Preclinical discovery and initial clinical data of WVT078, a BCMA × CD3 bispecific antibody.

B-cell maturation antigen (BCMA) is an ideal target in multiple myeloma (MM) due to highly specific expression in malignant plasma cells. BCMA-directed therapies including antibody drug conjugates, chimeric antigen receptor-T cells and bispecific antibodies (BsAbs) have shown high response rates in MM. WVT078 is an anti-BCMA× anti-CD3 BsAb that binds to BCMA with subnanomolar-affinity. It was selected based on potent T cell activation and anti-MM activity in preclinical models with favorable tolerability in cynomolgus monkey. In the ongoing first-in-human phase I dose-escalation study (NCT04123418), 33 patients received intravenous WVT078 once weekly at escalated dosing. At the active doses of 48-250 µg/kg tested to date (n = 26), the overall response rate (ORR) was 38.5% (90% CI: 22.6-56.4%) and the complete response rate (CRR, stringent complete response + complete response) was 11.5%, (90% CI: 3.2-27.2%). At the highest dose level tested, the ORR was 75% (3 of 4 patients). 26 (78.8%) patients reported at least one Grade ≥3 AE and 16 of these AEs were suspected to be drug related. 20 patients (60.6%) experienced cytokine release syndrome. WVT078 has an acceptable safety profile and shows preliminary evidence of clinical activity at doses tested to date.

[Prognostic factors of neurofibromatosis type 1-associated optic pathway gliomas in children]. / Facteurs pronostiques des gliomes des voies optiques associés à la neurofibromatose de type 1 chez les enfants.

INTRODUCTION: Optic pathway glioma (OPG) is a classic complication of neurofibromatosis type 1 (NF1) and can impair visual function in children with this condition. The objective of this study is to describe clinical, paraclinical and prognostic characteristics of OPG associated with NF1. MATERIALS AND METHODS: In this retrospective observational study of children followed for OPG associated with NF1 in a University Hospital, we analyzed the ophthalmological examination, brain and orbital imaging, management and the presence of associated endocrinopathy. RESULTS: We examined 114 children with NF1, of which 26 (22.81%) presented with OPG. Mean ages at diagnosis of NF1 and OPG were 3.83 years and 6.23 years, respectively. Mean visual acuity was 20/24.4 for the worse eye and 20/23.1 for the better eye. The RNFL (retinal nerve fiber layer) was thinner in subjects than in age-matched controls (p <0.0001). Retrochiasmal location of the OPG (DodgeC) was associated with lower binocular visual acuity than other locations and <20/32 (p=0.028); 28.03% of OPG (5 girls and 1 boy) were treated with chemotherapy, and the others were monitored; 19.23% had an associated endocrinopathy. CONCLUSIONS: OPG complicates 22.81% of NF1 cases in our series. Our study shows that retrochiasmal location of the glioma and female sex are poor prognostic factors. It also highlights the important role of OCT, since a decrease in RNFL is statistically associated with the presence of an OPG.

Quantitative determination of human interleukin 22 (IL-22) in serum using Singulex-Erenna® technology.

Interleukin-22 (IL-22) is a key mediator of inflammatory processes associated with diseases such as psoriasis, inflammatory bowel disease and rheumatoid arthritis. The measurement of this cytokine in human plasma may provide insight into safety, pharmacodynamics and efficacy of drugs targeting inflammatory pathways. However, commonly used immunoassays are not sufficiently sensitive to measure baseline concentrations of IL-22. Here we describe the analytical validation of an ultrasensitive assay for the measurement of IL-22 in human serum using the Erenna® system by Singulex (Alameda, CA). The lower limit of quantification (LLOQ) of the Erenna assay estimated at 0.2pg/mL was sensitive enough to measure IL-22 in all human serum samples tested. The assay ranged from 0.2 to 100.0pg/mL and showed good dilution linearity. The inter-assay and intra-assay imprecision were <9% and <7% CV respectively. The accuracy determined by spiked recovery in serum samples was >86%. In addition, the results using Erenna assay correlated well with those using the IL-22 Quantikine immunoassay (R&D Systems, Minneapolis, MN) with a coefficient R(2) of 0.9285. However the Erenna assay showed an improved sensitivity by approximately 2 logs. These results show that this novel assay offers a significant improvement over previous methods for high-sensitive quantitative measurement of IL-22 in human serum samples.

Herpes simplex virus glycoprotein B associates with target membranes via its fusion loops.

Herpes simplex virus (HSV) glycoproteins gB, gD, and gH/gL are necessary and sufficient for virus entry into cells. Structural features of gB are similar to those of vesicular stomatitis virus G and baculovirus gp64, and together they define the new class III group of fusion proteins. Previously, we used mutagenesis to show that three hydrophobic residues (W174, Y179, and A261) within the putative gB fusion loops are integral to gB function. Here we expanded our analysis, using site-directed mutagenesis of each residue in both gB fusion loops. Mutation of most of the nonpolar or hydrophobic amino acids (W174, F175, G176, Y179, and A261) had severe effects on gB function in cell-cell fusion and null virus complementation assays. Of the six charged amino acids, mutation of H263 or R264 also negatively affected gB function. To further analyze the mutants, we cloned the ectodomains of the W174R, Y179S, H263A, and R264A mutants into a baculovirus expression system and compared them with the wild-type (WT) form, gB730t. As shown previously, gB730t blocks virus entry into cells, suggesting that gB730t competes with virion gB for a cell receptor. All four mutant proteins retained this function, implying that fusion loop activity is separate from gB-receptor binding. However, unlike WT gB730t, the mutant proteins displayed reduced binding to cells and were either impaired or unable to bind naked, cholesterol-enriched liposomes, suggesting that it may be gB-lipid binding that is disrupted by the mutations. Furthermore, monoclonal antibodies with epitopes proximal to the fusion loops abrogated gB-liposome binding. Taken together, our data suggest that gB associates with lipid membranes via a fusion domain of key hydrophobic and hydrophilic residues and that this domain associates with lipid membranes during fusion.

Impact of image-space resolution modeling for studies with the high-resolution research tomograph.

UNLABELLED: Brain PET in small structures is challenged by low resolution inducing bias in the activity measurements. Improved spatial resolution may be obtained by using dedicated tomographs and more comprehensive modeling of the acquisition system during reconstruction. In this study, we assess the impact of resolution modeling (RM) during reconstruction on image quality and on the estimates of biologic parameters in a clinical study performed on a high-resolution research tomograph. METHODS: An accelerated list-mode ordinary Poisson ordered-subset expectation maximization (OP-OSEM) algorithm, including sinogram-based corrections and an experimental stationary model of resolution, has been designed. Experimental phantom studies are used to assess contrast and noise characteristics of the reconstructed images. The binding potential of a selective tracer of the dopamine transporter is also assessed in anatomic volumes of interest in a 5-patient study. RESULTS: In the phantom experiment, a slower convergence and a higher contrast recovery are observed for RM-OP-OSEM than for OP-OSEM for the same level of statistical noise. RM-OP-OSEM yields contrast recovery levels that could not be reached without RM as well as better visual recovery of the smallest spheres and better delineation of the structures in the reconstructed images. Statistical noise has lower variance at the voxel level with RM than without at matched resolution. In a uniform activity region, RM induces higher positive and lower negative correlations with neighboring voxels, leading to lower spatial variance. Clinical images reconstructed with RM demonstrate better delineation of cortical and subcortical structures in both time-averaged and parametric images. The binding potential in the striatum is also increased, a result similar to the one observed in the phantom study. CONCLUSION: In high-resolution PET, RM during reconstruction improves quantitative accuracy by reducing the partial-volume effects.

Antigenic and mutational analyses of herpes simplex virus glycoprotein B reveal four functional regions.

Glycoprotein B (gB), along with gD, gH, and gL, is essential for herpes simplex virus (HSV) entry. The crystal structure of the gB ectodomain revealed it to be an elongated multidomain trimer. We generated and characterized a panel of 67 monoclonal antibodies (MAbs). Eleven of the MAbs had virus-neutralizing activity. To organize gB into functional regions within these domains, we localized the epitopes recognized by the entire panel of MAbs and mapped them onto the crystal structure of gB. Most of the MAbs were directed to continuous or discontinuous epitopes, but several recognized discontinuous epitopes that showed some resistance to denaturation, and we refer to them as pseudo-continuous. Each category contained some MAbs with neutralizing activity. To map continuous epitopes, we used overlapping peptides that spanned the gB ectodomain and measured binding by enzyme-linked immunosorbent assay. To identify discontinuous and pseudocontinuous epitopes, a purified form of the ectodomain of gB, gB(730t), was cleaved by alpha-chymotrypsin into two major fragments comprising amino acids 98 to 472 (domains I and II) and amino acids 473 to 730 (major parts of domains III, IV, and V). We also constructed a series of gB truncations to augment the other mapping strategies. Finally, we used biosensor analysis to assign the MAbs to competition groups. Together, our results identified four functional regions: (i) one formed by residues within domain I and amino acids 697 to 725 of domain V; (ii) a second formed by residues 391 to 410, residues 454 to 475, and a less-defined region within domain II; (iii) a region containing residues of domain IV that lie close to domain III; and (iv) the first 12 residues of the N terminus that were not resolved in the crystal structure. Our data suggest that multiple domains are critical for gB function.

Mutational evidence of internal fusion loops in herpes simplex virus glycoprotein B.

Herpes simplex virus type 1 (HSV-1) glycoprotein B (gB) is one of four glycoproteins necessary and sufficient for HSV cellular entry. Recently, the crystal structures of HSV-1 gB and vesicular stomatitis virus glycoprotein G were determined. Surprisingly, the two proteins share remarkable structural homology. Both proteins are homotrimeric and center about a long alpha-helix, features reminiscent of class I fusion proteins, such as influenza virus hemagglutinin or paramyxovirus F. However, these structures revealed that G has internal fusion loops, similar to the fusion loops of the class II fusion proteins, and that these loops are structurally conserved in gB. To examine whether these putative fusion loops are important for gB function, we mutated potential membrane-interacting (hydrophobic) residues to charged amino acids. Of most interest were mutant gB proteins that were expressed on the cell surface and were recognized by monoclonal antibodies against conformational epitopes but lacked the ability to function in cell-cell fusion assays. We find that three of the five hydrophobic amino acids targeted in these loops, tryptophan 174, tyrosine 179, and alanine 261, are integral in the function of gB. Our data suggest that they are part of an important functional domain. We hypothesize that two loops in domain 1 of HSV gB function as fusion loops. Our data are further evidence that gB is a viral fusogen and suggest clues as to how gB may function.

Joint estimation of dynamic PET images and temporal basis functions using fully 4D ML-EM.

A fully 4D joint-estimation approach to reconstruction of temporal sequences of 3D positron emission tomography (PET) images is proposed. The method estimates both a set of temporal basis functions and the corresponding coefficient for each basis function at each spatial location within the image. The joint estimation is performed through a fully 4D version of the maximum likelihood expectation maximization (ML-EM) algorithm in conjunction with two different models of the mean of the Poisson measured data. The first model regards the coefficients of the temporal basis functions as the unknown parameters to be estimated and the second model regards the temporal basis functions themselves as the unknown parameters. The fully 4D methodology is compared to the conventional frame-by-frame independent reconstruction approach (3D ML-EM) for varying levels of both spatial and temporal post-reconstruction smoothing. It is found that using a set of temporally extensive basis functions (estimated from the data by 4D ML-EM) significantly reduces the spatial noise when compared to the independent method for a given level of image resolution. In addition to spatial image quality advantages, for smaller regions of interest (where statistical quality is often limited) the reconstructed time-activity curves show a lower level of bias and a lower level of noise compared to the independent reconstruction approach. Finally, the method is demonstrated on clinical 4D PET data.

Crystal structure of glycoprotein B from herpes simplex virus 1.

Glycoprotein B (gB) is the most conserved component of the complex cell-entry machinery of herpes viruses. A crystal structure of the gB ectodomain from herpes simplex virus type 1 reveals a multidomain trimer with unexpected homology to glycoprotein G from vesicular stomatitis virus (VSV G). An alpha-helical coiled-coil core relates gB to class I viral membrane fusion glycoproteins; two extended beta hairpins with hydrophobic tips, homologous to fusion peptides in VSV G, relate gB to class II fusion proteins. Members of both classes accomplish fusion through a large-scale conformational change, triggered by a signal from a receptor-binding component. The domain connectivity within a gB monomer would permit such a rearrangement, including long-range translocations linked to viral and cellular membranes.

Herpes simplex virus glycoprotein B binds to cell surfaces independently of heparan sulfate and blocks virus entry.

Virion glycoproteins gB, gD, and gH/gL play essential roles for herpes simplex virus (HSV) entry. The function of gD is to interact with a cognate receptor, and soluble forms of gD block HSV entry by tying up cell surface receptors. Both gB and the nonessential gC interact with cell surface heparan sulfate proteoglycan (HSPG), promoting viral attachment. However, cells deficient in proteoglycan synthesis can still be infected by HSV. This suggests another function for gB. We found that a soluble truncated form of gB bound saturably to the surface of Vero, A431, HeLa, and BSC-1 cells, L-cells, and a mouse melanoma cell line expressing the gD receptor nectin-1. The HSPG analog heparin completely blocked attachment of the gC ectodomain to Vero cells. In contrast, heparin only partially blocked attachment of soluble gB, leaving 20% of the input gB still bound even at high concentrations of inhibitor. Moreover, heparin treatment removed soluble gC but not gB from the cell surface. These data suggest that a portion of gB binds to cells independently of HSPG. In addition, gB bound to two HSPG-deficient cell lines derived from L-cells. Gro2C cells are deficient in HSPG, and Sog9 cells are deficient in HSPG, as well as chondroitin sulfate proteoglycan (CSPG). To identify particular gB epitopes responsible for HSPG-independent binding, we used a panel of monoclonal antibodies (MAbs) to gB to block gB binding. Only those gB MAbs that neutralized virus blocked binding of soluble gB to the cells. HSV entry into Gro2C and Sog9 cells was reduced but still detectable relative to the parental L-cells, as previously reported. Importantly, entry into Gro2C cells was blocked by purified forms of either the gD or gB ectodomain. On a molar basis, the extent of inhibition by gB was similar to that seen with gD. Together, these results suggest that soluble gB binds specifically to the surface of different cell types independently of HSPG and CSPG and that by doing so, the protein inhibits entry. The results provide evidence for the existence of a cellular entry receptor for gB.

Clinical impact of capsule endoscopy compared to push enteroscopy: 1-year follow-up study.

BACKGROUND AND STUDY AIMS: The long-term outcome for patients with obscure bleeding after capsule endoscopy (CE) is still unclear. In this study, the clinical outcome was used as the gold standard to determine the sensitivity and specificity of CE and push enteroscopy (PE) in the diagnosis of small-bowel lesions in patients with obscure bleeding. PATIENTS AND METHODS: Fifty-eight patients from a previous prospective study (comparing PE and CE) were included; the patients were contacted after 1 year. The final diagnosis, bleeding status, new gastrointestinal examinations, and treatments performed were recorded. On the basis of these data, each case was classified into true/false positive or true/false negative findings at PE and CE. The results were compared with the initial classification of lesions observed at CE: highly relevant (P2) and less relevant (P0, P1) lesions. RESULTS: Follow-up data were available for 56 patients. According to the defined true/false positive and negative cases, the sensitivity and specificity values for CE and PE were 92 % and 48 %, and 80 % and 69 %, respectively ( P < 0.01 for the difference between CE and PE). Highly relevant (P2) lesions observed at CE were more frequently classified into true-positive cases (15 of 18 versus seven of 22; P < 0.01) and led more frequently to therapeutic decisions (11 of 18 versus five of 22; P = 0.02) in comparison with less relevant lesions (P0, P1). CONCLUSIONS: CE is a highly sensitive examination for the detection of small-bowel lesions in patients with obscure gastrointestinal bleeding, with a specificity lower than that of PE when the clinical outcome is used as the gold standard.

Differential insertion of GPI-anchored GFPs into lipid rafts of live cells.

Partitioning of proteins in cholesterol and sphingolipid enriched plasma membrane microdomains, called lipid rafts, is critical for many signal transduction and protein sorting events. Although raft partitioning of many signaling molecules remains to be determined, glycosylphosphatidyl-inositol (GPI)-anchored proteins possess high affinity for lipid rafts and are currently exploited as markers to investigate fundamental mechanisms in protein sorting and signal transduction events. In this study, we demonstrate that two recombinant GPI-anchored green fluorescent proteins (GFP-GPIs) that differ in their GPI signal sequence confer distinct localization in plasma membrane microdomains. GFP fused to the GPI signal of the decay accelerating factor GFP-GPI(DAF) partitioned exclusively in lipid rafts, whereas GFP fused to the GPI signal of TRAIL-R3, GFP-GPI(TRAIL-R3), associated only minimally with microdomains. In addition, we investigated the unique ability of purified GFP-GPIs to insert into membrane microdomains of primary lymphocytes. This cell surface painting allows rapid, stable, and functional association of the GPI-anchored proteins with the target cell plasma membrane. The distinct membrane localization of the two GFP-GPIs was observed irrespective of whether the GPI-anchored molecules were painted or transfected. Furthermore, we show that painted GFP-GPI(DAF) was totally dependent on the GPI anchor and that the membrane insertion was increased by the addition of raft-associated lipids such as cholesterol, sphingomyelin, and dipalmitoyl-phosphatidylethanolamine. Thus, this study provides evidence that different GPI signal sequences lead to distinct membrane microdomain localization and that painted GFP-GPI(DAF) serves as an excellent fluorescent marker for lipid rafts in live cells.

Specific association of glycoprotein B with lipid rafts during herpes simplex virus entry.

Herpes simplex virus (HSV) entry requires the interaction of glycoprotein D (gD) with a cellular receptor such as herpesvirus entry mediator (HVEM or HveA) or nectin-1 (HveC). However, the fusion mechanism is still not understood. Since cholesterol-enriched cell membrane lipid rafts are involved in the entry of other enveloped viruses such as human immunodeficiency virus and Ebola virus, we tested whether HSV entry proceeds similarly. Vero cells and cells expressing either HVEM or nectin-1 were treated with cholesterol-sequestering drugs such as methyl-beta-cyclodextrin or nystatin and then exposed to virus. In all cases, virus entry was inhibited in a dose-dependent manner, and the inhibitory effect was fully reversible by replenishment of cholesterol. To examine the association of HVEM and nectin-1 with lipid rafts, we analyzed whether they partitioned into nonionic detergent-insoluble glycolipid-enriched membranes (DIG). There was no constitutive association of either receptor with DIG. Binding of soluble gD or virus to cells did not result in association of nectin-1 with the raft-containing fractions. However, during infection, a fraction of gB but not gC, gD, or gH associated with DIG. Similarly, when cells were incubated with truncated soluble glycoproteins, soluble gB but not gC was found associated with DIG. Together, these data favor a model in which HSV uses gB to rapidly mobilize lipid rafts that may serve as a platform for entry and cell signaling. It also suggests that gB may interact with a cellular molecule associated with lipid rafts.

Diagnostic value of endoscopic capsule in patients with obscure digestive bleeding: blinded comparison with video push-enteroscopy.

BACKGROUND AND STUDY AIMS: This study was designed to prospectively compare the diagnostic yield of the M2A endoscopic capsule with that of video push-enteroscopy in exploring the small intestine in patients with obscure digestive bleeding. PATIENTS AND METHODS: Patients with either occult or overt obscure digestive bleeding and a negative endoscopic work-up underwent a double intestinal investigation, with video push-enteroscopy and a wireless capsule, performed blindly by separate examiners. The diagnostic yield for each technique was defined as the frequency of detection of clinically relevant intestinal lesions, i. e. those having the potential for bleeding. RESULTS: 60 patients (27 men, 33 women; age 58 +/- 18 years; hemoglobin 9.4 +/- 2.5 g/dl) were included, 32 with occult and 28 with overt bleeding. Results were analyzed for 58 patients, who completed both examinations. Lesions were detected in 43 patients: with both techniques in 19, only by capsule in 21, and, conversely, only by push-enteroscopy in 3 ( P = 0.04). Final diagnoses were as follows: a P2 lesion with high bleeding potential in 28 patients (19 angiomata, 6 ulcerations, 2 tumors, 1 case of intestinal varices); a P1 lesion with intermediate bleeding potential in 15 patients (2 patients with mucosal erosions, 13 patients with mucosal red spots); and there were normal findings from 15 procedures. No procedure induced any complication. CONCLUSION: The use of the wireless endoscopy capsule detects significantly more clinically relevant intestinal lesions than video push-enteroscopy in patients with obscure digestive bleeding, raising the diagnostic yield to 67.2 %. Its influence on the clinical outcome for patients needs further investigation.

[Sulpiride: study of 669 patient presenting with pain of psychological origin]. / Sulpiride: étude chez 669 patients présentant un trouble douloureux d'origine psychologique.

Among somatoform disorders, pain disorder (DSM IV) appears to be relatively common in general practice and to cause social, psychological, and functional impairment. A previous study conducted by Lemoine (1997) has shown that sulpiride is more effective than placebo in reducing intensity and frequency of pain in this disorder. The aim of our study was to assess safety and efficacy of sulpiride in a large sample of patients under natural conditions of use, in general practice. In a multicenter, open clinical trial, 669 patients (mean age: 47 years +/- 12; male: 245, female: 424) fulfilling the DSM IV criteria for pain disorder (of gastrointestinal localization), were included by 321 general practitioners (GP) and treated for 6 weeks with sulpiride 150 mg/d. Investigators' evaluations were planned at D14 and D42. Furthermore a diary was given to each patient for self evaluation and intercurrent events reporting. The pain was of psychological type in 93% of cases and caused social or working disabilities in 78% of patients. At inclusion the mean score of the Hamilton Anxiety Rating Scale was 18 +/- 8, and the mean score of the depression scale HARD (Humeur, Angoisse, Ralentissement, Danger) was 14.8 +/- 6.4. During the study 7.9% of the patients had at least one adverse event, and 3% of patients were withdrawn for adverse event. Safety assessed with a specific variable (grouping together adverse events' reporting and results of CGI item 3) was good for 88% of patients. The principal criterion of efficacy was the clinician's evaluation of the intensity and frequency of abdominal pain on a four-point scale from 0 (asymptomatic) to 3 (important/continuous) from D0 to D End a decrease in pain intensity (91% of patients) and in pain frequency (89%) was observed as well as in frequency and intensity of related gastroenterological symptoms such as disturbances of bowel movements (79% and 78%), bloated symptoms (88% and 83%), nausea/vomiting (90% and 90%). A similar improvement (p < 0.001) was observed from D0 to End point on the self evaluation parameters (Visual Analogic Scales), assessing pain (mean score D0-D End: 17.1 +/- 15.9), quality of sleep (mean score D0-D End: 27.1 +/- 17.8), activity (mean score D0-D End: 24.4 +/- 18.8), and appetite (mean score D0-D End: 22.6 +/- 16.6). In conclusion these results confirm the usefulness of sulpiride in the treatment of pain disorders a symptomatology known to cause difficulties to GP's in their practice.

Comparative, open, randomized trial of the efficacy and tolerance of slow-release 5-ASA suppositories once daily versus conventional 5-ASA suppositories twice daily in the treatment of active cryptogenic proctitis: French Pentasa Study Group.

OBJECTIVE: The efficacy and tolerance of slow-release 5-ASA suppositories (Pentasa 1 g/day) were compared with those of conventional 5-ASA suppositories (Rowasa 0.5 g b.i.d.). METHODS: Two hundred and fifty-one (251) patients presenting with an exacerbation of cryptogenic proctitis were randomized. Clinical activity and rectal lesions were measured at days 1 and 14 (and at day 21 for patients not in remission at day 14), and each patient had to fill out a daily diary card (checklist). RESULTS: Results are given for slow-release and classical suppositories, respectively. The reduction in symptoms and lesions was identical in both groups. Treatment was continued until day 21 in 36% versus 33% of the patients, and minor or moderate side effects occurred in 5.6% versus 6.3% (NS). The tolerance of the suppositories was rated as satisfactory every day by 77% versus 54% (p = 0.001), and early suppository expulsion occurred in 0.5% versus 3.4% (p = 0.001). CONCLUSIONS: The treatments were equally effective and both were well tolerated. However, the advantages of the slow-release suppositories were that patients exhibited greater tolerance and early expulsion was less frequent.

Gastric lymphoma of the MALT with breast relapse.

The usual features of non-Hodgkin lymphomas (NHL) of the mucosa-associated lymphoid tissue (MALT) include monocytoid B-cell proliferation, and chronic inflammatory precursor lesions. Despite a reputation of being indolent, NHL of the MALT may disseminate to other MALT areas, and raise difficult therapeutic questions. We report a case of gastric NHL of the MALT whose evolution, despite an initial surgical treatment considered radical, was noticeable for a well documented breast relapse.

Twenty-four-hour monitoring of intragastric acidity: comparison between lansoprazole 30mg and pantoprazole 40mg.

OBJECTIVE: To date, there is no published study, comparing the effects of lansoprazole and pantoprazole on gastric acid secretion inhibition. The aim of this study, was to compare the effects of these two drugs on 24-h intragastric pH-metry. DESIGN: Twelve healthy volunteers were included in an open, randomized, crossover study. Each subject received lansoprazole 30mg during 7 days followed, after a 14-day wash-out period, by pantoprazole 40 mg for 7 days or vice versa. Intragastric 24-h pH monitoring was performed before the treatment, and then after the first and seventh intake in each treatment period. RESULTS: The decrease in gastric acidity on daytime, night-time and total 24-h periods during both treatments was significantly different from the base value. Significant differences in acid inhibition were found between lansoprazole 30mg and pantoprazole 40 mg during daytime and 24 h after the first intake. After repeated dose regimens, a significant difference was detected between treatment periods but only for pH above 4. After the first dose, the median pH value with lansoprazole was also significantly greater than for pantoprazole. Pantoprazole activity increased significantly from first to seventh intake, in contrast to lansoprazole. CONCLUSION: Lansoprazole 30 mg was significantly more potent than pantoprazole 40 mg on 24-h pH profiles on the first and seventh days. The antisecretory effect of lansoprazole was maximum after the first intake whereas pantoprazole activity increased significantly between the first and last intake.

Placebo-controlled clinical trial of mesalazine in the prevention of early endoscopic recurrences after resection for Crohn's disease. Groupe d'Etudes Thérapeutiques des Affections Inflammatoires Digestives (GETAID).

OBJECTIVE: Endoscopic postoperative recurrences occur early after 'curative' surgery for Crohn's disease. Pentasa has been shown to be effective in the maintenance treatment of quiescent Crohn's disease. The aim of this study was to test the efficacy of a 12-week oral intake of Claversal in the prevention of endoscopic recurrences after 'curative' resection for ileal, colonic or ileocolonic Crohn's disease. We conducted a multicentre double-blind controlled trial comparing Claversal (1g tid) with placebo, starting within 15 days after surgery. The macroscopic normality of the two anastomotic segments was assessed at surgery. Patients were clinically and biologically evaluated twice (6-week interval), and colonoscopy was performed at 12 weeks. Endoscopic relapse was defined by any anastomotic ulcerations or stenosis and staged according to a four-grade score. RESULTS: Between May 1989 and May 1991 12 centres included 126 patients, 70 women and 56 men, aged 33 +/- 12 years (range 16-70) in the study. Disease locations were ileal, colonic and ileocolonic in 45, 6 and 49%, respectively. Claversal and placebo groups were similar at inclusion, except for ESR (37 +/- 26 vs. 27 +/- 23 mm/h in the Claversal and placebo groups, respectively; P < 0.05). Nine patients were withdrawn from the study. Adverse reactions occurred only in six patients. Five patients were excluded for protocol violation. Finally, 106 patients could be evaluated at 12 weeks (55 Claversal and 51 placebo). An endoscopic relapse was observed in 50% and 63% of the Claversal and placebo groups, respectively (P = 0.16), with a similar grade distribution. Claversal was well tolerated. CONCLUSIONS: Our study confirms that a large proportion of endoscopic recurrences occur within 3 months of resection in Crohn's disease. There was a slight trend towards greater efficacy of Claversal; it could be worthwhile trying higher dosages and/or 5-ASA compounds with different intestinal release profiles.