H2 RA Research Articles

The Effect of Proton-Pump Inhibitors the on Development of Arrhythmia and Hypomagnesemia After Off-Pump Coronary Artery Bypass Surgery

Background: Long-term use of proton-pump inhibitors (PPI) can result in hypomagnesemia and arrhythmia. This study aimed to compare the effect of PPI and histamine 2-receptor antagonists (H2 RA) on the incidence of hypomagnesemia and arrhythmia in patients following off-pump coronary artery bypass surgery (CABG). Method: In this randomized-controlled clinical trial 290 patients admitted to the ICU after off-pump CABG were randomly divided into two groups of H2 RA (n=145) and PPI (n=145). For patients in the H2 RA group, 50 mg intravenous ranitidine was prescribed every 8 hours after the nothing by mouth (NPO) period, followed by 40 mg famotidine tablets after starting the oral regimen (PO). The PPI group received 40 mg pantozol IV injections every 12 hours during the NPO period and 40 mg pantozol tablets once daily after becoming PO. The patients were investigated for the development of hypomagnesemia and associated arrhythmia. Results: In total 271 patients with a mean age of 59.3±10 years completed the study (female/male=32.8%). Hypomagnesemia occurred in 60.1% of the patients, 76 (56.7%) in the H2 RA group and 87 (63.5%) in the PPI group (P=0.245), whereas arrhythmia had a prevalence of 12 (9.6%) and 15 (11.1%) cases, respectively (P=0.690). The mean time of occurrence of hypomagnesemia and arrhythmia was 1.75±1.08 and 3.0±0.9 days after the operation in the H2 RA group (P=0.111) and 1.47±0.7 and 2.9±1.5 days in the PPI group (P=0.897), respectively. Conclusion: Our study revealed that the short-term use of PPIs does not result in higher rates of hypomagnesemia and associated arrhythmia in comparison to H2 RA consumption after off-pump CABG.

The long-term risk for myocardial infarction or stroke after proton pump inhibitor therapy (2008-2018).

Proton pump inhibitors (PPIs) are well tolerated in the short term but have recently been associated with increased long-term cardiovascular risk in observational studies. To evaluate long-term risks of myocardial infarction (MI) and ischaemic stroke (IS) associated with PPI vs H2 -receptor antagonist (H2 RA) therapy in adults without pre-existing cardiovascular or cerebrovascular disease METHODS: Using administrative claims data (2008-2018), we emulated a target trial comparing MI and IS risks in new users of PPIs vs H2 RAs. Treatment was identified using dispensed prescriptions. MI and IS were defined using hospital discharge codes. Inverse probability weighting was used to adjust for confounding, and Cox models to estimate hazard ratios (HRs). Survival curves were estimated using weighted Kaplan-Meier estimators. We identified 1143948 new users of PPIs and 36229 new users of H2 RAs who were free of prevalent cardiovascular or cerebrovascular disease. The mean follow-up time was 6.2years for PPI initiators and 5.3years for H2 RA initiators. After 10years, the HRs for MI and IS were 0.96 (95% confidence interval (CI): 0.80-1.16) and 0.98 (95% CI: 0.89-1.08), respectively. This analysis of claims data of a large German health insurer did not provide evidence that PPI therapy increased the risk of MI or IS in the first decade after treatment initiation.

Effectiveness Of Ranitidine Providing Compared With Omeprazol In Children With Gastroesofageal Reflux Disease

Background. The drugs that are often given to children with GERD are stomach acidsuppressants, namely the H2 receptor antagonist and proton pump inhibitor (PPI) classof drugs, but the effectiveness of the two drugs is still controversial. Objective. Toevaluate the use of PPIs and H2 RA in children with GERD through evidence-basedcase studies. Methods. Systematic search for literature using the search instrumentPUBMED, Cochrane, Google Scholar, Pediatrica Indonesiana, and Sari Pediatri.Searches included systematic review articles, randomized controlled clinical trials andcohort studies. Abstract only studies, non-clinical evaluation results, and case reportswere excluded. Results. The study was obtained from three RCT studies comparingthe effectiveness of omeprazole and ranitidine in the treatment of GERD, all of whichhave differences. Azizollahi et al demonstrated that after 2 weeks of standard doses ofomeprazole or ranitidine there was a comparable significant improvement. Ummarinoet al demonstrated that omeprazole was significantly better than high-dose ranitidine.Cucchiara et al (1993) showed that high doses of ranitidine were as good as omeprazole.Another study by Pfefferkorn et al showed no significant effect on the addition ofomeprazole therapy combined with ranitidine in preventing the incidence of NAB. Astudy by Boccia et al comparing omeprazole, ranitidine, and non-therapy, found verylow relapse rates. Conclusion. Evidence regarding the use of ranitidine versusomeprazole in infants and children is lacking. Based on one study specifically in theinfant age group, omeprazole and ranitidine were of comparable effectiveness. A higherdose of ranitidine may have a better effect. In terms of complete symptom relief,omeprazole is likely to be superior to ranitidine.

Acid suppression therapy and its association with spontaneous bacterial peritonitis incidence: A systemic review and meta-analysis.

It is well known that the use of proton pump inhibitor (PPI) is widespread in patients with liver cirrhosis. PPI counteracts H2 receptor inhibitor (H2 RA) with its strong acid suppression effect. However, there is always a concern that PPI use may increase spontaneous bacteria peritonitis (SBP) development in cirrhotic patients. We aimed to investigate the association between acid suppression therapy (i.e. PPI or H2 RA) and SBP through meta-analysis. We searched PubMed, Medline, Web of Science, Cochrane library, and Embase for relevant studies published up to April 2019. Pooled OR and 95% CI were calculated by a random-effects model. Funnel plots and Egger's tests were performed for the evaluation of publication bias. Non-parametric "trim-and-fill" tests were conducted for sensitivity analysis. A total of 20 original articles including 9566 cirrhotic patients were analyzed. The overall meta-analysis highlighted that PPI use was associated with the risk of SBP (pooled OR 1.77, 95% CI 1.49-2.11). The conclusion was irrespective of study methods, whereas the result was inconsistent only in South America. However, the conclusion might not be stable enough and should be extrapolated with caution. Unlike PPI, we found H2 RA was not associated with SBP (pooled OR 1.06, 95% CI 0.75-1.48). In conclusion, PPI use, but not H2 RA, will increase the incidence of SBP in cirrhotic patients. In addition, H2 RA might be beneficial for patients who require long-term acid suppression therapy.

Effect of Gastric Acid Suppressants on Response to a Physical Activity Intervention and Major Mobility Disability in Older Adults: Results from the Lifestyle Interventions for Elders (LIFE) Study.

Proton pump inhibitors (PPIs) and histamine2 receptor antagonists (H2 RAs) are associated with pharmacologic effects that may be detrimental to mobility and response to physical activity. Mobility disability and injurious fall outcomes in PPI and H2 RA users were compared with nonusers in this secondary analysis of data from the Lifestyle Interventions for Elders (LIFE) study. Participants ages 70-89years were randomized to a physical activity (PA) or successful aging intervention and evaluated by medication use. Confounders included baseline demographic characteristics, physical function, cognitive function, sleep quality, and acid reflux symptoms that were adjusted via propensity score weighting. Outcomes were incident and persistent major mobility disability (MMD and pMMD) and injurious falls. Weighted proportional hazard models evaluated independent and interaction effects of PPIs and H2 RAs. No interaction was found between PPIs and H2 RAs and the PA intervention. Drug use associations were significant for H2 RAs (hazard ratio [HR] 1.74 [95% confidence interval [CI] 1.12-2.68]) and PPIs (HR 1.32 [95% CI 1.02-1.70]) compared with nonusers for pMMD. PPIs were associated with increased injurious falls compared with nonusers (HR 1.44 [95% CI 1.06-1.96]). Pooling of data from the H2 RA and PPI exposure groups showed a 26% increase in MMD (HR 1.26 [95% CI 1.07-1.48]), a 44% increase in pMMD (HR 1.44 [95% CI 1.16-1.77]), and a 48% increase in injurious falls (HR 1.48 [95% CI 1.15-1.91]) compared with nonusers. All direct comparisons between PPIs and H2 RAs were nonsignificant. Compared with nonusers, participants using either PPIs or H2 RAs had an increased risk of MMD, pMMD, and injurious falls. It is not known if these effects are related to the individual pharmacology of each medication, reduced acid secretion, or the underlying disease state. Further study is required to determine causality.

Efficacy of Surgicel® (Fibrillar) for preventing bleeding after endoscopic submucosal dissection for gastric epithelial tumors.

Surgicel (Fibrillar), i.e. oxidized regenerated cellulose, is used to control oozing bleeding after surgery, but few studies have assessed its effect on complications after endoscopic treatment. The aim of this study was to evaluate the efficacy of Surgicel for preventing bleeding after endoscopic submucosal dissection (ESD) for gastric epithelial tumors. From November 2012 to December 2013 patients scheduled for ESD of gastric epithelial tumors were prospectively enrolled in this study. Patients were assigned randomly to monotherapy with a proton pump inhibitor (PPI) (the MT group) or combination therapy with Surgicel and histamine-2 receptor antagonist (H2 RA) (the CT group) for preventing bleeding after ESD. Major bleeding rates and changes in hemoglobin at 1 and 7 days after ESD were evaluated. Among the 157 patients enrolled (111 men, 46 women), 78 were assigned to the MT group and 79 to the CT group; finally, 72 and 74 patients were included in the MT and CT groups. The major bleeding rate was lower in the CT group (6/74, 8.1%) than in the MT group (12/72, 16.7%), but the difference was not significant (P = 0.354). The change in hemoglobin was significantly less marked in the CT group than the MT group 1 day after ESD ([-6.2 ± 9.0] g/L vs [-8.9 ± 6.2] g/L, P = 0.045). Combination therapy with Surgicel and an H2 RA decreased the rate of bleeding similarly to PPI. Adding Surgicel to H2 RA could be considered for patients with bleeding tendencies, or who require continuous antiplatelet therapy to prevent bleeding after ESD.

Re-evaluating the Utility of Stress Ulcer Prophylaxis in the Critically Ill Patient: A Clinical Scenario-Based Meta-Analysis.

Because recent studies have challenged the efficacy of stress ulcer prophylaxis (SUP) in the critically ill patient, our objective was to evaluate the efficacy of SUP with proton pump inhibitors (PPIs) or histamine2 -receptor antagonists (H2 RAs) against placebo, control, no therapy, or enteral nutrition alone in critically ill adults. Meta-analysis with trial sequential analysis (TSA) of 34 randomized controlled trials. A total of 3220 critically ill adults who received PPIs or H2 RAs versus placebo, control, no therapy, or enteral nutrition. A systematic review was performed using a random effects meta-analysis with TSA according to a predefined protocol. Randomized controlled trials comparing PPIs or H2 RAs with either placebo, control, no therapy, or enteral nutrition alone were identified through a comprehensive search of the literature. Two blinded reviewers independently assessed studies for inclusion, risk of bias, and extracted data using Cochrane Collaborative methodology. The predefined primary outcomes were clinically important, overt, and any (clinically important plus overt) gastrointestinal bleeding. Secondary outcomes included pneumonia, Clostridium difficile-associated diarrhea (CDAD), and mortality. Subgroup analyses were conducted for the primary outcome by PPI or H2 RA use, intensive care unit (ICU) subtype, studies published after early goal-directed therapy (EGDT), the presence of risk factors for stress ulceration, and enteral nutrition use. Of the 34 trials included, 33 were judged as high risk of bias and 1 was judged as low risk. Use of SUP significantly reduced clinically important bleeding (risk ratio [RR] 0.53, 95% confidence interval [CI] 0.37-0.76, p<0.001; I2 =0%), overt bleeding (RR 0.55, 95% CI 0.39-0.76, p=0.0003; I2 =53%), and any bleeding (RR 0.54, 95% CI 0.41-0.71, p<0.00001; I2 =58%). TSA confirmed these findings. No significant differences in pneumonia, CDAD, or mortality were noted. Subgroup analyses revealed significant reductions in clinically important bleeding with SUP in neurosurgical patients (RR 0.37, p<0.05) but not in surgery/trauma or medical ICU patients with risk factors. SUP provided no benefit in studies published after EGDT. SUP significantly reduced clinically important bleeding regardless of the use of enteral nutrition (p<0.05). This meta-analysis demonstrated that SUP use was associated with significant reductions in bleeding but not mortality. SUP should not be abandoned until large randomized trials demonstrate the futility of this intervention.

Acid-suppressive drugs and risk of kidney disease: A systematic review and meta-analysis.

More concerns had been raised about the risk of kidney disease (KD) associated with acid-suppressive drugs. But whether they could directly increase such risk remained unclear. Meta-analysis was conducted to comprehensively investigate this relationship. PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and three Chinese databases were searched until April 2017 for observational studies investigating the associations between acid-suppressive drugs and KD. Pooled log (odds ratios [ORs]) or log (hazard ratios [HRs]) with standard errors for KD risk were calculated using the generic inverse variance method and random-effect model. Ten studies involving 128020 KD patients were included. Proton pump inhibitor (PPI) therapy was associated with higher risks of acute interstitial nephritis (OR, 2.78; 95% confidence interval [CI], 1.25-6.17), acute kidney injury (AKI) (HR, 1.85; 95% CI, 1.33-2.59), chronic kidney disease (CKD) (HR, 1.47; 95% CI, 1.03-2.09), and end-stage renal disease (ESRD) (HR, 1.61; 95% CI, 1.26-2.04) than non-PPI therapy. Additionally, PPI significantly increased the risks of AKI (HR, 1.32; 95% CI, 1.16-1.51), CKD (HR, 1.28; 95% CI, 1.24-1.33), and ESRD (HR, 1.96; 95% CI, 1.21-3.17) compared with histamine 2 receptor antagonist (H2 RA). Relationship between H2 RA therapy and AKI (OR, 0.98; 95% CI, 0.90-1.07) or CKD (OR, 1.00; 95% CI, 0.89-1.11) was not found. Proton pump inhibitor therapy significantly increased the risks of acute interstitial nephritis, AKI, CKD, and ESRD. Similar risks were not identified for H2 RA therapy. More clinical trials are needed to confirm our findings.

Proton pump inhibitor use and cancer mortality.

Proton pump inhibitors (PPIs) are commonly used as a supplement to cancer therapy. Yet, their effect on cancer mortality is largely unknown. Using data from Danish nationwide registries and Cox models regressing of both propensity scores and drug use, we estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for cancer-specific and noncancer death among PPI users (≥2 prescriptions within six months after diagnosis; n = 36,066) compared with nonusers (<2 prescriptions, n = 311,853) or users of histamine H2 -receptor antagonists (H2 RA; n = 5,152). Adjusted HRs for cancer-specific mortality among postdiagnostic PPI users as compared with nonusers or H2 RA users were 1.29 (95% CI, 1.27-1.32) and 1.15 (95% CI, 1.10-1.20), respectively. HRs for cancer mortality associated with PPI use were highest for ovarian (1.35; 95% CI, 1.20-1.52) and lowest for esophageal cancer (0.91; 95% CI, 0.81-1.04). The associations were stronger among new PPI users after cancer diagnosis, indicating potential confounding. To test the effect of PPIs on tumor growth in a model system free for confounding factors, we investigated the effect of pantoprazole on tumor growth in mice. Pantoprazole (5 mg/kg/day) enhanced tumor growth (p = 0.033) and reduced the antitumor activity of gemcitabine (p = 0.008) in fibrosarcoma-bearing Balb/c mice, but not in immunodeficient Balb/c nude mice. In breast carcinoma-bearing FVB/N mice, pantoprazole had no effect on tumor growth alone but it reduced the life-prolonging effect of doxorubicin significantly (p = 0.007). Taken together, these data raise concerns about the increasing use of PPIs and calls for further studies addressing their safety among cancer patients.

Lack of incremental effect of histamine receptor antagonists over proton pump inhibitors on the risk of neoplastic progression in patients with Barrett's esophagus: a cohort study.

Long-term acid suppression reduces the risk of progression to esophageal adenocarcinoma (EAC) in patients with Barrett's esophagus (BE). Given recent reports about the harmful effects of using chronic proton pump inhibitors (PPI) there is renewed interest in alternative methods of acid suppression. Hence, we studied the effect of H2 receptor antagonists (H2 RA) on the risk of progression to neoplasia in our BE cohort. This is a retrospective analysis of prospectively collected data of patients in our BE registry from 2002 to 2015. Patients' characteristics, endoscopic findings, such as the length of BE, hiatal hernia size and histological findings and patients' use of medications such as PPI, aspirin, H2 RA, metformin and antihyperlipidemic agents were studied. The cohort consisted of 1466 patients with a mean age of 61 ± 13 years. The patients had a predominance of male sex (76.7% [1118/1457]) and Caucasian race (96.6% [1209/1252]). After excluding prevalent high-grade dysplasia (HGD) or EAC, 1025 patients had a median follow up of 43.6 months during which 57 patients progressed to HGD or EAC. PPI use (56% in progressors vs 69% in non-progressors; P = 0.007) but not H2 RA use (12% progressors vs 19% in non-progressors P = 0.162) was associated with lower risk of neoplastic progression. On multivariate analysis, there was no synergistic effect of addition of H2 RA to PPI on risk of neoplastic progression to HGD or EAC (relative risk 0.33; confidence intervals 0.05-2.29, P = 0.262). H2 RA do not seem to have a chemopreventive role in patients with BE.

Proton Pump Inhibitors Are Not Associated With Acute Kidney Injury in Critical Illness.

Recent epidemiologic data linking proton pump inhibitor (PPI) use to acute and chronic kidney dysfunction is yet to be validated in other populations, and mechanisms have not been explored. Using a large, well phenotyped inception cohort of 15 063 critically ill patients, we examined the risk of acute kidney injury (AKI), as defined by the Kidney Disease Improving Global Outcomes criteria guidelines, according to prior use of a PPI, histamine-2 receptor antagonist (H2 RA), or neither. A total of 3725 (24.7%) patients reported PPI use prior to admission, while 905 (6.0%) patients reported H2 RA use. AKI occurred in 747 (20.0%) and 163 (18.0%) of PPI and H2 RA users respectively, compared to 1712 (16.2%) of those not taking acid suppressive medications. In unadjusted analysis, PPI and H2 RA users had a 28% (95%CI 1.17-1.41, P< .001) and 10% (95%CI 0.91-1.30, P = .31) higher risk of AKI compared to those taking neither class of medication. However, in sequential models that included adjustment for demographics, cardiovascular comorbidities, indications for PPI use, and severity of illness, the effect of PPI on the risk of AKI was attenuated, and in the adjusted analysis, PPI was not associated with AKI (OR 1.02; 95%CI 0.91-1.13, P = .73). The presence of sterile pyuria and hypomagnesemia did not modify the association between PPI use and AKI. In summary, after adjustment for demographics, illness severity, and the indication for PPI use, PPI use prior to admission is not associated with critical illness AKI.

Concomitant Administration of a Histamine2 Receptor Antagonist and Proton Pump Inhibitor Enhances Gastric Acid Suppression

Because it has been hypothesized that histamine2 receptor antagonists (H2 RAs) might interfere with the action of proton pump inhibitors (PPIs) when the drugs are given concomitantly, we sought to compare the pharmacodynamic effects of simultaneous administration of a PPI and an H2 RA with the effects of each drug administered alone. Prospective, randomized, double-blind, three-way crossover study. Esophageal motility laboratory at a large teaching hospital. Twenty-one healthy volunteers. Subjects were randomized to one of three treatment arms: an H2 RA (ranitidine 300 mg) plus placebo, a PPI (omeprazole 40 mg) plus placebo, or ranitidine 300 mg plus omeprazole 40 mg, all given once/day at 8 a.m., 30 minutes before a standard breakfast, for 1 week. The subjects then received the other two treatments, with each treatment period separated by a 1-week washout period. The primary outcome was length of time that the gastric pH remained higher than 4. Secondary outcomes were median gastric pH higher than 4 and percentage of time that the gastric pH remained higher than 4. On day 7, ambulatory intragastric pH was recorded over an 8-hour period in each treatment arm. The combination of ranitidine and omeprazole resulted in a significantly longer time that the gastric pH remained higher than 4 (median 410.5 min [interquartile range (IQR) 298.5-454.25 min]) versus either omeprazole alone (median 356.7 min [IQR 254.9-419.2 min], p=0.023) or ranitidine alone (134.1 min [IQR 99.9-302.5 min], p<0.0001). Median gastric pH was also significantly higher when omeprazole and ranitidine were given in combination (pH 5.92 [IQR 4.75-6.46]) than either omeprazole alone (pH 4.88 [IQR 4.27-6.11], p=0.001) or ranitidine alone (pH 2.31 [IQR 2.04-5.27], p=0.0003). Likewise, the percentage of time that the gastric pH remained higher than 4 was significantly higher when omeprazole and ranitidine were given in combination (median 85.52%) than either omeprazole alone (74.31%, p=0.027) or ranitidine alone (27.94%, p=0.0002). When a PPI and H2 RA were administered concomitantly 30 minutes before breakfast, the H2 RA did not decrease the acid suppressive ability of the PPI; rather, it improved gastric acid control. Thus these results failed to support the initial hypothesis of this study. Further prospective studies are needed to test these findings in patients with gastroesophageal reflux disease as well as those with erosive esophagitis.

Exposure to acid-suppressing drugs during pregnancy and the risk of asthma in childhood: an observational cohort study.

Some research has suggested a potential link between prenatal exposure to proton pump inhibitors (PPIs) or H2 -receptor antagonists (H2 RAs) and the development of childhood asthma. To quantify the relative risk of asthma in children who experienced pre-natal exposure to PPIs and/or H2 RAs, adjusting for potential confounders. In this observational cohort study (NCT01787435), women aged 18-45 years with completed pregnancies between January 1996 and December 2010 were identified from The Health Improvement Network in the United Kingdom, and were linked to infants. Hazard ratios (HRs) were estimated using Cox proportional hazard models. Our analysis identified 2371 prenatally exposed and 7745 unexposed infants. The incidence of asthma (per 1000 person-years) was 19.52 in the unexposed cohort, 23.88 in the PPI cohort and 32.16 in the H2 RA cohort. After adjusting for maternal healthcare utilisation during the year before pregnancy, the HR for asthma in infants whose mothers received prescriptions at any time during pregnancy was 1.12 (95% confidence interval: 0.88-1.44) for PPIs and 1.43 (1.20-1.70) for H2 RAs, when compared with unexposed infants. With further adjustment for maternal comorbidities and other medications, the HR for asthma was 1.03 (0.76-1.40) for PPIs and 1.32 (1.05-1.64) for H2 RAs. Our analysis showed no association between prenatal exposure to PPIs and asthma in childhood after adjusting for confounders. The association found for H2 RAs may be explained largely by underlying environmental or genetic factors, as suggested by reductions in hazard ratio estimates following adjustment for maternal comorbidities.

Famotidine, a Histamine H2 Receptor Antagonist, Does Not Reduce Levodopa‐Induced Dyskinesia in Parkinson's Disease: A Proof‐of‐Concept Study

The neural mechanisms underlying levodopa-induced dyskinesia (LID) in Parkinson's disease (PD) may involve histamine (H2) receptors on striatopallidal pathways. We recently demonstrated that the clinically available oral histamine H2 receptor antagonist (H2 RA), famotidine, can reduce l-dopa-induced chorea in MPTP-lesioned macaques. We hypothesized that famotidine may be useful in the treatment of LID in PD patients. We performed a proof-of-concept, double-blind, randomized, multiple cross-over (4×) trial. Seven PD subjects with bothersome dyskinesia were randomized to oral famotidine 80, 120, and 160mg/day and placebo. Each subject was randomized to receive each of the four treatment phases for 14days followed by a 7-day wash-out period between each treatment phase. The primary outcome measure was change in the Unified Dyskinesia Rating Scale (UDysRS; part III) between placebo and famotidine. Secondary outcomes were UDysRS (parts I and II), Global Impression of Change, Lang-Fahn Activities of Daily Living Dyskinesia Scale, Unified Parkinson's Disease Rating part III, and adverse events (AEs). Outcomes were evaluated pre- and post-treatment per dose and analyzed using a mixed-effects linear model. There was no significant effect of famotidine treatment on any of the primary or secondary outcome measures compared to placebo (each dose and all doses combined). There were no significant AEs. Even though the sample size of the current study is limited, famotidine seems to be safe in patients with PD and LID, but showed no potential as an antidyskinetic agent.

Nonsteroidal Anti‐Inflammatory Drugs, Gastroprotection, and Benefit–Risk

BackgroundGastroprotective agents (GPA) substantially reduce morbidity and mortality with long-term nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin.ObjectiveTo evaluate efficacy of NSAIDs, protection against NSAID-induced gastrointestinal harm, and balance of benefit and risk.MethodsFree text searches of PubMed (December 2012) supplemented with “related citation” and “cited by” facilities on PubMed and Google Scholar for patient requirements, NSAID effectiveness, pain relief benefits, gastroprotective strategies, adherence to gastroprotection prescribing, and serious harm with NSAIDs and GPA.ResultsPatients want 50% reduction in pain intensity and improved fatigue, distress, and quality of life. Meta-analyses of NSAID trials in musculoskeletal conditions had bimodal responses with good pain relief or little. Number needed to treat (NNTs) for good pain relief were 3 to 9. Proton pump inhibitors (PPI) and high-dose histamine-2 receptor antagonists (H2RA) provided similar gastroprotection, with no conclusive evidence of greater PPI efficacy compared with high-dose H2RA. Prescriber adherence to guidance on use of GPA with NSAIDS was 49% in studies published since 2005; patient adherence was less than 100%. PPI use at higher doses over longer periods is associated with increased risk of serious adverse events, including fracture; no such evidence was found for H2RA. Patients with chronic conditions are more willing to accept risk of harm for successful treatment than their physicians.ConclusionGuidance on NSAIDs use should ensure that patients have a good level of pain relief and that gastroprotection is guaranteed for the NSAID delivering good pain relief. Fixed-dose combinations of NSAID plus GPA offer one solution.

Prophylaxis for stress-related gastrointestinal hemorrhage

The incidence of clinically important stress-related gastrointestinal hemorrhage (SRGIH) has decreased without the use of prophylaxis. This decline is probably attributable to improved care in the modern intensive care unit: aggressive correction of hypovolemia, adequate respiratory support, maintenance of tissue perfusion, and improved nutritional support. The majority of patients admitted to intensive care units are not at risk of developing clinically important SRGIH. Patients who are at high risk for SRGIH, and who may, therefore, benefit from prophylaxis, are those with at least one of the factors listed in Table 1. Antacids, histamine type 2-receptor antago-nists (H2 RA), proton pump inhibitors, and sucralfate all provide comparable protection from SRGIH. The choice of pharmacologic agent for prophylaxis therefore depends on other considerations, such as cost, side effects, and ease of administration. In this regard, it is still unclear whether these prophylactic medications increase the inci-dence of nosocomial pneumonia when administered to intensive care unit patients. Antacids may pose the greatest risk for developing pneumonia, followed by H2RA, and sucralfate. More research is necessary to resolve this important issue. Pharmacologic prophylaxis for SRGIH is cost effective only in high- risk populations. Based on existing literature, the cost of using of routine prophylaxis is prohibitive for at least two-thirds of patients admitted to intensive care units who are at low risk of SRGIH. When prophylaxis is administered to high-risk patients, the cost-per-averted-bleeding episode for sucralfate is lower than for other medications.

Quantitation of glycolysis and skeletal muscle glycogen synthesis in humans.

We measured the net rates of skeletal muscle glycogen synthesis and glycolysis (conversion of [3-3H]glucose to 3H2O) in healthy overnight-fasted volunteers. Two studies were performed. In study 1, seven subjects participated in two paired infusions under basal conditions of either [2-3H]glucose (H2) or [3-3H]glucose (H3). Total glucose uptake (Rd) and rates of whole body 3H2O formation (3H2O Ra) were measured. With H2, Rd and 3H2O Ra were similar. With H3, 3H2O Ra, equal to glycolysis, was 65% of Rd. In study 2, six different subjects underwent a 3-h, 40 mU.m-2 x min-1 euglycemic insulin clamp. [6,6-2H2]glucose was infused throughout and H3 was infused during the last hour of the study. Open muscle biopsies were obtained at 150 and 180 min. Glycogen synthesis was assessed by three independent means: 1) direct measurement, as 3H disintegrations per minute in isolated muscle glycogen per plasma H3 specific activity; 2) extrapolation from the activity of glycogen synthase assayed in the presence of the concentrations of glucose 6-phosphate and UDP-glucose measured in the biopsy; and 3) the difference between Rd and glycolysis. Despite a wide range in Rd [24.5-58.8 mumol.kg fat-free mass (FFM)-1 x min-1] and glycolysis (14.2-26.1), the three methods yielded similar results of 20.0 +/- 3.9, 22.5 +/- 3.7, and 20.6 +/- 3.7 mumol.kg FFM-1 x min-1 and correlated highly with each other (r2 = 0.92-0.96). Our results (study 1) indicate that the rate of plasma tritiated water formation reflects the intracellular detritiation of tritiated glucose. Under hyperinsulinemic conditions (study 2) the net rate of muscle glycogen synthesis can be accurately estimated from the glycogen synthase activity and from the difference between total glucose uptake and glycolysis. Thus, at high physiological plasma insulin concentrations resulting in submaximal stimulation of muscle glycogen synthesis, the latter can be accurately measured in humans.