Navigating the transition: a multidisciplinary approach to inflammatory bowel disease in children.

PURPOSE: A multidisciplinary approach to Inflammatory Bowel Disease (IBD) has recently demonstrated a positive impact in pediatric patients, reducing dropout rates and facilitating the transition to adult care. Our study aims to evaluate how this approach influences disease activity, dropout rates, and transition. METHODS: We conducted a longitudinal observational study including all patients diagnosed with IBD during pediatric-adolescent age, with a minimum follow-up period of 12 months. For each patient, endpoints included therapeutic approach, need for surgery and transition features. RESULTS: We included 19 patients: 13 with Ulcerative Colitis (UC) and 6 with Crohn's disease (CD). Most patients required multiple lines of therapy, with over 50% in both groups receiving biological drugs. Compliance was good, with a single dropout in each group (10, 5%). The need for surgery was significantly higher in the CD group compared to the UC group (16% vs. 7.7%, p < 0.01). Mean age at transition was significantly higher in the UC group compared to the CD group (19.2 ± 0.7 years SD vs. 18.3 ± 0.6 years SD, p < 0.05). CONCLUSIONS: In our experience, the multidisciplinary approach to IBD in transition-age patients appears effective in achieving clinical remission, offering the potential to reduce therapeutic dropouts.

Bioimpedance-derived body composition parameters predict mortality and dose-limiting toxicity: the multicenter ONCO-BIVA study.

BACKGROUND: In patients with cancer, lean body mass loss is frequent and associated with worse outcomes, including reduced treatment tolerance and survival. Bioelectrical impedance analysis (BIA) is a popular method for body composition assessment. We evaluated the value of BIA-derived body composition parameters in predicting mortality and, for the first time, dose-limiting toxicity (DLT). PATIENTS AND METHODS: We conducted a prospective multicenter (n = 12) observational study in adult patients with solid neoplastic disease and receiving primary systemic treatment. We collected information on BIA-derived parameters: phase angle (PhA) <5th percentile of age and gender-specific normative values; standardized PhA (SPA) <-1.65; Nutrigram® <660 mg/24 h/m and <510 mg/24 h/m for males and females, respectively. The primary outcome and the key secondary were 1-year mortality and DLT (any-type severe toxicity requiring a delay in systemic treatment administration or a reduction of its dosage), respectively. RESULTS: In total, 640 patients were included. At 12 months, death occurred in 286 patients (47.6%). All BIA-derived body composition parameters were independently associated with death: SPA, hazard ratio (HR) = 1.59 [95% confidence interval (CI) 1.30-1.95] (P < 0.001); PhA, HR = 1.38 (95% CI 1.13-1.69) (P = 0.002); Nutrigram®, HR = 1.71 (95% CI 1.42-2.04) (P < 0.001). DLT occurred in 208 patients (32.5%) and body composition parameters were associated with this outcome, particularly SPA: odds ratio = 6.37 (95% CI 2.33-17.44) (P < 0.001). CONCLUSIONS: The study confirmed that BIA-derived body composition parameters are independently associated not only with survival but also with DLT. Although our findings were limited to patients receiving first-line systemic treatment, the evidence reported may have important practice implications for the improvement of the clinical work-up of cancer patients.

Efficacy of a Disease-Specific Nutritional Support for Pressure Ulcer Healing: A Systematic Review and Meta-Analysis.

OBJECTIVES: The aim of this systematic review was to summarize the evidence on the efficacy of high-calorie, high-protein nutritional formula enriched with arginine, zinc, and antioxidants (disease-specific support) in patients with pressure ulcers (PUs). METHODS: Randomized controlled trials in English published from January 1997 until October 2015 were searched for in electronic databases (EMBASE, Medline, PubMed, and CINAHL). Studies comparing a disease-specific nutritional support (oral supplements or tube feeding) to a control nutritional intervention enabling the satisfaction of energy requirements regardless of the use of high-calorie formula or placebo or no support for at least 4 weeks were considered eligible. Study outcomes were the percentage of change in PU area, complete healing and reduction in the PU area ≥40% at 8 weeks, and the percentage of change in area at 4 weeks. RESULTS: A total of 3 studies could be included in the meta-analysis. Compared with control interventions, formulas enriched with arginine, zinc and antioxidants resulted in significantly higher reduction in ulcer area (-15.7% [95%CI, -29.9, -1.5]; P=0.030; I2=58.6%) and a higher proportion of participants having a 40% or greater reduction in PU size (OR=1.72 [95%CI, 1.04, 2.84]; P=0.033; I2=0.0%) at 8 weeks. A nearly significant difference in complete healing at 8 weeks (OR=1.72 [95%CI, 0.86, 3.45]; P=0.127; I2=0.0%) and the percentage of change in the area at 4 weeks (-7.1% [95%CI, -17.4, 3.3]; P=0.180; I2=0.0%) was also observed. CONCLUSIONS: This systematic review shows that the use of formulas enriched with arginine, zinc and antioxidants as oral supplements and tube feeds for at least 8 weeks are associated with improved PU healing compared with standard formulas.

Nutritional Care Needs in Elderly Residents of Long-Term Care Institutions: Potential Implications for Policies.

OBJECTIVES: To collect information on actual nutritional intervention requirements in long-term care institutions and on the role of institutional factors in nutritional care. DESIGN: A cross-sectional analysis of baseline data (collected between September 2011 and September 2013) within the context of a multicenter prospective cohort study. SETTING: Nineteen long-term care institutions. PARTICIPANTS: Thirteen hundred and ninety-four resident elderly (age ≥60 years). MEASUREMENTS: The prevalence of nutritional derangements (MNA-Short Form) and the need to introduce nutritional interventions on the residents. RESULTS: Prevalence of malnutrition and risk of malnutrition were 35.2% [95%CI, 32.8-37.8] and 52.6% [95%CI, 50.0-55.2], respectively. Malnutrition was more frequent upon admission and in larger institutions (≥50 beds). Overall, 50% of the residents requiring an individualized nutritional care plan (any type) were not receiving it. Oral diet, the use of fluid thickeners and oral nutritional supplements had to be introduced in 306 (22.5%), 201 (15%) and 175 (13%) residents, respectively. The need to implement the oral diet was mainly due to inadequacy of texture according to chewing and swallowing capabilities. In gender and age-adjusted multivariable logistic regression models, nutritional interventions were associated with worse nutritional status (P<0.001 for all). Moreover, while the duration of stay was unrelated to the need for nutritional interventions, we observed that residents living in larger long-term care institutions (≥50 beds) were more likely to require improvement in nutrition care. CONCLUSIONS: In long-term care elderly residents nutritional derangements are very common, underdiagnosed and undertreated. Nutritional screening should be part of routine care. However, also the systematic involvement of a nutritional care specialist appears to be an urgent need, particularly in larger institutions where the standards of care are likely to be lower.

Inverse relationship between body mass index and mortality in older nursing home residents: a meta-analysis of 19,538 elderly subjects.

Body mass index (BMI) and mortality in old adults from the general population have been related in a U-shaped or J-shaped curve. However, limited information is available for elderly nursing home populations, particularly about specific cause of death. A systematic PubMed/EMBASE/CINAHL/SCOPUS search until 31 May 2014 without language restrictions was conducted. As no published study reported mortality in standard BMI groups (<18.5, 18.5-24.9, 25-29.9, ≥30 kg/m(2)), the most adjusted hazard ratios (HRs) according to a pre-defined list of covariates were obtained from authors and pooled by random-effect model across each BMI category. Out of 342 hits, 20 studies including 19,538 older nursing home residents with 5,223 deaths during a median of 2 years of follow-up were meta-analysed. Compared with normal weight, all-cause mortality HRs were 1.41 (95% CI = 1.26-1.58) for underweight, 0.85 (95% CI = 0.73-0.99) for overweight and 0.74 (95% CI = 0.57-0.96) for obesity. Underweight was a risk factor for higher mortality caused by infections (HR = 1.65 [95% CI = 1.13-2.40]). RR results corroborated primary HR results, with additionally lower infection-related mortality in overweight and obese than in normal-weight individuals. Like in the general population, underweight is a risk factor for mortality in old nursing home residents. However, uniquely, not only overweight but also obesity is protective, which has relevant nutritional goal implications in this population/setting.

Anthropometric indices of fat distribution and cardiometabolic risk in Parkinson's disease.

BACKGROUND & AIMS: To investigate the association between anthropometric indices of body fat distribution and cardiometabolic risk factors in a population of Parkinson's disease (PD) patients. METHODS & RESULTS: One hundred and fifty-seven PD patients (57.3% males) were studied measuring: waist circumference (WC), waist-hip ratio (WHR), waist-to-height ratio (WtHR), body fat percentage (BF%) by impedance, fasting glucose, serum lipids. Information was collected also on diabetes, hypertension and metabolic syndrome (MetS). Increased cardiometabolic risk was defined by ≥2 MetS component traits other than abdominal adiposity. In the whole population, prevalence of overweight and obesity were 35.0% and 19.2%, respectively. However, prevalence of MetS and elevated cardiometabolic risk were 14.6% and 18.5%, respectively. Prevalence was similar between genders, with one exception: adverse fat distribution according to WC and WHR was more common in females (P < 0.001). Using a multivariable model (adjustments: age, smoking status and disease duration), indices were highly correlated with BF% in both genders. WC and WtHR were associated with the number of MetS criteria and elevated risk. The only cardiometabolic parameters associated with anthropometric indices were HDL in men and triglycerides in women. After adjusting also for BMI all the associations found with anthropometric indices disappeared. CONCLUSIONS: Despite their correlation with BF%, anthropometric indices of body fat distribution appear to poorly account for the reduced cardiometabolic risk of the PD patient. This finding suggests a low metabolic activity within the adipose tissue. The implications of fat distribution on the cardiometabolic risk of PD patients clearly deserves further investigation.

Clinical features of Parkinson disease when onset of diabetes came first: A case-control study.

OBJECTIVE: Recent literature suggests that diabetes is a risk factor for Parkinson disease (PD). We investigated the clinical features of patients with idiopathic PD (IPD) in whom the onset of diabetes came first. METHODS: We designed a case-control study. From the cohort of all new patients with IPD free of vascular disease (n = 783) admitted and evaluated at our institute over a 3-year period (2007-2010), we included all the patients with a diagnosis of diabetes prior to PD onset (n = 89) and a control group (n = 89) matched (1:1) for gender, body mass index (± 1 kg/m(2)), and duration of PD (± 1 year). The Unified Parkinson's Disease Rating Scale (UPDRS) motor score was the primary endpoint. RESULTS: At study entry, patients with diabetes were similar to controls in terms of most demographic, lifestyle, and general medical features with exception of statins (18% vs 3.4%; p = 0.003). However, diabetes was associated with higher UPDRS motor (22.3 ± 9.0 vs 19.3 ± 7.9; p = 0.019) and activities of daily living (9.7 ± 5.1 vs 8.3 ± 4.3; p = 0.049) scores, more severe Hoehn & Yahr staging (p = 0.009), and higher treatment doses of levodopa (mg/day, 448 ± 265 vs 300 ± 213; p < 0.0001; mg/kg/day, 5.8 ± 4.0 vs 3.8 ± 2.9; p < 0.0001). CONCLUSIONS: Onset of diabetes before the onset of PD appears to be a risk factor for more severe PD symptoms. These findings support the hypothesis that diabetes has a role in the etiopathogenesis of PD. Neurologists should be aware of the potential impact of diabetes on overall PD management.

Nutritional care routines in Italy: results from the PIMAI (Project: Iatrogenic MAlnutrition in Italy) study.

BACKGROUND/OBJECTIVES: Disease-related malnutrition is a common comorbidity at hospital admission. The purpose of the present report was to describe the data on nutritional care routines collected during the Project: Iatrogenic MAlnutrition in Italy (PIMAI) study, as these may be helpful to avoid iatrogenic malnutrition and improve nutritional policies. SUBJECTS/METHODS: Standards of nutritional care were assessed on the basis of (1) adherence to study protocol (completeness of data collected); (2) attitude in assessing the nutritional status; (3) prescription of nutritional therapy (within 3 days) at least in patients presenting with overt malnutrition (body mass index (BMI) <18.5 kg/m(2) or significant weight loss (>or=10% in 3 months and/or >or=5% in the last month)), regardless of its adequacy, and adherence to current guidelines and (4) attitude in monitoring nutritional status during the stay (number of weight measurements performed compared with those expected). RESULTS: In total, 1583 subjects were assessed. A minimum data set for performing the Nutritional Risk Screening 2002 tool was available in 1284 patients (81.1%), but nutritional screening was possible in every patient by alternative analytical criteria related to food intake, anthropometry and biochemistry. However, several missing values were recorded, particularly in biochemical parameters due to lack of prescription by admission wards. According to ward practices, only 38.2% of the patients had the BMI calculated. A nutritional support was prescribed only to 26/191 patients (13.6%) presenting with overt malnutrition. Finally, we recorded that only 21.6% of the patients (207/960 were randomly selected) had their weight monitored on a scheduled basis. This reality was worse in surgical rather than medical departments (17 vs 26%; P<0.001). CONCLUSION: Present results confirm that in Italy, nutritional care routines are still poor and need improvements.

Estimated height from knee-height in Caucasian elderly: implications on nutritional status by mini nutritional assessment.

OBJECTIVES: To investigate if the use of estimated height (EH) by currently available prediction formulas might affect the screening and outcome prediction attitudes of both the Mini Nutritional Assessment (MNA) and its short-form version (MNA-SF). DESIGN: A 6-month observational study. SETTING: Two long-term cares of the province of Como. PARTICIPANTS: 266 resident elderly (102 men, 164 women; mean age +/- SD: 80.4 +/- 8.6 years). MEASUREMENTS: Subjects were studied by anthropometry (weight, standing height, knee-height, arm and calf circumferences, triceps skinfold) and biochemistry (albumin and prealbumin). Nutritional status was assessed using both MNA and MNA-SF. At 6 months, major outcome were: death, infections and bedsores. RESULTS: In overall population, prediction formulas significantly underestimated real height. The bias by Italian-specific equation was higher than that by nationally-representative formulas for white Americans. The use of EHs produced significant differences in body mass index (BMI) but these did not affect nutritional status scoring by MNA and MNA-SF (r > or =0.99, p < 0.0001). Cohen's kappa statistic also showed an almost perfect concordance (kappa > 0.9). Moreover, similar degrees of correlation were found between nutritional parameters and both MNA and MNA-SF scores by BMI from SH and EHs. After 6 months, major complications occurred in twenty-eight patients (11.6%). The use EHs did not affect the distribution of events among MNA and MNA-SF nutritional classes. CONCLUSION: In Italian elderly, height prediction by nationally representative equations for white Americans should be preferred to that by ethnic-specifc formula. However, the use of both models does not seem to affect nutritional screening and outcome prediction by MNA and MNA-SF.

Chemical investigation and effects of the tea of Passiflora alata on biochemical parameters in rats.

Passiflora alata (Passifloraceae) is a native plant from the South-America tropical forest that provides a much appreciated fruit known as "maracujá-doce". Although tea of the leaves of Passiflora alata is used in folk medicine as a sedative and tranquilizer, there are no investigations about its effects on biochemical parameters in blood or from its major chemical composition. The purpose of this study was to evaluate the effects of the tea of the leaves of Passiflora alata on biochemical parameters (antioxidant system, glucose and cholesterol levels) and to perform a phytochemical investigation of the tea. We isolated and identified two saponins and five C-glycosylflavones derived from apigenin, luteolin and chrysoeriol. Three of them are new in this species. Passiflora alata extract was administrated orally in rats at dose of 1000 mg/kg and it was observed an increase in high-density lipoprotein level (HDL-cholesterol).

Antagonistic properties of McNeil-A-343 at 5-HT4 and 5-HT3 receptors.

1. This study describes the in vitro interaction of the muscarinic ligand McNeil-A-343 with two 5-hydroxytryptamine (5-HT) receptor subtypes, the 5-HT4 and 5-HT3 receptors, using functional as well as radioligand binding studies. 2. In the rat oesophageal muscularis mucosae, precontracted with carbachol, McNeil-A-343 was a competitive antagonist (pA2 6.2) of the 5-HT4 receptor which mediates the relaxation induced by 5-HT. The compound per se relaxed the oesophagus at high concentration only (> or = 10 microM), an effect unchanged by desensitization of the 5-HT4 receptor with 10 microM 5-methoxytryptamine. In the same preparation in the absence of tone, McNeil-A-343 displaced the carbachol concentration-response curve to the right, yielding an apparent affinity (pA2) of 4.9 for muscarinic receptors. 3. In the rat isolated superior cervical ganglion preparation, after blockade of muscarinic and nicotinic receptors, McNeil-A-343 caused a concentration-dependent depolarization that was unaffected by 100 nM ondansetron. The concentration-fast depolarization curve to 5-HT, mediated by the 5-HT3 receptor, was displaced to the right by McNeil-A-343, which showed an apparent affinity (pA2) of 4.8 for the 5-HT3 subtype. 4. In binding studies, McNeil-A-343 recognized a single population of 5-HT4 receptors in pig caudate nucleus, with a pKI of 5.9. The binding affinity of McNeil-A-343 for 5-HT3 receptors in NG 108-15 cells was approximately four times lower (pKI 5.3). Binding affinities (pKI) for muscarinic receptor subtypes in rat tissues were 5.3 (M1, cortex), 5.2 (M2, heart) and 4.9 (M3, submandibular glands), respectively. 5. McNeil-A-343 is an antagonist at 5-HT4 and 5-HT3 receptors; the interaction of the compound with these receptor subtypes (notably the 5-HT4) occurs in a range of concentrations which generally overlaps that relevant to the interaction with muscarinic receptors.

Medicinal chemistry of muscarinic agonists for the treatment of dementia disorders.

Alzheimer disease (AD) is a neurodegenerative disorder lacking an effective therapy. The etiology is controversial and among different drug strategies, the cholinergic approach has gained great interest owing to biochemical and pharmacological evidence of the crucial role of acetylcholine in cognitive functions. Several attempts exploiting the boosting of the cholinergic system are currently under way. Inhibitors of the acetylcholinesterase enzyme sustain the availability of the natural transmitter by limiting its removal from the synapse. In a different approach, exogenous agonists may substitute acetylcholine itself. In this way the issue of the extensive cholinergic cell loss occurring in AD and leading to a reduction of cholinergic functions, could be advantageously bypassed. Moreover the discovery of different muscarinic receptor subtypes, most notably the M1 subtype as that involved in the postsynaptic transmission, has offered new opportunities to face the problem in a very specific way. In this line of research, we have now identified BIMC 182 as a new functionally selective M1 agonist. Whereas its affinity for the different receptor subtypes is almost similar (radioreceptor binding), its functional selectivity is pointed out by specific "in vitro" models. BIMC 182 behaves as a full agonist at M1 (rat superior cervical ganglion, pD2 4.8) and as a partial agonist at M2 and M3 sites (g.p. heart pD2 = 5.4 and g.p. ileum pD2 = 4.5). The agonist profile is further confirmed in hm1 transfected CHO cells where the compound stimulates PI turnover. BIMC 182 penetrates well the brain as shown by the increase in the energy of the low frequency band (theta waves) in the cortical EEG of rabbits (3 mg/kg i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium density measurement in histological samples of trabecular bone of normal subjects: relationship with aging.

It is well-known that bone volume decreases with age both in normal subjects and particularly in osteoporotic patients. It is not well demonstrated, however, whether bone loss is associated with changes in the composition of bone tissue and especially with altered concentration of mineral elements. To verify whether calcium density changes with aging, autoptic specimens, of iliac crest trabecular bone from 20 normal subjects between 21 and 66 years, 10 males and 10 females were analyzed by using a new method which allows the measurement of calcium density in a non-destructive way, on entire histologic sections of the bone. Bone specimens were embedded in araidite and tissue sections, about 3 microm thick and 4x4 mm size, were mounted onto polyvinyl acetate films and analyzed by PIXE (proton induced X-ray emission) using the CISE setup for calcium content determination. The same bone tissue sections were then mounted on glass slides, stained with the Von Kossa method and the volume of calcified bone was measured with a semiautomatic image analyzer (Videoplan). 3 to 4 sections from each subject were analyzed and the values of calcium concentration were derived in microg/microl. Similar values of calcium density were found in males and females (535.6+77.1 and 539.2+74.1 microg/microl, respectively). No significant correlation between calcium density and age was observed either in all cases (r=0.0925) or in males (r=-0.0687) and in females (r=0.2676) separately. The unchanged calcium density during aging obtained by combining PIXE and histomorphometric techniques demonstrates that the skeletal calcium reduction observed in old age and probably during osteoporosis, is mainly due to the decrease of bone volume.

Substituent effect on the stereochemistry of H2-receptor antagonists of the phenylformamidine series. A conformation-dependent mode of interaction with the H2 receptor.

The influence of alkyl substitution on the stereoisomerism of the formamidine cation (E,E vs E,Z) of several N-substituted (imidazolylphenyl)formamidines (1-10) was investigated. As (imidazolylphenyl)formamidines having alkyl substituents of more than three carbon atoms bind to H2-receptor preparations in a pseudoirreversible mode causing unsurmountable antagonism, the four isomeric butylformamidines (5-7 and 9) having comparable lipophilic character but different E,E/E,Z composition were investigated in H2-receptor assays to determine quantitatively any difference in their pseudoirreversible inhibitory pattern. It was found that the geometry of the formamidine cation is affected by the steric bulk of the substituent on the formamidine nitrogen. A relationship between the percentage of the E,E conformation of the formamidine cation and degree of pseudoirreversible antagonism was also found. The present studies support the hypothesis that bidentate hydrogen bonding plays an important role in the interaction of (imidazolylphenyl)formamidines with the H2 receptor.

New CCK antagonists derived from the amino acid residues of the CCK-8 fragment.

The synthesis of lipophylic derivatives of the amino acid residues of the CCK-8 fragment is described. According to "in vitro" binding studies and functional test, nearly all the compounds behaves as CCK-antagonists; moreover some compounds are able to interact differentially with CCK-A and CCK-B receptor subtype. In particular, compounds 2c, 2g, and 2h possess a high affinity for the CCK-A receptor subtype coupled with a low affinity for the CCK-B subtype. This results in an interesting selectivity profile. However, the same compounds are not able to antagonize the effects exerted by CCK-itself, when tested in "in vivo" assays.

Synthesis and biological evaluation of new antimuscarinic compounds with amidine basic centers. A useful bioisosteric replacement of classical cationic heads.

Amidines (guanidine, formamidine, and acetamidine) were introduced as substitutes for the cationic heads present in atropine, scopolamine, and corresponding quaternary derivatives. Amidine systems are intermediate in structure between tertiary amines and quaternary compounds, at least as regards ionization and electronic properties, but differ from the latter in shape (planar not tetrahedral). They have additional binding opportunities on account of their hydrogen-bond-forming capacity. The effect of the introduction of these cationic heads on the affinity for different muscarinic acetyl choline receptor (m-AcChR) subtypes was investigated in vitro, in binding displacement studies, and in functional tests on isolated organs. All new compounds (3a,b-5a,b) showed high affinity for the m-AcChR considered, comparable or slightly inferior to that of the parent drugs (1a-e). The new amidine derivatives proved effective as spasmolytic agents, with little tendency to cause central effects. However, no separation was achieved of spasmolytic and other untoward effects, like inhibition of salivation. Thus, amidine moieties are effective bioisosteric substitutes for conventional cationic heads present in antimuscarinic agents. Their unusual physical-chemical properties make them useful tools when modulation of pharmacokinetic or pharmacodynamic effects is required.

Hexocyclium derivatives with a high selectivity for smooth muscle muscarinic receptors.

1. The affinity of a number of derivatives of the muscarinic antagonist, hexocyclium, containing an amidine cationic head, for guinea-pig cardiac and ileal receptors was investigated. 2. All the compounds studied displayed a greater affinity for muscular than for cardiac muscarinic receptors. 3. The 5 fold ileal selectivity of hexocyclium was increased by a number of chemical substitutions. The largest discrimination between receptors (about 200 fold) was found for the formamidine derivative. 4. The selectivity displayed by the hexocyclium derivatives stemmed from a greater decrease in affinity towards cardiac as compared to ileal receptors.

Irreversible H2-antagonism of the four isomeric butyl analogues of mifentidine.

It has been hypothesized that bidentate hydrogen bonding plays an important role in the interaction of imidazolylphenylformamidines with the H2-receptor. The present study, in which the degree of pseudo-irreversible H2-antagonism of the four isomeric butyl substituted mifentidine analogues was determined on the spontaneously beating right atrium of the male guinea-pig, lends further support to this hypothesis. In solution the EE/EZ ratio is different for the four isomeric butylated mifentidine analogues. The rank order of the percentage of E,E conformation, which favors a bidentate interaction, of the formamidine moiety parallels the rank order of pseudo-irreversible H2-antagonism.