Granulomatous peritoneal disease associated with oxaliplatin-based chemotherapy for ampullary adenocarcinoma: a case report.

Adenocarcinomas of the ampulla of Vater represent only 0.2% of all gastrointestinal cancers. Due to the low incidence no large clinical trials evaluating efficacy of treatments are available. Adjuvant therapy is often administered in patients with stage IB or higher. Oxaliplatin is considered as an effective and well tolerated therapeutic option. Adverse events associated with this therapy include cardio-, neuro-, nephrotoxicity and myelosuppression. Previously granulomatous pulmonary and liver manifestations have been described in oxaliplatin-based chemotherapy. In this report peritoneal manifestation of granulomatous disease associated with oxaliplatin is described for the first time. Sarcoidlike reactions may be misinterpreted as tumour progression or metastatic disease, and may consequently result in over-treatment.

A survey among Flemish gastroenterologists about endoscopic sedation practices in colorectal cancer screening.

Background & study aims: The sedation levels and methods used for colonoscopy in colorectal cancer screening programs vary from country to country and from continent to continent. Little is known in the literature about how frequently the different sedation levels are used in colorectal cancer screening colonoscopies. We made a survey among all Flemish gastroenterologists (GI) to determine how frequently they use the different sedation modalities in this target population and to determine the motives of the GI to opt for one or another sedation modality. Patient and methods: An online survey was sent to all 329 Flemish GI by e-mail. A reminder e-mail was sent one month later. Participants could indicate how frequently (by percentage) they used the different sedation methods (no sedation, minimal sedation, conscious sedation, deep sedation) and which sedative medication they administered. In addition, they were asked to indicate their main motives for choosing a specific sedation method. Descriptive statistics were used. Results: 112 out of 329 GI answered the questionnaire (response rate 34%). Anesthesia monitored care is the most frequently used sedation modality, followed by conscious sedation. Patient preference is the main motive for most GI to use each sedation modality. Conclusions: Anesthesia monitored care is currently the most frequently used sedation regimen to perform a colonoscopy in the FIT positive population or in the colorectal cancer screening program in Flanders. The motives given by the GI for choosing one or another sedation modality are not always congruent with current scientific evidence or guidelines.

Efficacy of switching to infliximab in patients with Crohn's disease with loss of response to adalimumab.

BACKGROUND AND STUDY AIMS: Anti-TNF monoclonal antibodies are a cornerstone in the treatment of Crohn's disease. Prospective data on switching from the subcutaneous and human adalimumab (ADM) to the intravenous and chimeric infliximab (IFX) are scarce. PATIENTS AND METHODS: In this prospective, observational, multicentre cohort study we included 21 patients with loss of response to ADM despite at least 4 consecutive weekly injections. Clinical response (CDAI drop≥70 points) and remission (CDAI≤150) were assessed after switching from ADM to IFX after 10 weeks, 6 and 12 months. Predictive factors of response/remission, the need for therapy intensification, discontinuation and safety were investigated. RESULTS: Short-term response and remission (10 weeks) were seen in 57% and 48% respectively. Mid- and long-term clinical response and remission were achieved in 40% and 25% after 6 months and in 45% and 20% after 12 months respectively. At 12 months, 81% still were on IFX. IFX therapy intensification was needed in half of the patients at 6 months and three quarter of patients at 12 months. Undetectable ADM trough levels (despite weekly injections) were a predictive factor for short-term response and remission to IFX. About half of the patients with response at week 10 maintained response at 6 and 12 months. CONCLUSIONS: Switching from ADM to IFX can be efficacious in patients with loss of response, in particular in case of undetectable ADM trough levels. The majority of patients however will need IFX therapy intensification during their first year of treatment.

Changes in multifidus and abdominal muscle size in response to microgravity: possible implications for low back pain research.

PURPOSE: In microgravity, muscle atrophy occurs in the intrinsic muscles of the spine, with changes also observed in the abdominal muscles. Exercises are undertaken on the International Space Station and on Earth following space flight to remediate these effects. Similar effects have been seen on Earth in prolonged bed rest studies and in people with low back pain (LBP). The aim of this case report was to examine the effects of microgravity, exercise in microgravity and post-flight rehabilitation on the size of the multifidus and antero-lateral abdominal muscles. METHODS: Ultrasound imaging was used to assess size of the multifidus, transversus abdominis and internal oblique muscles at four time points: pre-flight and after daily rehabilitation on day one (R + 1), day 8 (R + 8) and day 14 (R + 14) after return to Earth (following 6 months in microgravity). RESULTS: Exercises in microgravity maintained multifidus size at L2-L4, however, after spaceflight, size of the multifidus muscle at L5 was reduced, size of the internal oblique muscle was increased and size of transversus abdominis was reduced. Rehabilitation post-space flight resulted in hypertrophy of the multifidus muscle to pre-mission size at the L5 vertebral level and restoration of antero-lateral abdominal muscle size. CONCLUSIONS: Exercise in space can prevent loss of spinal intrinsic muscle size. For the multifidus muscles, effectiveness varied at different levels of the spine. Post-mission rehabilitation targeting specific motor control restored muscle balance between the antero-lateral abdominal and multifidus muscles, similar to results from intervention trials for people with LBP. A limitation of the current investigation is that only one astronaut was studied, however, the microgravity model could be valuable as predictable effects on trunk muscles can be induced and interventions evaluated. Level of Evidence Case series.

Maintenance therapy for ulcerative colitis has no impact on changes in the extent of ulcerative colitis.

BACKGROUND AND AIM: Although the efficacy of maintenance remission therapy in ulcerative colitis (UC) has been proved in many studies, little is known about its possible effect on the extent of the disease. The aim of the present multicenter Belgian study was to evaluate the potential role of UC maintenance therapy on the colonic extension of the disease. MATERIALS AND METHODS: A total of 98 patients, 56 males, 42 females, mean age 52 years, range 22-82 years, from 12 medical centers in Belgium, with an acute exacerbation of well-established, endoscopically and histologically proven left-sided UC, were included. The colonic extension was endoscopically determined at the time of the initial diagnosis and at the actual flare-up. The mean duration of UC was 93+72 months, median was 84 months, and range was 3-372 months. Active smoking was reported in only 7% of patients, while the majority were no-smokers (63%) or ex-smokers (30%). The median colonic extension at the time of initial diagnosis was 25 cm, range 2-70 cm from the anal merge. Sixty-six percent of the patients had quiescent disease without flare-ups during last year. The χ(2)-test was used for statistical analysis. RESULTS: 29/98 (29.6%) patients had not used any maintenance therapy in the last 3 months before the actual exacerbation. The most commonly used maintenance therapy was 5-ASA (43%), while combined therapy with 5-ASA, corticosteroids or immunosuppresives (mainly azathioprine) in all possible combinations was reported by 29.6% of patients. The extent of UC had not changed in 50.7% and 51.7% of patients, respectively, with and without maintaining therapy (NS, p=0.99). Some degree of regression was observed in, respectively, 21.7% and 20.7% (NS, p=0.99), and some degree of extension in, respectively, 27.5% and 27.6% (NS, p=0.99). Furthermore, no relationship was found between changes in colonic extent and type of maintaining therapy, smoking habits or disease activity during the last year before the acute exacerbation. A tendency of beneficial effect of maintenance therapy on disease extent was observed in patients with continuous active disease of short duration. CONCLUSIONS: According to this multicenter study, maintenance remission therapy for left-sided UC was not found to have a statistically significant effect on colonic extension. Further long-term studies are necessary to confirm these results.

Characterization of muscarinic autoreceptors in the rabbit hippocampus and caudate nucleus.

Oxotremorine-induced inhibition of electrically evoked release of 3H-acetylcholine from brain slices preincubated with 3H-choline was used to characterize muscarinic autoreceptors in rabbit hippocampus and caudate nucleus. From the shifts to the right of the concentration-response curves of oxotremorine in the presence of muscarinic receptor antagonists, the following pKB values [95% C.I.] were determined in the hippocampus: tripinamide: 8.7 [8.5, 8.8]; himbacine: 8.4 [8.3, 8.5]; AQ-RA 741: 8.3 [8.2, 8.5]; 4-DAMP: 8.2 [8.0, 8.3]; hexahydrosiladifenidol: 7.4 [7.2, 7.5]; AF-DX 116: 7.3 [7.1, 7.4]; pirenzepine: 6.8 [6.6, 7.0]; and PD102807: 6.3 [6.0, 6.5]. In the caudate nucleus: tripinamide: 9.1 [8.9, 9.2]; 4-DAMP: 8.3 [8.2, 8.5]; himbacine: 8.1 [8.0, 8.2]; AQ-RA 741: 8.1 [8.0, 8.3]; hexahydrosiladifenidol: 7.3 [7.2, 7.4]; AF-DX 116: 7.1 [7.0, 7.2]; pirenzepine: 6.7 [6.6, 6.8]; and PD102807: 6.5 [6.2, 6.8]. These pKB values fit best to literature values for M2 receptors, suggesting that the muscarinic autoreceptor of the rabbit hippocampus and caudate nucleus is the m2 gene product.

NF449: a subnanomolar potency antagonist at recombinant rat P2X1 receptors.

Antagonistic effects of the novel suramin analogue 4,4',4",4"'-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis-benzene-1,3-disulfonic acid (NF449) were studied on contractions of the rat vas deferens elicited by alpha,beta-methylene ATP (alphabetameATP; mediated by P2X1 receptors), contractions of the guinea-pig ileal longitudinal smooth muscle elicited by alphabetameATP (mediated by P2X3 receptors) or adenosine 5'-O-(2-thiodiphosphate) (ADPbetaS; mediated by P2Y1 receptors), ATP-induced increases of [Ca2+]i in human embryonic kidney (HEK) 293 cells (mediated by P2Y2 receptors), inward currents evoked by ATP in follicle cell-free Xenopus laevis oocytes expressing rP2X1 or rP2X3 receptors and degradation of ATP by ecto-nucleotidases in folliculated Xenopus laevis oocytes. In addition, NF449 was examined for its P2 receptor specificity in rat vas deferens (alpha1A-adrenoceptors) and guinea-pig ileum (histamine H1 and muscarinic M3 receptors). At native (pIC50=7.15) and recombinant (pIC50=9.54) P2X1 receptors, NF449 was a highly potent antagonist. The P2X3 receptors present in guinea-pig ileum (pIC50=5.04) or expressed in oocytes (pIC50 approximately 5.6) were much less sensitive for NF449. It also was a very weak antagonist at P2Y1 receptors in guinea-pig ileum (pIC50=4.85) and P2Y2 receptors in HEK 293 cells (pIC50=3.86), and showed very low inhibitory potency on ecto-nucleotidases (pIC50<3.5). NF449 (100 microM) did not interact with alpha1A-adrenoceptors or histamine H1 and muscarinic M3 receptors. Thus, the antagonism by NF449 is highly specific for P2 receptors. In conclusion, the subnanomolar potency at rP2X1 receptors and the rank order of potency, P2X1 >> P2X3 > P2Y1 > P2Y2 > ecto-nucleotidases, make NF449 unique among the P2 receptor antagonists reported to date. NF449 may fill the long-standing need for a P2X1-selective radioligand.

Design and pharmacology of quinuclidine derivatives as M2-selective muscarinic receptor ligands.

In our search for M2-selective muscarinic receptor antagonists, we synthesized 1,3-disubstituted indenes. The effects of different basic moieties with regard to binding and selectivity towards the five distinct muscarinic receptor subtypes were investigated. The results show that the quinuclidine series afforded the most promising compounds in terms of both receptor affinity and M2-subtype selectivity.

Agonists and antagonists acting at P2X receptors: selectivity profiles and functional implications.

P2X receptors are nucleotide-gated cation channels composed of homomeric or heteromeric assemblies of three subunits. In the past 7 years, an extended series (P2X1-7) of P2X subunits has been cloned from vertebrate tissues. In this rapidly expanding field, one of the main current challenges is to relate the cloned P2X receptor subtypes to the diverse physiological responses mediated by the native P2X receptors. However, the paucity of useful ligands, especially subtype-selective agonists and antagonists as well as radioligands, acts as a considerable impediment to progress. Most of the ligands available are highly limited in terms of their kinetics of action, receptor-affinity, subtype-selectivity and P2X receptor-specificity. Their suspected ability to be a substrate for ecto-nucleotidases or to inhibit these enzymes also complicates their use. A number of new antagonists at P2X receptors have recently been described which to some degree are more potent and more selective than earlier antagonists like suramin or pyridoxal-5'-phosphate-6-azophenyl 2',4'-disulfonate (PPADS). This work moves us closer to the ideal goal of classifying the recombinant and native P2X receptor subtypes on the basis of antagonist profiles. This review begins with a brief account of the current status of P2X receptors. It then focuses on the pharmacological properties of a series of key P2 receptor agonists and antagonists and will finish with the discussion of some related therapeutic possibilities.

The suramin analogue NF279 is a novel and potent antagonist selective for the P2X(1) receptor.

The suramin analogue 8,8'-(carbonylbis(imino-4, 1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)) bis(1,3,5-naphthalenetrisul fonic acid) (NF279) was analysed with respect to its potency and P2X receptor subtype selectivity. Two-electrode voltage-clamp measurements were performed with Xenopus laevis oocytes expressing homomultimeric rat P2X(1), P2X(2), P2X(3) and human P2X(4) receptors. For the fast desensitising P2X(1) and P2X(3) receptors, IC(50) values strongly depended on whether oocytes were pre-incubated with NF279 prior to ATP superfusion or exposed to NF279 simultaneously with ATP. With a 10 s pre-incubation period of NF279, IC(50) values of 19 nM and 1.62 microM were obtained for rat P2X(1) and P2X(3), respectively. Without pre-incubation, IC(50) values amounted to 2 microM and 85.5 microM for P2X(1) and P2X(3), respectively. For the non-desensitising rat P2X(2) receptor NF279 appeared to act as a competitive antagonist with an IC(50) value of 0.76 microM and a K(B) value of 0.36 microM, as derived from Schild analysis. P2X(4) receptors were the least sensitive subtypes for NF279 (IC(50)>300 microM). The antagonism was fully reversible at all P2X subtypes analysed. Our results indicate that NF279 is a potent P2X(1) receptor-selective and reversible antagonist.

The novel heteromeric bivalent ligand SB9 potently antagonizes P2Y(1) receptor-mediated responses.

Effects of 6-[(4,6,8-trisulfo-1-naphthyl)iminocarbonyl-1, 3-(4-methylphenylene)iminocarbonyl-1, 3-phenylene-azo]-pyridoxal-5'-phosphate (SB9), a heterodimeric bivalent ligand consisting of pyridoxal-5'-phosphate and the suramin monomer, were studied on contractions of the rat vas deferens elicited by alpha beta-methylene ATP (alpha beta meATP; mediated by P2X(1)-like receptors), contractions of the guinea-pig ileal longitudinal smooth muscle elicited by adenosine 5'-O-(2-thiodiphosphate) (ADP beta S mediated by P2Y(1)-like receptors), and the degradation of ATP by ecto-nucleotidases in folliculated Xenopus laevis oocytes. SB9 (0.1-10 microM) antagonized contractile responses produced by alpha beta meATP or ADP beta S in a concentration-dependent manner. Schild analysis yielded linear regression lines of unit slope, indicating competitive antagonism. From the rightward shifts of the agonist concentration-response curves pA(2) values of 6.05+/-0.13 (vas deferens) and 6.98+/-0.07 (ileum) were derived. In both preparations, SB9 behaved as a slow onset, slow offset antagonist. Incubation of three oocytes in the presence of ATP produced an increase in inorganic phosphate (P(i)) over a 30-min period, which amounted to 35.1+/-1.9 microM P(i) from 100 microM ATP. SB9 (10-1000 microM) reduced this degradation (pIC(50)=4.33+/-0.10). The results illustrate that SB9 is a high-affinity P2Y(1) receptor antagonist with a remarkable selectivity for P2Y(1) vs. P2X(1) receptors (about 10-fold) and ecto-nucleotidases (447-fold). These properties make it unique among the pyridoxal-5'-phosphate and suramin derivatives reported to date.

Functional role of muscarinic M(2) receptors in alpha,beta-methylene ATP induced, neurogenic contractions in guinea-pig ileum.

1. The muscarinic acetylcholine receptors mediating the contractile response elicited to endogenous acetylcholine released by the selective P2X receptor agonist alpha,beta-methylene ATP (mATP) were investigated in guinea-pig ileum. 2. mATP (0.1 - 30 microM) elicited a concentration-dependent neurogenic contractile response inhibited by tetrodotoxin (TTX) and antagonized by the non-selective muscarinic receptor antagonist N-methylscopolamine (NMS). 3. The contractile response to mATP was pertussis toxin-insensitive, irreversibly antagonized by N-(2-chloroethyl)-4-piperidinyl diphenylacetate (4-DAMP mustard), and unaffected by the muscarinic M(2)/M(4) receptor selective antagonist AF-DX 116 (1 microM). 4. When measured in the presence of histamine and isoproterenol after treatment with 4-DAMP mustard, mATP elicited a pertussis toxin-sensitive contractile response potently antagonized by AF-DX 116. 5. Collectively, our data suggest that endogenous acetylcholine released by mATP can elicit a direct contractile response through the muscarinic M(3) receptor and an indirect contractile response through the muscarinic M(2) receptor by antagonizing the relaxant effects of isoproterenol on histamine induced contraction.

Muscarinic properties of compounds related to arecaidine propargyl ester.

A series of new analogues of the arecaidine propargyl ester (CAS 35516-99-5), APE, 1a) with alcohols consisting of 4 or 5 carbon atoms were investigated at muscarinic receptor subtypes. The muscarinic activity of the quaternary and tertiary salts of the APE-related compounds were assayed on the isolated guinea-pig ileum (M3 receptor subtype) and guinea-pig left atria (M2 receptor subtype) as well as on rabbit isolated vas deferens (M1 receptor subtype). The structural variations made in the APE molecule, replacing the triple bond in the ester side chain with structures such as double bond, an allene moiety, a single bond, a cyclopropyl group or two triple bonds should alter the selectivity and potency in favour of the M2 subtype. Enhanced, though modest, selectivity for M2 receptors was achieved with the 2-butynyl ester 2a. The other structural variations resulted in a loss of potency, but not necessarily of efficacy.

Antagonism by the suramin analogue NF279 on human P2X(1) and P2X(7) receptors.

The effect of the suramin analogue 8,8'-(carbonylbis(imino-4, 1-phenylenecarbonylimino-4,1-phenylenecarbonylimino))bis(1,3 , 5-naphthalenetrisulfonic acid) (NF279) was analyzed on human P2X(1) and P2X(7) receptor subtypes (human P2X(1) and human P2X(7)) heterologously expressed in Xenopus oocytes using the two-microelectrode voltage-clamp technique. At activating ATP concentrations of 1 microM (human P2X(1)) and 10 microM ATP (human P2X(7)), IC(50) values of 0.05 microM and 2.8 microM were found for human P2X(1) and human P2X(7) receptors, respectively. An increase in the activating [ATP] shifted the NF279 concentration-inhibition curve rightwards for both receptors. NF279 slowed the activation of both human P2X(1) and human P2X(7) as well as the desensitization of human P2X(1). The data support a model in which desensitization of P2X(1) is dependent on preceding activation of these P2X receptors. It is concluded that NF279 acts as a competitive antagonist with much higher potency at human P2X(1) than at P2X(7) receptors. NF279 may hence be suited to discriminate between both receptors in native tissues.

The novel pyridoxal-5'-phosphate derivative PPNDS potently antagonizes activation of P2X(1) receptors.

Pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonat e) (PPNDS) potently antagonized P2X(1) receptor-mediated responses in rat vas deferens (pK(B)=7.43) and Xenopus laevis oocytes (pIC(50)=7. 84). It showed lower (up to 20,000-fold) inhibitory potency on ecto-nucleotidase in Xenopus oocytes and on P2Y(1) receptors in guinea-pig ileum (pA(2)=6.13). PPNDS did not interact with alpha(1A)-adrenoceptors, adenosine A(1) and A(2B), histamine H(1) and muscarinic M(3) receptors. Thus, PPNDS is a novel, specific P2 receptor antagonist and represents the pyridoxal-5'-phosphate derivative with the highest potency at P2X(1) receptors.