H, 4H)-isoquinolindione (ARC-239) (representative alpha(2B/2C)-adrenoceptor blocking agents) and opioid receptor antagonists naloxone (a non-selective, moderately mu-opioid receptor preferring antagonist), naltrindole and naltriben delta-opioid receptor antagonists). The centrally injected naltrindole (0.5 nmol/rat) antagonised also the gastroprotective effect of clonidine --but not that of the delta-agonist [D-Ala(2), D-Leu(5)]enkephalin--administered peripherally. The results suggest that central alpha(2B/2C)-adrenoceptor subtypes and opioid--particularly delta--receptors are likely to be involved in the gastric mucosal protective effect of clonidine.

Marked chromogranin A elevation in a patient with bilateral adrenal incidentalomas, and its rapid normalization after discontinuation of proton pump inhibitor therapy

Chromogranin A (CgA) is a well-recognized tumour marker for various neuroendocrine tumours. 1 In their recent article Grossrubatscher et al. demonstrate the utility of CgA in the diagnosis and follow-up of phaeochromocytoma. 2 As the secretory activity of these tumours can be episodic, CgA measurement is of great value in cases where urinary catecholamines are negative. False-positive elevated CgA, however, can be related to various conditions, 1 including proton pump inhibitor (PPI) and steroid therapy, or be associated with impaired renal function and type A gastritis, and can lead to serious differential diagnostic problems in patients with adrenal tumours. Here, we report a case of highly elevated serum CgA level in a patient with bilateral adrenal adenomas, that was clearly associated with proton pump inhibitor therapy. As the patient also suffered from hypertension, the possibility of phaeochromocytoma had to be excluded. Discontinuation of PPI intake for 5 days normalized serum CgA, indicating that even a short interruption of PPI therapy can solve the differential diagnostic dilemma. A 73-year-old woman with a history of hypertension and gastrooesophageal reflux disease was examined for bilateral adrenal incidentalomas revealed by ultrasonography and subsequent computed tomography (CT). Although the clinical picture did not clearly suggest endocrine disease, routine endocrinological examination was undertaken. Hypercortisolism and primary aldosteronism were excluded. Serum CgA determined by radioimmunoassay (CISBio International, Gil-Sur-Yvette, France), however, was highly elevated (728 ng/ml, normal range 18–98·1 ng/ml). By contrast, urinary catecholamine metabolites (vanillylmandelic acid, normetanephrine, metanephrine, homovanillic acid) were normal, and 131 I-metaiodobenzylguanidine (MIBG) scintigraphy was also negative. Abdominal MRI showed that the signal intensities of bilateral adrenal tumours were different from those seen in phaeochromocytomas. 3 Serum creatinine and blood urea nitrogen were normal. As the patient had been treated with PPI for at least 8 years (omeprazole, and presently lansoprazole in a daily dose of 2 × 30 mg), iatrogenic elevation of CgA was suspected. To solve the serious differential diagnostic problem, we decided to suspend PPI therapy and replace it with sucralphate (4 × 1 g/day). Serum CgA returned to normal within 5 days (Fig. 1), and after a single dose (30 mg) of lansoprazole it increased again above the upper normal limit (132·4 ng/ml). Immunohistochemical analysis for CgA in mucosal biopsy samples from the gastric corpus indicated mild, simple (diffuse), enterochromaffin cell-like (ECL) hyperplasia. Although our patient did not present symptoms characteristic of phaeochromocytoma, suspicion was raised because of the highly elevated CgA together with the history of hypertension. As all other diagnostic examinations characteristic of phaeochromocytoma were negative, the possibility of PPI-related CgA elevation was raised. Short-, mediumand long-term PPI therapy has been shown to raise serum CgA. 4,5 Giusti et al . described the elevation of CgA in response to short-term (5–90 days) PPI therapy. 4 Our observation showing that a single dose of PPI may raise CgA above normal also supports a high sensitivity of serum CgA to PPI therapy. Elevation of CgA, however, was unusually high in the case presented. Available literature describes CgA levels up to 400 ng/ml (approx. 8 n m ), even after long-term PPI therapy. 5

Involvement of central KATP channels in the gastric antisecretory action of α2-adrenoceptor agonists and β-endorphin in rats

Abstract The intracerebroventricularly (i.c.v.) injected presynaptic α2-adrenoceptor agonists, clonidine and oxymetazoline, exerted a dose-dependent inhibition on the gastric acid secretion in pylorus-ligated rats; the ED50 values were 20 and 7.5 nmol/rat, respectively. Moreover, β-endorphin, given i.c.v., also decreased acid secretion (ED50=0.25 nmol/rat i.c.v.). The antisecretory effect of these compounds was highly reduced by glibenclamide (10 nmol/rat i.c.v.), a selective blocker of KATP channels. These results suggest that KATP channels in the central nervous system are likely to be involved in the centrally initiated antisecretory action of both α2-adrenoceptor agonists and β-endorphin.

Activation of central opioid receptors may induce gastric mucosal defence in the rat.

The effect of different opioid peptides on acidified ethanol- and indomethacin-induced gastric mucosal lesions was studied following intracerebroventricular (i.c.v.) administration. It was found that both the selective delta opioid receptor agonists--deltorphin II, [D-Ala(2), D-Leu(5)]-enkephalin (DADLE), [D-Pen(2), D-Pen(5)]-enkephalin (DPDPE)-, mu-opioid receptor agonist--[D-Ala(2), Phe(4), GlyT-ol]-enkephalin (DAGO)--as well as beta-endorphin inhibited the mucosal damage induced by both ethanol and indomethacin in pmolar dose range. In contrast, the gastric acid secretion was not influenced by DADLE in the dose of 16 nmol/rat and only a slight reduction (40%) was induced by DAGO in the dose of 1.9 nmol/rat. The protective effect was abolished in both ulcer models by bilateral cervical vagotomy. N(G)-nitro-L-arginine, an inhibitor of NO synthase, reduced the protective action in ethanol-induced, but not in indomethacin-induced gastric damage. The results suggest that activation of supraspinal delta and mu-opioid receptors resulted in inhibition of gastric mucosal lesions elicited by ethanol or indomethacin. The gastroprotective action is independent from the effect of opioids on acid secretion. Vagal nerve is involved in conveying the central action to the periphery. The mechanism of the gastroprotective effect of opioids is different in ethanol- and indomethacin-ulcer models: prostaglandins and nitric oxide are likely to be involved in the protective action of opioid peptides in ethanol-, but not in the indomethacin-ulcer model.

Involvement of the opioid system in the central antisecretory action of alpha-2 adrenoceptor agonists in rat

The aim of the present study was to analyse the role of the central alpha-2 adrenoceptors in the regulation of gastric acid secretion in pylorus ligated rats. It was found that the intracerebroventricularly (icv.) injected presynaptic alpha-2 adrenoceptor agonist clonidine and the alpha-2A adrenoceptor subtype selective stimulant oxymetazoline exerted a dose dependent inhibition on gastric acid secretion. The antisecretory ED(50) values for clonidine and oxymetazoline were 20 and 7.5 nmol/rat icv., respectively. The antisecretory effect of these compounds was antagonised by the presynaptic adrenoceptor antagonist yohimbine (50 nmol/rat icv.) indicating that the action is mediated through central presynaptic alpha-2 adrenoceptors. Moreover, naloxone (50 nmol/rat icv.)--non-selective opioid antagonist--and naltrindole (0.5 nmol/rat icv.)--delta-opioid receptor selective antagonist--also decreased the antisecretory effect of clonidine and oxymetazoline suggesting that the endogenous opioid system is likely to be involved in the central antisecretory action of alpha-2 adrenoceptor stimulants.

Probiotics in the Management of Crohn's disease and Ulcerative Colitis

Probiotics are nowadays frequently used by patients with inflammatory bowel disease, however literature data are conflicting related to their importance. In mild to moderate ulcerative colitis probiotics can be used effectively in induction and maintaining remission, and prevention of pouchitis. As the other side of the shield, there is not sufficient evidence to support the use of probiotics in daily clinical practice in Crohns disease. The aim of the present review is to provide help for clinicians about the probiotic use in patients with inflammatory bowel disease. The comparison of literature data is limited by the large number of probiotic strains, various combined preparations, and different doses applied in the clinical studies. Small number of comparable protocols and lack of standardization encumber the analysis of study results.