Dapsone possesses anti-infective and anti-imflammatory properties, but its CYP-mediated metabolism to hydroxylamines causes dose-dependent haematological toxicity which impairs patient tolerance. In the 1990s cimetidine-mediated partial inhibition of the oxidative metabolism of dapsone was demonstrated clinically to lower methaemoglobin formation and subsequent case studies with fragile and immunosuppressed patients with multiple complex pathologies, showed cimetidine could minimize dapsone-mediated methaemoglobin formation in the place of methylene blue, when G6PD status is unknown, is deficient or there is prior sensitization. Pre-clinical and in vitro studies also suggest that prior administration of the antioxidant α-lipoic acid may potentially augment cimetidine's attenuation of dapsone-mediated methaemoglobin's formation through its conversion to dihydrolipoic acid which can restrict methaemoglobin formation within the erythrocyte. Overall, combined with novel buccal dapsone formulations which avoid first-pass metabolism, concomitant α-lipoic acid may augment cimetidine-mediated amelioration of dapsone's- haematological toxicity, potentially promoting the drug's patient tolerance and clinical utility.

Hepatoerythropoietic porphyria (HEP) is a rare autosomal recessive disorder of heme biosynthesis caused by severe deficiency of uroporphyrinogen decarboxylase (UROD). It typically presents in infancy or early childhood with marked photosensitivity, skin fragility, blistering, dyspigmentation, hypertrichosis, and dark urine. We report a girl from Brazil who developed blistering and ulcerative lesions of the face and upper extremities beginning at 10 months of age, along with dark urine and gray discoloration of the teeth. She was 2.5 years old when first evaluated at the Massachusetts General Hospital Porphyria Center. Prior genetic testing in Brazil had already identified two UROD variants, c.239C>G (p.Ala80Gly) and c.464C>T (p.Ala155Val). At our center, erythrocyte UROD activity was markedly reduced to approximately 5% of normal, and plasma, urine, stool, and erythrocyte porphyrins were all substantially elevated, confirming the diagnosis of HEP. Erythrocyte protoporphyrin was 83.5% zinc-chelated. The patient also had persistent mild hepatosplenomegaly and mild transaminase elevation. Management included strict photoprotection and sequential trials of cholestyramine and cimetidine, followed by serial therapeutic phlebotomy while continuing cimetidine. Neither cholestyramine nor therapeutic phlebotomy was associated with clear biochemical improvement, whereas cimetidine was temporally associated with a decline in urinary porphyrins, although other biomarkers were more variable. This case highlights the importance of considering HEP in children with blistering lesions on sun-exposed skin.

Regulatory agencies request the assessment of the potential of new drugs to cause transporter-mediated drug-drug interactions (DDI). This assessment can be improved by integrating endogenous biomarkers during drug development. Regarding the renal excretion of drugs such as metformin, the organic cation transporter (OCT) 2 and multidrug and toxin extrusion proteins (MATE) 1 and 2-K are of major importance. However, fully validated, sensitive, and specific biomarkers for these transporters are still lacking. In previous in vivo and in vitro studies, 5-aminovaleric acid betaine (5AVAB), serotonin (5HT), and 1-methylhistamine (1MH) emerged as promising biomarker candidates for OCT2/MATE-mediated DDI. Therefore, we further investigated their suitability for clinical risk assessment by evaluating the effects of the OCT2/MATE inhibitor trimethoprim in healthy volunteers and by determining IC50 values for the inhibition of OCT2- and/or MATE1-mediated uptake of the potential biomarkers by trimethoprim, cimetidine, pyrimethamine, and dolutegravir in vitro. Trimethoprim reduced the amount excreted into urine of 5AVAB, 5HT, and 1MH in vivo by 95.1 ± 5.67%, 78.9 ± 6.56%, and 51.9 ± 14.3%, respectively (all P < 0.001) as well as the renal clearance of 5AVAB and 5HT by 93.6 ± 5.85% and 73.8 ± 12.8%, respectively (both P < 0.001). When comparing the IC50 values with unbound inhibitor plasma concentrations, trimethoprim, cimetidine, and pyrimethamine preferentially inhibit the MATE1-mediated transport, whereas dolutegravir inhibits the OCT2-mediated transport of the biomarker candidates. In conclusion, this study further supports the suitability of 5-aminovaleric acid betaine (5AVAB), serotonin (5HT), and 1-methylhistamine (1MH) as promising biomarkers for OCT2/MATE-mediated DDI.

Around the world, theophylline (1,3-dimethylxanthine) is primarily used as a bronchodilator for patients with asthma and chronic obstructive pulmonary disease (COPD). However, in the United States, asthma and COPD are mainly treated with other agents, and theophylline is largely used to treat bradycardia and apnea in premature newborns. Theophylline causes the endogenous release of catecholamines through indirect stimulation of beta-1 and beta-2 receptors, which at therapeutic levels cause desired bronchodilation. Unfortunately, theophylline has a narrow therapeutic window, and even levels slightly above this therapeutic window can have many adverse effects in the setting of acute and chronic toxicity. The excess circulating catecholamines cause serious clinical effects that are associated with theophylline toxicity. Depending on the dose and route of administration, theophylline can have a wide range of cardiovascular, neurologic, metabolic, musculoskeletal, and gastrointestinal manifestations. Emergency department providers should become familiar with managing patients with theophylline toxicity since arrhythmias, seizures, hyperglycemia, and rhabdomyolysis are several of the complications that can arise.

The arachnoid mater-forming cells, which exhibit expressions of organic anion and cation transporters, as well as tight junction proteins, form the blood-arachnoid barrier. The purpose of the present study was to clarify the roles of the arachnoid mater transporters in the cerebrospinal fluid (CSF) clearance of prostaglandin D2 (PGD2) and metformin by using an intracisternal administration method for evaluating arachnoid mater-mediated transport in rats. Global proteomics of rat leptomeninges showed the transporter expression of Slc22a6/Oat1, Slc22a8/Oat3, Slco2a1/Oatp2a1, Slc22a2/Oct2, and Slco2b1/Oatp2b1. The CSF clearance of PGD2 and metformin was greater than that of FITC-inulin, which is a marker of CSF bulk flow and parenchymal diffusion. The CSF elimination of PGD2 was significantly inhibited by p-aminohippuric acid, diclofenac (substrates/inhibitors of Slc22a6/Oat1 and Slc22a8/Oat3), and taurocholate (a broad substrate/inhibitor of Slco family transporters), whereas that of metformin was blocked by cimetidine, tetraethylammonium, and thiamine (substrates/inhibitors of Slc22a2/Oct2). The CSF-to-circulating blood transfer of metformin was inhibited by tetraethylammonium. These results suggested that the PGD2 clearance from the CSF most likely occurred via Slc22a6/Oat1, Slc22a8/Oat3, Slco2a1/Oatp2a1, and Slco2b1/Oatp2b1, while the metformin clearance was primarily mediated by Slc22a2/Oct2, in the arachnoid mater. These transporters would regulate the CSF concentrations of pharmacologically active substances and drugs.

Despite sharing tonsillar immune dysregulation as a common pathogenic mechanism, concurrent presentation of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome with immunoglobulin A (IgA) nephropathy (IgAN) remains exceptionally rare, with only 1 previous case reported in the literature receiving multidrug immunosuppressive therapy before tonsillectomy. In this study, we report the first pediatric case in which both conditions achieved sustained remission following early tonsillectomy without additional immunosuppression. A 6-year-old boy with a 3-year history of PFAPA developed gross hematuria coinciding with febrile episodes. Kidney biopsy confirmed IgAN. Owing to the poor response to cimetidine and significant disruption to schooling, palatine tonsillectomy was performed at 7 years. Following surgery, PFAPA episodes completely resolved, and hematuria ceased. Repeat kidney biopsy at 11 months postoperatively showed marked histological improvement, with resolution of mesangial hypercellularity and reduced endocapillary proliferation. This case provides the first pediatric case demonstrating that early tonsillectomy alone can effectively treat coexisting PFAPA and IgAN without the need for additional immunosuppressive therapy. The simultaneous clinical and histological remission supports a shared pathogenic mechanism involving tonsillar immune dysfunction and highlights tonsillectomy as a potentially curative intervention for select patients with concurrent tonsil-driven diseases.

Cimetidine is a drug with the indication of peptic ulcer disease, gastroesophageal reflux disease, and dermatological conditions including warts, urticaria, mastocytosis, and erythropoietic protoporphyria. This medication is an H2 receptor antagonist. This activity will describe cimetidine's indications, actions, and contraindications in these disorders. Cimetidine is available as an over-the-counter medication and by prescription. Therefore, this activity will further highlight the mechanisms of action, adverse effect profile, and other key factors pertinent to interprofessional team members in managing patients by using cimetidine.

Antibiotics are commonly used to treat Enterotoxigenic Escherichia coli (ETEC)-induced diarrhea, but bacterial resistance is worsening and efficacy is unsatisfactory. Based on the functions of intestinal alkaline phosphatase (IAP) such as degrading lipopolysaccharide (LPS), anti-inflammation, and enhancing intestinal barrier function, this study evaluated its therapeutic effect in mice. Thirty SPF BALB/c mice were randomly divided into five groups: the control group, the ETEC model group, and three IAP intervention groups (200, 300, and 400 U/mL). All groups received daily gavage for 3 consecutive days: the Control and ETEC groups were given phosphate-buffered saline (PBS), while the three IAP groups received IAP at their respective doses. On day 4, the model and intervention groups were pretreated with cimetidine followed by ETEC challenge. On day 7, intestinal permeability, inflammatory factors, barrier function, morphological structure, and intestinal LPS level were detected. Results showed IAP alleviated weight loss and reduced disease activity index (DAI), with 400 U/mL restoring DAI to baseline within 96 h. The 300 and 400 U/mL groups degraded LPS content in colonic contents, reduced bacterial load in the liver, improved jejunal morphology, upregulated Occludin, ZO-1, MUC2 expressions, enhanced antioxidant capacity, and downregulated inflammatory factors and TLR4/MyD88/NF-κB pathway genes (all P < 0.05). The 400 U/mL group further reduced diamine oxidase and D-lactate (P < 0.05). In conclusion, IAP effectively alleviated ETEC-induced diarrhea in mice, providing a theoretical basis for the development of novel therapeutic agents against diarrhea.

Inflammatory bowel disease (IBD) is a chronic and recurrent gastrointestinal disease, the pathogenesis of which has not been fully elucidated. Increasing evidence suggests that the disorder of mitochondrial metabolism is closely related to the pathogenesis of IBD, but its specific regulatory network and key genes remain to be further investigated. IBD-related transcriptome datasets (GSE3365 and GSE75214) and single-cell sequencing dataset (GSE134809) were obtained from the Gene Expression Omnibus database. Differentially expressed genes and hub genes were identified through differential expression analysis and weighted gene co-expression network analysis, and candidate genes were obtained by intersecting these with mitochondrial metabolism-related genes, followed by functional enrichment analysis. Machine learning algorithms were used to screen key genes and construct risk prediction models. Additionally, analysis of GSE134809 single-cell data identified characteristic cell types and expression distribution of key genes in IBD and explored communication between different cell types. Furthermore, immune cell infiltration, competitive endogenous RNA (ceRNA) network, and transcription factor prediction were performed. Finally, the diagnostic performance of key genes was validated in GSE75214 and reverse transcription-quantitative polymerase chain reaction. Two key genes, mitochondrial ribosomal protein L35 (MRPL35) and MRPL39, were identified, which were downregulated in IBD, and had good diagnostic potential. Single-cell analysis revealed that key genes were predominantly highly expressed in mononuclear phagocyte (MNP) cells. MNP cells communicated with other cells through receptor ligands including MIF-(CD74 + CXCR4), MDK-SDC1, and ITGB2-ICAM2, which are complexly related to mitochondrial metabolism. With the progression of IBD, infiltration levels of resting natural killer cells, naive B cells, M2 macrophages, and naive CD4 T cells decreased, and correlations between different cells continuously changed. A ceRNA network centered on XIST, hsa-miR-103a-3p, and MRPL35 was constructed. Additionally, therapeutic drugs targeting key genes were predicted, including cimetidine, eugenol, chlortetracycline, vincristine, irinotecan, bisacodyl, and sulpiride, with molecular docking validating high affinity between these drugs and key targets. This study constructed a multiomics integrated analysis strategy and identified MRPL35 and MRPL39 as potential markers and therapeutic targets, providing new insights for the diagnosis and treatment of IBD.

Investigating chitosan nanoparticles (CS NPs) as drug carriers for improving cimetidine delivery (CMT), regulating drug-protein interactions and maintaining protein function, this study considers adsorption mechanisms, molecular interactions, protein conformation and biological function. Characterisation using methods, such as scanning electron microscopy and dynamic light scattering, indicates that CMT is loaded onto CS NPs non-covalently through hydrogen bonding, forming stable complexes with porous structures. The average particle size of the complex is 415.7 nm, and the zeta potential is +31.52 mV. The adsorption kinetics and isotherm fitting results show that the adsorption of CMT on CS NPs follows the pseudo-second-order kinetic model and the Langmuir isotherm adsorption model, with a maximum adsorption capacity of 1.67 mg g[-1]; the adsorption process is spontaneous and exothermic. Under optimal adsorption conditions, the drug loading capacity reaches 9.76%. In vitro simulated digestion experiments demonstrate that the total bioaccessibility of the CS NPs-CMT complex in simulated gastrointestinal environments is enhanced to 80%. Spectral analysis shows that, compared with free CMT, the interaction between CS NPs-CMT complex and bovine serum albumin (BSA) is significantly enhanced, manifesting as greater binding affinity (Kb = 5.57 × 10[6] M[-1]) and strong fluorescence quenching (quenching rate of 59.95%). The CS NPs-CMT complex induces more pronounced structural alterations in BSA (α-helix content decreases from 55.60% to 49.50%). Site-competition experiments reveal that free CMT primarily binds to Site II of BSA, whereas upon loading onto CS NPs, its binding site shifts to Site I. In addition, loading onto CS NPs partially alleviates the competitive inhibition of BSA esterase activity by CMT, while retaining the protective effect of CMT on BSA thiol groups.

A heavy-atom-free and non-toxic spirocyclic C-BODIPY singlet oxygen photosensitizer was successfully incorporated into electrospun polymeric nanofibers. Optimization of the material composition revealed that polycaprolactone (PCL), an FDA- and EMA-approved, biodegradable, easily accessible, and cost-efficient polymer, doped with BODIPY at a concentration of only 0.15 wt %, is an efficient photocatalyst for the degradation of the pharmaceutical agents ranitidine, propranolol, and cimetidine, selected as model water pollutants. The obtained nanofibers showed smooth and uniform morphology along with very high durability and resistance toward oxidation, remaining active even after 20 reaction cycles. EDX, ToF-SIMS and XPS analyses confirmed the homogenous distribution of BODIPY within the polymeric matrix. Furthermore, the materials showed significant photoinactivation of Staphylococcus aureus under white light irradiation compared to the control experiment performed without irradiation. These findings highlight the potential of the electrospun PCL nanofibers as optimal matrix for the immobilization with singlet oxygen photosensitizers and subsequent application in the decontamination of water from pollutants and pathogens.