Risk of Post-Myocardial Infarction Pneumonia with Proton Pump Inhibitors, H2 Receptor Antagonists and Mucoprotective Agents: A Retrospective Nationwide Cohort Study

Patients with myocardial infarction (MI) are at high risk of developing pneumonia. Proton pump inhibitors (PPI) and H2-receptor antagonists (H2RA) are commonly used acid-suppressive medications to the patients with MI for gastrointestinal (GI) protection, which may increase the risk for pneumonia. We evaluated whether PPI, H2RA, and mucoprotective agents without anti-acid properties increase the risk of post-MI pneumonia. We performed a retrospective cohort study based on the National Health Insurance Service—National Sample Cohort in Korea. The study included 3701 patients discharged with MI without prior history of pneumonia. During follow-up, treatments with PPI, H2RA, and mucoprotective agents were collected as time-dependent variables based on the prescription records. We performed multivariate time-dependent Cox regression analyses for the development of post-MI pneumonia. During the mean 4.85 ± 3.75 years follow-up, 999 participants developed pneumonia. In the multivariate analyses (adjusted hazard ratio; 95% confidence interval), the risk for pneumonia was significantly increased in treatment with PPI (2.25; 1.57–3.21) and H2RA (1.50; 1.16–1.93). Meanwhile, the risk for pneumonia was not increased in treatment with mucoprotective agents. When we evaluated GI bleeding event according to the medications as a secondary outcome analysis, mucoprotective agents were associated with increased GI bleeding risk, but PPI and H2RA were not. In the use of the GI medications in the treatment of patients with MI, the influence of these drugs on bleeding and pneumonia should be considered.

Clinical Evidence for Improved Outcomes with Histamine Antagonists and Aspirin in 22,560 COVID-19 Patients

COVID-19 has spurred much interest in the therapeutic potential of repurposed drugs. A family of acid-reducing drugs, known as histamine H2 receptor antagonists (H2RA), competitively bind the H2R and block its stimulation by histamine; examples of such drugs are famotidine (e.g., Pepcid) and ranitidine (e.g., Zantac). A dense web of functionalities between histamine and H2RAs, on the one hand, and downstream cellular pathways, on the other hand, links disparate physiological pathways in gastrointestinal contexts (e.g., acid reduction) to the dysregulated inflammatory cascades (cytokine storm) underlying the pathophysiology of COVID-19. Is famotidine beneficial in treating COVID-19? This question remains unresolved, though not for lack of effort: over 10 studies have examined the potential therapeutic value of famotidine in COVID-19, but have found conflicting results (pro-famotidine, anti-famotidine, and neutral). Given the contradictory reports, we have undertaken the new analysis reported herein. Notably, studies published thus far rest upon substantially smaller datasets than drawn upon in the pre-sent work. We analyzed a cohort of 22,560 COVID-19 patients taking H1/H2 receptor antagonists, focusing on 1,379 severe cases requiring respiratory support. We analyzed outcomes for treatment with the H1RAs loratadine (e.g., Claritin) and cetirizine (e.g., Zyrtec), the H2RA famotidine, aspirin, and a famotidine & aspirin combination. For cases that reached the point of respiratory support, we found a significantly reduced fatality risk for famotidine treatment. We did not detect a benefit from dual-histamine receptor blockade (concurrently targeting H1 and H2 receptors). Notably, famotidine combined with aspirin did exhibit a significant synergistic survival benefit (odds ratio of 0.55). The relative risk for death decreased by 32.5%--an immense benefit, given the more than 2.6 million COVID-19-related deaths thus far. We found lower levels of serum markers for severe disease (e.g., C-reactive protein) in famotidine users, consistent with prior findings by others and with a role for famotidine in attenuating cytokine release. The large, international, multi-center retrospective study reported here, sampling over 250,000 COVID-19 cases, hopefully helps clarify the possible value of clinically-approved histamine antagonists such as famotidine. Given these findings, alongside the cost-effectiveness and mild side-effects of popular drugs like famotidine and aspirin, we suggest that further prospective clinical trials, perhaps utilizing the aspirin combination reported here, are advisable.

Hematidrosis: Pathophysiology and Therapeutic Strategy

Background: Hematidrosis is an extremely rare and mysterious disorder. The etiology and pathophysiology of this disorder remain mostly unknown, and there is no specific therapeutic strategy available up to now.Methods: The clinical features, hemostatic and other laboratory tests, and bloody exudates of seven patients were investigated, and histologic examination of the affected skin was performed. They were treated with a new therapeutic regimen. Results: The bleeding episodes could appear under different conditions, but often following physical or emotional stress, with some prodromes. The frequency and amount of bleeding varied with each individual. The effluent bloody samples showed all the components of the peripheral blood, mingled with a few epithelial cells. Histologic examination of the affected skin showed normal sweat glands containing no blood. Each of patients was treated individually, and a multi-drug "cocktail therapy" regimen mainly consisting of beta-receptor blocker, anxiolytic, and histamine H1/H2 receptor antagonists proved successful. Although most patients could relapse within 6 to 12 months, the treatment was still effective and they were finally cured. Conclusion: nervous system-hypothalamus-autonomic nervous system pathway in association with histaminergic activation. A multi-drug "cocktail therapy" in accordance to this hypothesis would become a new effective regimen.

Maculopapular delayed exanthema due to ranitidine

Ranitidine is a widely used drug in Europe and its intake is usually well tolerated. Hypersensitivity reactions due to ranitidine are uncommon. The immediate mild reactions type are the most prevalent. In some special cases a delayed type reaction such as contact dermatitis or severe reactions with systemic involvement have been reported. In the present paper, a case report of a 78-year old patient who experienced a maculopapular eruption after 7 days of oral treatment with ranitidine is described. Patch tests were performed twice with ranitidine with positive results confirming the diagnosis. In order to discard a double sensitization and a possible cross-reactivity phenomenon, patch test was performed once with famotidine, with a negative result. This is the first maculopapular exanthema reported as type IV hypersensitivity reaction to ranitidine confirmed by patch testing. Moreover, there are only two reported cases showing a double sensitization to ranitidine and to other H2-receptor antagonists by patch testing after a delayed reaction due to ranitidine, the other being H2-receptor antagonists involving cimetidine and nizatidine, not famotidine.

Studies on Histamine H2-Receptor Antagonists by Using Density Functional Theory

Density functional theory (DFT) is a quantum mechanical approach used to investigate the electronic structure (principally the ground state) of many-body systems, in particular atoms, molecules, and the condensed phases. In this work, we have used DFT/B3LYP/6-31+G(d) level of theory to get insight into the molecular geometry and thermochemical properties of histamine H2-receptor antagonists. Histamine H2-receptor antagonists or H2 blockers are a group of pharmaceutical ingredients that reduce the amount of acid produced by the cells in the lining of the stomach. The potential H2 blockers include cimetidine, famotidine, nizatidine, and ranitidine. The detailed theoretical investigation on the listed H2 blockers in terms of their thermochemical parameters and global descriptive parameters revealed that, though famotidine is the best among them with highest Gibbs free energy, nizatidine showed higher biological activity with high softness, low hardness, and high electrophilicity index. The theoretical vibrational spectra of these four Histamine H2-receptor antagonists were analyzed and the infrared spectra of nizatidine was compared with the experimental IR spectra, and found to be good agreement with the experimental values. Further, frontier molecular orbitals especially the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) were determined and the activation energy of the selected samples were calculated. In addition to this, the amorphisation technique were employed to enhance the solubility and bio availability of the best biologically active H2 blocker nizatidine using broadband dielectric spectroscopy.

Histamine H2-Receptor Antagonists Improve Non-Steroidal Anti-Inflammatory Drug-Induced Intestinal Dysbiosis

Dysbiosis, an imbalance of intestinal flora, can cause serious conditions such as obesity, cancer, and psychoneurological disorders. One cause of dysbiosis is inflammation. Ulcerative enteritis is a side effect of non-steroidal anti-inflammatory drugs (NSAIDs). To counteract this side effect, we proposed the concurrent use of histamine H2 receptor antagonists (H2RA), and we examined the effect on the intestinal flora. We generated a murine model of NSAID-induced intestinal mucosal injury, and we administered oral H2RA to the mice. We collected stool samples, compared the composition of intestinal flora using terminal restriction fragment length polymorphism, and performed organic acid analysis using high-performance liquid chromatography. The intestinal flora analysis revealed that NSAID [indomethacin (IDM)] administration increased Erysipelotrichaceae and decreased Clostridiales but that both had improved with the concurrent administration of H2RA. Fecal levels of acetic, propionic, and n-butyric acids increased with IDM administration and decreased with the concurrent administration of H2RA. Although in NSAID-induced gastroenteritis the proportion of intestinal microorganisms changes, leading to the deterioration of the intestinal environment, concurrent administration of H2RA can normalize the intestinal flora.

Association of Proton Pump Inhibitor and Histamine H2-Receptor Antagonists with Restless Legs Syndrome

Restless Legs Syndrome (RLS) is a common sensorimotor disorder, which can disrupt sleep and is thought to be caused in part by low cellular iron stores. Proton pump inhibitors (PPI) and histamine H2-receptor antagonists (H2A) are among the most commonly used drugs worldwide and show evidence of causing iron deficiency. We conducted a case/non-case observational study of blood donors in the U.S. (N=13,403; REDS-III) and Denmark (N=50,323; Danish Blood Donor Study, DBDS), both of which had complete blood count measures and a completed RLS assessment via the Cambridge Hopkins RLS questionnaire (CH-RLSq). After adjusting for age, sex, race, BMI, blood donation frequency, smoking, hormone use, and iron supplement use, PPI/H2A use was associated with RLS (Odds Ratio [OR] = 1.41; 95% confidence interval [CI], 1.13-1.76; P=0.002) in REDS-III for both PPI (OR = 1.43; CI, 1.03 – 1.95; P = 0.03) and H2A (OR = 1.56; CI, 1.10 – 2.16; P = 0.01). DBDS exhibited a similar association with PPIs/H2As (OR = 1.29; CI, 1.20 - 1.40; P < 0.001), and for PPIs alone (OR = 1.27; CI, 1.17-1.38; P < 0.001), but not H2As alone (OR = 1.18; CI, 0.92-1.53; P = 0.2). We found no evidence of blood iron stores mediating this association. The association of PPI, and possibly H2A, consumption with RLS independent of blood iron status and other factors which contribute to RLS risk suggest the need to re-evaluate use of PPI/H2A in populations at particular risk for RLS.

Comparative histological and histochemical studies between ranitidine and nizatidine in treatment of peptic ulcer with evaluation of their adverse effects on male sex hormones

Background Peptic ulcer is an excoriated area of stomach or intestinal mucosa. Two experimental designs were proceeded: the first aimed. on twenty adult male albino rats, used to study the protective effect of both ranitidine and nizatidine; on the second, including sixty adult male albino rats, was used to study the therapeutic effect of ranitidine and nizatidine after induction of ulcer and also to evaluate the adverse effects of therapeutic doses of H2-receptor antagonists on male hormonal profile. The study aims to assess the gastroprotective effects of nizatidine and ranitidine and on treating of non-steroidal anti-inflammatory drugs (NSAIDs) induced peptic ulcer and to evaluate its adverse effect on male sex hormones. Result The result revealed that ranitidine and nizatidine reduced incidence of ulceration. Histopathological findings showed a significant recovery of the alteration, and disturbance in male sex hormones. Conclusion Nizatidine is better than ranitidine in the management of NSAIDs induced peptic ulcer in rats.