Proton pump inhibitors therapy vs H_2 receptor antagonists therapy for upper gastrointestinal bleeding after endoscopy: A meta-analysis

AIM: To compare the therapeutic effects of proton pump inhibitors vs H2 receptor antagonists for upper gastrointestinal bleeding in patients after successful endoscopy.METHODS: We searched the Cochrane library, MEDLINE, EMBASE and Pub Med for randomized controlled trials until July 2014 for this study. The risk of bias was evaluated by the Cochrane Collaboration's tool and all of the studies had acceptable quality. The main outcomes included mortality, re-bleeding, received surgery rate, blood transfusion units and hospital stay time. These outcomes were estimated using odds ratios(OR) and mean difference with 95% confidence interval(CI). Rev Man 5.3.3 software and Stata 12.0 software were used for data analyses. RESULTS: Ten randomized controlled trials involving 1283 patients were included in this review; 678 subjects were in the proton pump inhibitors(PPI) group and the remaining 605 subjects were in the H2 receptor antagonists(H2RA) group. The meta-analysis results revealed that after successful endoscopic therapy, compared with H2 RA, PPI therapy had statistically significantly decreased the recurrent bleeding rate(OR = 0.36; 95%CI: 0.25-0.51) and receiving surgery rate(OR = 0.29; 95%CI: 0.09-0.96). There were no statistically significant differences in mortality(OR = 0.46; 95%CI: 0.17-1.23). However, significant heterogeneity was present in both the numbers of patients requiring blood transfusion after treatment [weighted mean difference(WMD),-0.70 unit; 95%CI:-1.64- 0.25] and the time that patients remained hospitalized [WMD,-0.77 d; 95%CI:-1.87- 0.34]. The Begg's test(P = 0.283) and Egger's test(P = 0.339) demonstrated that there was no publication bias in our meta-analysis.CONCLUSION: In patients with upper gastrointestinal bleeding after successful endoscopic therapy, compared with H2 RA, PPI may be a more effective therapy.

Effects of 5-HT2B, 5-HT3 and 5-HT4 receptor antagonists on gastrointestinal motor activity in dogs

AIM:To study the effects of 5-hydroxytryptamine(5-HT)receptor antagonists on normal colonic motor activity in conscious dogs.METHODS:Colonic motor activity was recorded using a strain gauge force transducer in 5 dogs before and after 5-HT2B,5-HT3 and 5-HT4 receptor antagonist administration.The force transducers were implanted on the serosal surfaces of the gastric antrum,terminal ileum,ileocecal sphincter and colon.Test materials or vehicle alone was administered as an intravenous bolus injection during a quiescent period of the whole colon in the interdigestive state.The effects of these receptor antagonists on normal gastrointestinal motor activity were analyzed.RESULTS:5-HT2B,5-HT3 and 5-HT4 receptor antagonists had no contractile effect on the fasting canine terminal ileum.The 5-HT3 and 5-HT4 receptor antagonists inhibited phaseⅢof the interdigestive motor complex of the antrum and significantly inhibited colonic motor activity.In the proximal colon,the inhibitory effect was dose dependent.Dose dependency,however,was not observed in the distal colon.The 5-HT2B receptor antagonist had no contractile effect on normal colonic motor activity.CONCLUSION:The 5-HT3 and 5-HT4 receptor antagonists inhibited normal colonic motor activity.The5-HT2B receptor antagonist had no contractile effect on normal colonic motor activity.

Spectrofluorimetric method for determination of some angiotensin II receptor antagonists

A simple, rapid, accurate and highly sensitive spectrofluorimetric method has been developed for determination of some angiotensin II receptor antagonists (AIIRA’s), namely Losartan potassium (Los-K), Irbesartan (Irb), Valsartan (Val) and Candesartan cilexetil (Cand) in pure forms as well as in their pharmaceutical dosage forms. All the variables affecting the relative fluorescence intensity (RFI) were studied and optimized. Under the optimum conditions, linear relationships with good correlation coefflcients (0.9982–0.9991) were obtained over the concentration range from 0.006 mg/mL to 1.7 mg/mL. Good accuracy and precision were successfully obtained for the analysis of tablets containing each drug alone or combined with hydrochlorothiazide (HCTZ) without interferences from the co-formulated HCTZ or the additives commonly present in tablets.

Endothelin receptor antagonists for the treatment of diabetic nephropathy:A meta-analysis and systematic review

BACKGROUND Diabetic nephropathy(DN)is the main cause of chronic kidney disease and endstage renal disease worldwide.Although available clinical trials have shown that endothelin receptor(ER)antagonists may be a novel and beneficial drug for DN,no consistent conclusions regarding their sufficient effectiveness and safety for patients with DN have been presented.AIM To assess the effectiveness and safety of ER antagonists among patients with DN.METHODS The EMBASE,PubMed,MEDLINE,Cochrane,and ClinicalTrials.gov databases were searched without any language restrictions.Relative risks with 95%confidence intervals(CIs)for dichotomous data and mean differences or standardized mean difference with 95%CIs for continuous data were calculated using Review Manager 5.3 software.Publication bias was assessed using Egger’s test with Stata/SE software.RESULTS We enrolled seven studies with six data sets and 5271 participants.The ER antagonists group showed a significantly greater reduction in albuminuria and more patients with 40%reduction in urinary albumin-to-creatinine ratio than the control group(P<0.0001 and P=0.02,respectively).Subgroup analysis for reductions in estimated glomerular filtration rate(eGFR)showed that for the middle-dosage subgroup,the ER antagonists group exhibited lower eGFR reduction than the control group(P<0.00001;mean difference,0.7095%CI:0.66,0.74).Moreover,significant reductions in systolic and diastolic blood pressure were observed in the invention group.CONCLUSION ER blockades combined with angiotensin converting enzyme inhibitor/angiotensin II type 1 receptor blockers may be an effective treatment to lower blood pressure and reduce proteinuria in DN with declined eGFR.However,attention should be given to adverse events,including cardiac failure,anemia,and hypoglycemia,as well as serious adverse events.

Design and synthesis of 2-alkylbenzimidazole derivatives as novel non-peptide angiotensin Ⅱ AT1 receptor antagonists

A series of 2-alkylbenzimidazole derivatives 9a-n have been designed and synthesized as a novel class of non-peptide angiotensin H AT1 receptor antagonists. The synthesized compounds were evaluated for their antagonism of angiotensin H, induced contraction in the rabbit thoracic aortic ring and the results showed that compounds 9a, 9g and 9j exhibited potent antagonistic activity of AT1 receptor.

Support vector classification for SAR of 5-HT3 receptor antagonists

In this work, support vector classification （SVC） algorithm was used to build structure-activity relationship （SAR） model of the 5-hydroxytryptamine type 3 （5-HT3 ） receptor antagonists with 26 compounds. In a benchmark test, SVC was compared with several techniques of machine learning currently used in the field. The prediction performance of the model was discussed on the basis of the leave-one-out cross-validation. The results show that the accuracy of prediction of SVC model was higher than those of back propagation artificial neural network （BP ANN）, K-nearest neighbor （KNN） and Fisher methods.

Efficacy and anti-inflammatory analysis of glucocorticoid,antihistamine and leukotriene receptor antagonist in the treatment of allergic rhinitis

BACKGROUND There are many adverse reactions in the treatment of allergic rhinitis(AR)mainly with conventional drugs.Leukotriene receptor antagonists,glucocorticoids and nasal antihistamines can all be used as first-line drugs for AR,but the clinical effects of the three drugs are not clear.AIM To examine the impact of glucocorticoids,antihistamines,and leukotriene receptor antagonists on individuals diagnosed with AR,specifically focusing on their influence on serum inflammatory indexes.METHODS The present retrospective study focused on the clinical data of 80 patients diagnosed and treated for AR at our hospital between May 2019 and May 2021.The participants were categorized into the control group and the observation group.The control group received leukotriene receptor antagonists,while the observation group was administered glucocorticoids and antihistamines.Conducted an observation and comparison of the symptoms,physical sign scores,adverse reactions,and effects on serum inflammatory indexes in two distinct groups of patients,both before and after treatment.RESULTS Subsequent to treatment,the nasal itching score,sneeze score,runny nose score,nasal congestion score,and physical signs score exhibited notable discrepancies(P<0.05),with the observation group demonstrating superior outcomes compared to the control group(P<0.05).The interleukin(IL)-6,IL-10,tumor necrosis factor-alpha,Soluble Intercellular Adhesion Molecule-1,Leukotriene D4 after treatment were significantly different and the observation group It is better than the control group,which is statistically significant(P<0.05).Following the intervention,the incidence of adverse reactions in the observation group,including symptoms such as nasal dryness,discomfort in the throat,bitter taste in the mouth,and minor erosion of the nasal mucosa,was found to be 7.5%.This rate was significantly lower compared to the control group,which reported an incidence of 27.5%.The difference between the two groups was statistically significant(P<0.05).CONCLUSION Glucocorticoids and antihistamines have obvious therapeutic effects,reduce serum inflammatory index levels,relieve symptoms and signs of patients,and promote patients'recovery,which can provide a reference for clinical treatment of AR.

Therapy for acute pancreatitis with platelet-activating factor receptor antagonists

Acute pancreatitis (AP) causes release of platelet- activating factor (PAF), which induces systemic effects that contribute to circulatory disturbances and multiple organ failure. PAF is a cell surface secretion of bioactive lipid, which could produce physiological and pathological effects by binding to its cell surface receptor called platelet-activating factor receptor (PAF-R). Studies showed that PAF participates in the occurrence and development of AP and administration of platelet-activating factor receptor antagonists (PAF-RAs) could significantly reduce local and systemic events after AP. PAF has also been implicated as a key mediator in the progression of severe AP, which can lead to complications and unacceptably high mortality rates. Several classes of PAF-RA show PAF- RAs significant local and systemic effects on reducing inflammatory changes. As a preventive treatment, PAF-RA could block a series of PAF-mediated inflammatory injury and thus improve the prognosis of AP. This review introduces the important role of PAF-RA in the treatment of AP.

Effects of mineralocorticoid receptor antagonists on responses to hemorrhagic shock in rats

AIM To evaluate the effects of mineralocorticoid receptor(MR) antagonists on mortality and inflammatory responses after hemorrhagic shock(HS) in rats.METHODS One hundred and two male Sprague–Dawley rats were randomly assigned to one of the following three groups: Control, spironolactone (SPL), and eplerenone(EP) groups. HS was induced by the removal of blood. One half of rats were evaluated to determine mortality, hemodynamics, plasma tumor necrosis factor-alpha(TNF-α) concentrations, and arterial blood gas at 8 h afterHS recovery. In the remainder of rats, the expression levels of genes encoding cytokines were evaluated in liver tissue samples at 1 h after HS recovery. RESULTS The survival rates 8 h after HS recovery were 71%, 94%, and 82% in the control, SPL, and EP groups, respectively. There were no significant differences in survival rates among the three groups (P = 0.219). Furthermore, there were no significant differences in gene expression levels in the liver or plasma TNF-α concentrations among the three groups(P = 0.888).CONCLUSION Pretreatment with MR antagonists did not improve mortality or cytokine responses in the liver after HS recovery in rats.

Effect of endothelin-1 receptor antagonists on histological and ultrastructural changes in the pancreas and trypsinogen activation in the early course of caerulein-induced acute pancreatitis in rats

AIM: To assess the effect of non-selective ETA/B (LU 302872)and selective ETA (LU 302146) antagonist on pancreatic histology and ultrastructure of acinar cells in connection with trypsinogen activation in early caerulein-induced AP.METHODS: Male Wistar rats with caerulein-induced AP,lasting 4 h, were treated i.p. with 10 and 20 mg/kg b.w.of each antagonist. Edema, inflammatory infiltration,necrosis and vacuolization of acinar cells in the pancreas were scored at 0-3 scale. Free active trypsin (FAT), total potential trypsin (TPT) after activation with enterokinase,and index of trypsinogen activation (%FAT/TPT) were assayed in pancreatic homogenates.RESULTS: In untreated AP, the edema, inflammatory infiltration, necrosis and vacuolization increased as compared to control healthy rats (P＜0.01). None of the treatment exerted any meaningful effect on the edema and inflammatory infiltration. The selective antagonist increased slightly the necrosis score to 0.82±0.06 at higher dose (P＜0.05) vs 0.58±0.06 in untreated AP. The nonselective antagonist increased slightly the vacuolization score to 2.41±0.07 at higher dose (P＜0.01) vs 1.88±0.08in untreated AP. The decrease in the number of zymogen granules, disorganization of endoplasmic reticulum,autophagosomes and cytoplasmic vacuoles were more prominent in treated AP than in untreated AP groups.%FAT/TPT in untreated AP increased about four times (18.4±3.8 vs4.8±1.3 in control group without AP, P＜0.001).Treatment of AP with both antagonists did not affect significantly augmented trypsinogen activation.CONCLUSION: The treatment with endothelin-1 receptors (non-selective ETA/B and selective ETA) antagonists has essential effect neither on the edema and inflammatory infiltration nor on trypsinogen activation observed in the early course of caerulein-induced AP. Nevertheless a slight increase of the necrosis and vacuolization score and some of the ultrastructural data could suggest the possibility of their undesired effects in caerulein-induced AP at investigated doses.

The seeming paradox of adenosine receptors as targets for the treatment of Alzheimer's disease: agonists or antagonists?

Alzheimer＇s disease （AD） is the most common neurodegenerative disorder, and its incidence is relatively high among elderly people, affecting about 1-2% of the population between 60-65 years old and rising dramatically （about 30%） in people aged 80 years or older （Selkoe, 2002）. Nowadays, considering the increasing mean lifespan of populations in developed countries, the disease is becoming more and more a health concern, and the search for an effective cure has turned into＂a real need＂.

Head-to-head comparison of H_2-receptor antagonists and proton pump inhibitors in the treatment of erosive esophagitis: A meta-analysis

AIM: To systematically evaluate the efficacy of H2-receptor antagonists (H2RAs) and proton pump inhibitors in healing erosive esophagitis (EE).METHODS: A meta-analysis was performed. A literature search was conducted in PubMed, Medline, Embase, and Cochrane databases to include randomized controlled head-to-head comparative trials evaluating the efficacy of H2RAs or proton pump inhibitors in healing EE. Relative risk (RR) and 95% confidence interval (CI) were calculated under a random-effects model.RESULTS: RRs of cumulative healing rates for each comparison at 8 wk were: high dose vs standard dose H2RAs,1.17 (95%CI, 1.02-1.33); standard dose proton pump inhibitors vsstandard dose H2RAs, 1.59 (95%CI, 1.44-1.75);standard dose other proton pump inhibitors vs standard dose omeprazole, 1.06 (95%CI, 0.98-1.06). Proton pump inhibitors produced consistently greater healing rates than H2RAs of all doses across all grades of esophagitis, including patients refractory to H2RAs. Healing rates achieved with standard dose omeprazole were similar to those with other proton pump inhibitors in all grades of esophagitis.CONCLUSION: H2RAS are less effective for treating patients with erosive esophagitis, especially in those with severe forms of esophagitis. Standard dose proton pump inhibitors are significantly more effective than H2RAs in healing esophagitis of all grades. Proton pump inhibitors given at the recommended dose are equally effective for healing esophagitis.

Novel Method for Synthesis of Diarylpyrazole Derivatives as Cannabinoid CB_1 Receptor Antagonists

A novel and efficient method was developed for the synthesis of diarylpyrazole derivatives as cannabinoid CB1 receptor antagonist via four step reactions. The key step was the synthesis of a diarylpyrazole skeleton, which involved initial condensation of the sodium salt of compound 12 with diazonium compounds, and further cyclization by heating at reflux in acetic acid. Eight diarylpyrazole derivatives and nine new synthesized compounds were characterized by 1H NMR, IR, MS, and elemental analysis. The reaction conditions were mild and the overall yields of the target compounds ranged from 26% to 44%.

Growth Hormone Releasing Hormone Receptors Antagonists and Cancers: Do GHRH-R Antagonists Play a Role in the Management of Prostate Cancer?

Growth hormone-releasing hormone (GHRH) and its receptors have been implicated in the progression of various tumors such as those of the prostate. Treatment modalities for prostate cancer in a localized stage or when it is still castration-sensitive yield good results in most patients. However, such treatments are only palliative in the advanced stage. Therefore, new therapeutic targets like growth hormone-releasing hormone receptor (GHRH-R) and its splice variants should be found in order to get effective treatments for more aggressive stages in prostate cancer. This review talks about the GHRH-R and its splice variants, the signaling pathways induced by GHRH to produce cancer, the structure activity relationship of GHRH-R antagonists and the resume of some in vitro and in vivo studies on the role of GHRH-R antagonists in the treatment of prostate cancer.

Controlling Chemotherapy-Induced Nausea and Vomiting with Neurokinin-1 Receptor Antagonists in Patients on AC-Based Chemotherapy—Are We There Yet?

Chemotherapy-induced nausea and vomiting (CINV) are distressing side effects of chemotherapy. Neurokinin-1 receptor antagonists (NK1-RAs) have been incorporated in the contemporary management of CINV. However, clinical studies on NK1-RAs have shown mixed results in reducing CINV risk. Most studies focused on the use of aprepitant (APR) and casopitant (CAS) in breast cancer patients receiving AC-type (doxorubicin and cyclophosphamide) chemotherapy. In this study, we compared the study design and clinical efficacies of these NK1-RAs in reducing CINV risk. Among the selected eight studies, 4 APR Randomized Controlled Trials (RCTs), 2 APR Observational Studies (OSs) and 2 CAS RCTs were identified. Patient-related characteristics such as the proportion of females (60.0% - 100.0%), age (46.5 - 59.5 years), histories of motion (5.6% - 47.0% in NK1-RA arms) and morning sicknesses (14.2% - 45.0% in NK1-RA arms) and types of antiemetic regimens;as well as chemotherapy-related characteristics such as the proportion of patients on AC chemotherapy (15.0% - 100.0%) varied greatly. In terms of efficacies, both APR and CAS improved overall CR and vomiting in majority of the studies. None of the studies, however, demonstrated that NK1-RA could provide adequate nausea control. To conclude, NK1-RAs are effective in improving vomiting and overall CR, but not useful in controlling nausea or attaining CC, the ideal CINV endpoint. A shift in paradigm is needed for future CINV research. As healthcare providers continue to strive for optimum CINV control in their patients, we hope this review can help them make better informed clinical decisions.

In vivo immunomodulatory profile of histamine receptors(H1,H2,H3 and H4):a comparative antagonists study

Objective:To delineate the comparative immunomodulatory roles of H1R-H4R in antibody generation profile in rabbit model.Methods:The cohort comprised of eight groups containing 18(9 male and 9 female) rabbits in each group.GroupⅠremained non-immunized and received only vehicle(sterile distilled water,1 mL/kg×b.i.d.) intramuscularly.GroupⅡreceived vehicle (1 mL/kg×b.i.d.) while GroupsⅢ-Ⅶ(drugs-treated) received subcutaneous histamine (100μg/kg×b.i.d.),and intramuscular H1R-antagonist(pheniramine,10 mg/kg×b.i.d.), H2R-antagonist(ranitidine,10 mg/kg×b.i.d.),H3R-antagonist(iodophenpropit,1μg/kg×b.i.d.) and H4R-antagonist(JNJ 7777120,10μg/kg×b.i.d.),and GroupⅧDMSO(1 mL/kg×b.i.d.),respectively for 10 days(starting from day 1).They were subsequendy immunized with intravenous injection of sheep red blood cells(SRBC) at day 3.The estimation of serum Igs,IgM and IgG were done by ELISA,and observed at day 0(pre-immunization),and 7,14,21,28 and 58(post-immunization).Results:It was shown that histamine and HRs-antagonists could influence a detectable antibody response to SRBC as early as day 7-post-immunization(post-Ⅰ), which lasted until day 58 post-Ⅰ.The results were found statistically significant(P【0.05,). Conclusions:This study suggests that histamine receptors play important roles in modulation of antibody generation in which H1R,H2R and H4R have immunosuppressive roles and conversely, H3R playes an immune enhancing role.The findings of this study may have clinical significance and provide the baseline information for future study.

Renin-angiotensin system blockers-SGLT2 inhibitorsmineralocorticoid receptor antagonists in diabetic kidney disease:A tale of the past two decades!

Several pharmacological agents to prevent the progression of diabetic kidney disease(DKD)have been tested in patients with type 2 diabetes mellitus(T2DM)in the past two decades.With the exception of renin-angiotensin system blockers that have shown a significant reduction in the progression of DKD in 2001,no other pharmacological agent tested in the past two decades have shown any clinically meaningful result.Recently,the sodium-glucose cotransporter-2 inhibitor(SGLT-2i),canagliflozin,has shown a significant reduction in the composite of hard renal and cardiovascular(CV)endpoints including progression of end-stage kidney disease in patients with DKD with T2DM at the top of reninangiotensin system blocker use.Another SGLT-2i,dapagliflozin,has also shown a significant reduction in the composite of renal and CV endpoints including death in patients with chronic kidney disease(CKD),regardless of T2DM status.Similar positive findings on renal outcomes were recently reported as a top-line result of the empagliflozin trial in patients with CKD regardless of T2DM.However,the full results of this trial have not yet been published.While the use of older steroidal mineralocorticoid receptor antagonists(MRAs)such as spironolactone in DKD is associated with a significant reduction in albuminuria outcomes,a novel non-steroidal MRA finerenone has additionally shown a significant reduction in the composite of hard renal and CV endpoints in patients with DKD and T2DM,with reasonably acceptable side effects.

Histamine_2-receptor antagonists: Rapid development of tachyphylaxis with repeat dosing

Histamine_2-receptor antagonists(H_2RAs) are availableover-the-counter (OTC) for the treatment and prevention of heartburn, but more than occasional, singledose use can lead to rapid development of tachyphylaxis. The aim of this review is to assess the publishedevidence regarding the development of tachyphylaxiswith repeat usage of H_2RAs. PubMed and SCOPUS were searched across all years to identify clinical studies thatexamined the development of tachyphylaxis with repeated dosing of H_2RAs. Although a single (first) doseof an H_2RA can be effective for controlling gastric acidand preventing or relieving food-related heartburn, numerous studies confirm that tachyphylaxis, also knownas tolerance, is consistently detected at the first timepoint assessed after the first dose, including the second day and/or second dose. Even if symptom relief isachieved with an H_2RA, it may be due to desensitizationof the esophagus to acid exposure, potentially providingsymptom relief without significantly decreasing esophageal acid exposure. When recommending OTC drugsfor treatment of frequent heartburn, clinicians shouldbe aware of the potential for rapid development oftachyphylaxis in patients who use H_2RAs for 2 or more consecutive days. Even if symptom relief is achieved, it may be due to desensitization of the esophagus to acid by the H_2RA, potentially providing symptom relief without significantly decreasing esophageal acid exposure. Other strategies, such as an OTC proton pump inhibitor, may be needed to optimize management of frequent heartburn.

Motor Effects of 1,3-Disubstituted 8-Styrylxanthines as A_(1) and A_(2) Adenosine-Receptor Antagonists in Rats

A series of 1,3-substituted 8-styrylxanthines (11a-d) was synthesized, under chemo- and regioselective conditions, in a good overall yield. The compounds showed affinity towards both A1 and A2A-adenosine receptors by radioligand binding by means of in vitro assays. The (E)-3-ethyl-1-propyl-8-styrylxanthine (11a) showed the greatest affinity towards the A2A receptor, whereas (E)-3-pentyl-1-propyl-8-styrylxanthine (11d) showed the greatest affinity for the A1 receptor. When the 8-styrylxanthines 11a (A15Et) and 11c (A15Bu) were administrated in rats, which were previously injured with 6-hydroxydopamine at the substantia nigra pars compacta (SNc), the turning behavior decreased 50%. Based on these results we propose to A15Et as a potential compound to treat some symptoms of Parkinson’s disease.