Acidifying agents impact erlotinib and gefitinib pharmacokinetic parameters and elevate liver enzymes in Wistar rats

Background: Erlotinib (ERL) and gefitinib (GEF) are extensively metabolized by CYP450 enzymes. Aspartame (ASP), an artificial sweetener, induces CYP2E1 and CYP3A2 enzymes in the brain and could increase liver enzymes. In this work, the influence of ASP on the pharmacokinetics (PK) of ERL and GEF in Wistar rats was evaluated. Methods: The PKs of ERL and GEF were evaluated after receiving 175 mg/kg or 1000 mg/kg of ASP for four weeks using UPLC-MS/MS. Levels of liver enzymes after four weeks of ASP consumption were also evaluated. Results: ASP 175 mg/kg was able to significantly alter levels of Cmax (36% increase for ERL, 38% decrease for GEF), AUC0–72 (205% increase for ERL, 41% increase for GEF), and AUC0–∞ (112% increase for ERL, 14% increase for GEF). Moreover, ASP 175 mg/kg decreased the apparent oral clearance ERL and GEF by 58% and 13%, respectively. ASP 1000 mg/kg increased Cmax of ERL by 159% and decreased GEF’s Cmax by and 73%. Both AUC0–72 and AUC0–∞ were increased by ASP 1000 for ERL and decreased for GEF. CL/F decreased by 64% for ERL and increased by 38.8% for GEF. Moreover, data indicated that ASP significantly increased levels of liver enzymes within two weeks of administration. Conclusions: Although ASP 175 and 1000 mg/kg alter ERL and GEF PKs parameters, ASP 1000 mg/kg has the highest impact on most parameters. ASP 1000 mg/kg also can significantly increase activities of liver enzymes indicating the possibility of inducing liver injury. Therefore, it might be of clinical importance to avoid the administration of aspartame containing products while on ERL or GEF therapy.

Both gefitinib and erlotinib are selective epidermal growth factor-receptor tyrosine kinase inhibitors (EGFR-TKI), and are effective in the treatment of advanced non-small-cell lung cancer (NSCLC). Drug-related adverse events are usually mild in degree when using these drugs. However, some patients may develop acute severe intersititial pneumonia or hepatitis, which is sometimes fatal. We describe herein the cases of two patients with NSCLC who suffered from gefitinib-induced acute interstitial pneumonia and hepatitis, respectively, and recovered after stopping gefitinib treatment; the patients subsequently received erlotinib treatment uneventfully. Case one was a 58-year-old man with stage Ⅳ NSCLC who received gefitinib as first-line therapy. He had a partial response after gefitinib treatment. However, progressive dyspnea occurred after six months of gefitinib therapy. Chest X-ray showed new-onset right upper and lower lobe ground-glass opacity and consolidation compatible with acute interstitial pneumonitis. Gefitinib therapy was discontinued, and the patient received oral corticosteroid and supplemental oxygen treatment. After the clinical symptoms subsided, the patient took erlotinib as second-line therapy without recurrence of pulmonary symptoms or interstitial pneumonia. Case two was a 77-year-old woman with stage IV adenocarcinoma who had received gefitinib as first-line therapy. She had a partial response to gefitinib after one month of treatment. However, the patient developed a poor appetite, nausea sensation, and grade 3 hepatitis after 2 months of treatment. After stopping gefitinib for two weeks, her liver function tests gradually improved, but did not return to normal range. She then took erlotinib (75 mg/day) as second-line therapy. She tolerated erlotinib therapy well, and liver enzymes (AST and ALT) returned to normal range again. When treating NSCLC patients with EGFR-TKI, it is important to evaluate carefully any new-onset respiratory and gastrointestinal symptoms. Arranging radiographic and hepatic examinations accordingly is needed whenever pulmonary or hepatic toxicity is suspected. Thus, a change from one EGFR-TKI to another EGFR-TKI is an appropriate choice if further EGFR-TKI treatment is still needed.

Cough induced by low pH

17117 Background: Gefitinib (GEF) may act by inhibiting anti-apoptotic signals transduced by mutant EGFR kinase (Science 305:1163,04). Cell culture assays with cell death endpoints could be informative for GEF activity. Methods: We tested 568 biopsies of fresh human tumors (TUM) with 2 concentrations of GEF (22 and 11 μg/ml) for 96 hrs, each with 2 separate cell death endpoints (DISC and MTT), detailed methods http://weisenthal.org/w_ovarian_cp.pdf . Results classified as resistant (RES), intermediate (INT), or sensitive (SEN) based on means and standard deviations of training set data (ref ibid), reported prospectively to 3 different physicians: surgeon, pathologist, and oncologist. Assay evaluability rate > 90%. Results: Based on overall % control cell death, the following TUM showed (on average) no greater RES or SEN than the universe of 568 assays: NSCLC (n = 72), colon (33), breast (106), ovarian (109), melanoma (23), pancreatic (20), endometrial (12). The following showed (on avg) significantly greater RES: soft tissue sarcomas (n = 24), carcinoid/islet (16), renal (15), and mesothelioma (8). For NSCLC, there was no avg difference between female (32) vs male (35) or untreated (34) vs previously treated (38). For 32 unRxd pts with survival data, there was no significant difference in overall surv for 20 pts with prospectively reported GEF RES (GR) assays vs 12 pts with SEN or INT (GSI) assays. For 31 pts with prior chemoRx (med surv = 155 days), there was significant survival disadvantage for 14 pts with prospectively reported GR vs 17 pts with GSI (median 85 vs 380 days, P2 < 0.0001, HR 3.7; 95% C.I. 2.6–19). For pts with known post-assay Rx, there were 7 pts with GSI subsequently receiving GEF or erlotinib (ERLOT), with med surv = 485 days; 9 pts with GSI not receiving GEF or ERLOT, med surv = 135 days; 10 pts with GR not receiving GEF or ERLOT, med surv = 76 days, and 3 pts with GR receiving GEF or ERLOT, med surv = 75 days. Survival of group of 7 pts was significantly greater than those of groups of 9, 10, and 3 pts (P2 = 0.02, P2 < 0.0001, and P2 = 0.002, respectively). Conclusions: GEF-induced cell death in cultures of fresh TUM from prev-treated NSCLC pts may identify pts with favorable prognosis, particularly when treated with GEF or ERLOT. [Table: see text]

Objective To compared the clinical efficacy and pharmacoeconomics of gefitinib, erlotinib, icotinib in the treatment of non-small cell lung cancer (NSCLC), thus to provide guidance on drug selection for patients from safety, efficiency and economical aspects after medical reform. Methods The patients with NSCLC who admitted to the First Affiliated Hospital of China Medical University from 2014 to 2017 and treated by gefitinib, erlotinib, icotinib were selected (30 patients in each group). All the patients were diagnosed with NSCLC by tissue or cytology study and eventually disease progressed.The clinical efficacy of the three drugs was evaluated by retrospective analysis.Specially, cost-effectiveness and cost-utility were evaluated in terms of disease control rates(DCR) and quality adjusted life years(QALY), respectively. Results The results demonstrated that the progression free survival (PFS) of gefitinib, erlotinib and icotinib were 0.934 years, 1.079 years and 1.063 years, respectively.There was no statistically significant difference in PFS among the three groups(F=0.001, P=0.9 990). The major drug adverse reactions were rash, diarrhea and hepatic injury.The DCR of gefitinib, erlotinib and icotinib were 66.7%, 70.0% and 63.3%, respectively, the difference was statistically significant(χ2=0.300, P=0.8 607). The total cost of treatment in the three groups were 85 118 CNY, 70 513 CNY and 7 2213 CNY, respectively.The cost-utility ratios of three drugs were 91 133, 65 389 and 67 973, respectively.The cost-effectiveness ratios of three drugs were 1 276, 1 007 and 1 141, respectively.The erlotinib group had lower cost and higher utility (effectiveness). Sensitivity analysis showed that the conclusion was relative stable when the price of three drugs changed at the same time. Conclusion All of the three drugs are applicable for targeted therapy of NSCLC and show similar curative effect and adverse reaction.However, erlotinib shows better economy than others. Key words: Carcinoma, non-small-cell lung; Costs and cost analysis; Gefitinib; Erlotinib; Icotinib

Gas permeable membranes (GPM) are a promising technology for the capture and recovery of ammonia (NH3). The work presented herein assessed the impact of the capture solution and temperature on NH3 recovery for suspended GPM systems, evaluating at a laboratory scale the performance of eight different trapping solutions (water and sulfuric, phosphoric, nitric, carbonic, carbonic, acetic, citric, and maleic acids) at 25 and 2 °C. At 25 °C, the highest NH3 capture efficiency was achieved using strong acids (87% and 77% for sulfuric and nitric acid, respectively), followed by citric and phosphoric acid (65%) and water (62%). However, a remarkable improvement was observed for phosphoric acid (+15%), citric acid (+16%), maleic acid (+22%), and water (+12%) when the capture solution was at 2 °C. The economic analysis showed that water would be the cheapest option at any working temperature, with costs of 2.13 and 2.52 €/g N (vs. 3.33 and 3.43 €/g N for sulfuric acid) in the winter and summer scenarios, respectively. As for phosphoric and citric acid, they could be promising NH3 trapping solutions in the winter months, with associated costs of 3.20 and 3.96 €/g N, respectively. Based on capture performance and economic and environmental considerations, the reported findings support that water, phosphoric acid, and citric acid can be viable alternatives to the strong acids commonly used as NH3 adsorbents in these systems.

Objective To compare the clinical outcomes of gefitinib and erlotinib treating non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation in either exon 19 or 21. Methods A total of 242 patients diagnosed as NSCLC with EGFR mutation in either exon 19 or 21 from May 2013 to December 2014 in our hospital were chosen in this study. According to age, sex, smoking history, eastern cooperative oncology group performance status and types of EGFR mutation, all the patients were matched to 121 pairs, and randomly divided into group A and B. Patients in group A received gefitinib treatment, and those in group B received erlotinib treatment. Based on the response evaluation criteria in solid tumors (RECIST), overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS) were assessed. To assess the independent risk factors for PFS by univariate and multivariate Cox regression analysis. The subgroup analysis was performed for the 63 NSCLC patients using these two drugs as the first-line treatment. To evaluate the adverse drug reactions and quality of life between A and B groups. Results The median PFS of group A and B were 11.6 months and 9.5 months, respectively, with no significant difference (HR=0.39, P>0.05). The ORR and DCR in the two groups were 76.9%, 74.4% (χ2=1.03, P=0.58) and 90.1%, 86.8% (χ2=1.46, P=0.31). The independent risk factors of poor PFS were ECOG PS≥2 (HR=2.60, 95%CI: 1.54-4.43, P=0.001) and non-adenocarcinoma (HR=3.61, 95%CI: 1.54-8.66, P=0.003). For patients receiving these two drugs as the first-line treatment, there was no significant difference between two groups in overall response rates (76.6% vs. 90.2%, χ2=0.83, P=0.12) and median PFS (11.6 months vs. 14.4 months, HR=0.59, P>0.05). The adverse drug reactions were significant differences in emotion function (F=10.27, P=0.03), diarrhea (F=10.24, P=0.03) and pain (F=9.02, P=0.04). After receiving drug treatment, the quality of life scores were improved, and most of the differences were statistically significant between A and B groups(P<0.05). Conclusion As for NSCLC with EGFR mutation in either exon 19 or 21, both gefitinib and erlotinib are well tolerated and have similar clinical effectiveness. Key words: Carcinoma, non-small-cell lung; Receptor, epidermal growth factor; Gefitinib; Erlotinib

The reported incidence of tooth erosion caused by acidic soft drinks has been increasingly documented. Citric and phosphoric acids are the two main dietary acids present in these soft drinks. Many variables need to be determined in order to assess risk factors for dental erosion caused by beverage consumption including pH, titratable acidity, pKa, buffering capacity, hence the aim of these in vitro investigations. Methodologies included profiling flat enamel and dentine samples (< +/- 0.3 microm profile) from unerupted human third molars. Groups of five specimens were placed in acidic solutions adjusted with alkali over the available pH range; citric, phosphoric and hydrochloric acid were adjusted with sodium hydroxide and citric acid with trisodium citrate. Tissue loss was calculated by profilometry. Results showed that under these conditions citric acid caused far more erosion over the pH range employed than phosphoric acid for both tissue types. Citric acid compared with hydrochloric acid highlighted dissolution and chelation effects. Phosphoric acid caused minimal erosion over pH 3 for enamel and pH 4 for dentine. These factors could be considered in order to reduce the erosivity of acidic soft drinks.

The reported incidence of tooth erosion caused by acidic soft drinks has been increasingly documented. Citric and phosphoric acids are the two main dietary acids present in these soft drinks. Many variables need to be determined in order to assess risk factors for dental erosion caused by beverage consumption including pH, titratable acidity, pKa, buffering capacity, hence the aim of these in vitro investigations. Methodologies included profiling flat enamel and dentine samples (&lt; ± 0·3 μm profile) from unerupted human third molars. Groups of five specimens were placed in acidic solutions adjusted with alkali over the available pH range; citric, phosphoric and hydrochloric acid were adjusted with sodium hydroxide and citric acid with trisodium citrate. Tissue loss was calculated by profilometry. Results showed that under these conditions citric acid caused far more erosion over the pH range employed than phosphoric acid for both tissue types. Citric acid compared with hydrochloric acid highlighted dissolution and chelation effects. Phosphoric acid caused minimal erosion over pH 3 for enamel and pH 4 for dentine. These factors could be considered in order to reduce the erosivity of acidic soft drinks.

ObjectiveTo evaluate and compare the effects of different etching systems on etch patterns and mineral retention in primary tooth enamel.Materials and methodsForty extracted, noncarious primary teeth were randomly divided into four groups, each containing 10 teeth. The groups were as follows: group I (Control)—no intervention, group II—etched with 37% phosphoric acid, group III—etched with 37% phosphoric acid combined with tricalcium phosphate (TCP), and group IV—etched with 10% citric acid combined with TCP. The sectioned buccal surfaces were etched for 15 seconds, rinsed for 15 seconds, and air-dried for 30 seconds. The etched surfaces were analyzed using scanning electron microscopy (SEM) to observe etch patterns, and energy dispersive X-ray spectroscopy (EDX) to assess calcium and phosphorus retention.ResultsScanning electron microscopy analysis revealed distinct etch patterns across the groups. group II (37% phosphoric acid) produced a highly porous surface, indicative of aggressive demineralization, while group III (phosphoric acid + TCP) demonstrated a more controlled etch pattern with higher calcium retention. Group IV (citric acid + TCP) produced the smoothest surface with minimal porosity, reflecting a milder etch effect. EDX analysis showed that group III had the highest calcium retention (41.47 ± 0.56%), whereas group IV had the lowest phosphorus content (9.39 ± 0.13%).ConclusionThe addition of TCP to phosphoric and citric acid etching systems reduced the aggressive demineralization typically seen with phosphoric acid alone. The phosphoric acid + TCP combination offered an optimal balance between effective etching and mineral preservation, making it a promising etching system for primary teeth. Citric acid + TCP, while gentler, may be suitable for cases where enamel conservation is prioritized.How to cite this articleSudev SS, Pooja VR. Effect of Novel Etching System on Etch Pattern in Primary Teeth: An In Vitro Study. Int J Clin Pediatr Dent 2025;18(9):1077–1081.

BackgroundErlotinib (ERL) and Gefitinib (GEF) are considered first line therapy for the management of non-small cell lung carcinoma (NSCLC). Like other tyrosine kinase inhibitors (TKIs), ERL and GEF are mainly metabolized by the cytochrome P450 (CYP450) CYP3A4 isoform and are substrates for transporter proteins with marked inter-/intra-individual pharmacokinetic (PK) variability. Therefore, ERL and GEF are candidates for drug-drug and food-drug interactions with a consequent effect on drug exposure and/or drug-related toxicities. In recent years, the consumption of flavoured water (FW) has gained in popularity. Among multiple ingredients, fruit extracts, which might constitute bioactive flavonoids, can possess an inhibitory effect on the CYP450 enzymes or transporter proteins. Therefore, in this study we investigated the effects of different types of FW on the PK parameters of ERL and GEF in Wistar rats.MethodsERL and GEF PK parameters in different groups of rats after four weeks consumption of different flavours of FW, namely berry, peach, lime, and pineapple, were determined from plasma drug concentrations using ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS).ResultsData indicated that tested FWs altered the PK parameters of both ERL and GEF differently. Lime water had the highest impact on most of ERL and GEF PK parameters, with a significant increase in Cmax (95% for ERL, 58% for GEF), AUC0–48 (111% for ERL, 203% for GEF), and AUC0–∞ (200% for ERL, 203% for GEF), along with a significant decrease in the apparent oral clearance of both drugs (65% for ERL, 67% for GEF). The order by which FW affected the PK parameters for ERL and GEF was as follows: lime > pineapple > berry > peach.ConclusionThe present study indicates that drinking FW could be of significance in rats receiving ERL or GEF. Our results indicate that the alteration in PKs was mostly recorded with lime, resulting in an enhanced bioavailability, and reduced apparent oral clearance of the drugs. Peach FW had a minimum effect on the PK parameters of ERL and no significant effect on GEF PKs. Accordingly, it might be of clinical importance to evaluate the PK parameters of ERL and GEF in human subjects who consume FW while receiving therapy.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) such as gefitinib and erlotinib are the first generation of EGFR inhibitors that were developed more than a decade ago. Beginning with the disappointing results of phase III trials that combined EGFR TKIs with chemotherapy in unselected patients with non-small cell lung cancer (NSCLC) (IDEAL-I and IDEAL–II for gefitinib, TALENT and TRIBUTE for erlotinib), both TKIs had a history of ups (BR.21 for erlotinib, INTEREST for gefitinib) and downs (ISEL for gefitinib), until the recent success of pivotal studies comparing EGFR TKIs to doublet chemotherapy in patients with activating EGFR mutations (IPASS, NEJ002 and WJTOG3405 for gefitinib, OPTIMAL and EURTAC for erlotinib).

Received March 16, 2004; revision received July 23, 2004; accepted September 30, 2004. With improving survival, the heart transplant recipient faces an increasing number of medical problems caused by both aging and the cumulative complications of immunosuppressive drugs.1 The availability of new drugs to treat infection, obesity, hypertension, hyperlipidemia, renal insufficiency, diabetes, osteoporosis, gout, and malignancies has resulted in the heart transplant recipient and their physicians facing an almost overwhelming number of important drug–drug interactions. In parts 1 through 3 of this series, we reviewed commonly used immunosuppressive drugs and their pharmacology, as well as the common medical problems faced by the heart transplant recipient. In this article, we provide an overview of the mechanisms of common and important potential drug–drug interactions and guidelines for avoiding these interactions. The risk for drug–drug interactions is increased by advanced age, polypharmacy, medications with a narrow therapeutic index, or medications requiring intensive monitoring. All of these factors except advanced age are present in the heart transplant recipient. A 10-fold interpatient variability may exist in the magnitude of a drug interaction resulting from patient-related and drug-related factors.2 Patient-related factors predisposing to drug interactions include concomitant diseases, genetics, diet, and environmental exposures. For example, commonly used immunosuppressants, antifungal agents, and lipid-lowering medications are metabolized through the cytochrome P450 (CYP450) enzyme system and effluxed from cells by the multiple drug resistance transporter protein p-glycoprotein (P-gp). Both systems are found in the liver and gastrointestinal tract and exhibit genetic polymorphism.2 The CYP450 enzymes belong to a superfamily of oxygenases; the primary purpose of these oxygenases is to add a functional group to a drug to increase its polarity and to promote its excretion from the body. If enzymes possess >40% homology, they are grouped together into families designated by an Arabic numeral (eg, the …

Background and importanceTyrosine kinase inhibitors (TKI) are oral drugs that have demonstrated efficacy against metastatic non-small cell lung cancer (mNSCLC) with mutation of EGFR.Aim and objectivesTo evaluate the efficacy and...

Chlorinated wash water and pH regulators affect chlorine gas emission and disinfection by-products