Skip to main content

Open Access 12.02.2024 | Original Research Article

Pharmacokinetic and Safety Study of Bismuth Potassium Citrate Formulations in Healthy Subjects

verfasst von: Hong-Yu Luo, Shuo-Guo Xu, Li-Chen Gao, Hui-Zhi Long, Zi-Wei Zhou, Feng-Jiao Li, Shang-Ming Dai, Jin-Da Hu, Yu Su, Yan Cheng

Erschienen in: Drugs in R&D

Abstract

Background

Potassium bismuth citrate is a gastric mucosal protector and a key drug for treating peptic ulcers.

Objective

To evaluate the pharmacokinetic characteristics and safety of 120-mg bismuth potassium citrate formulations administered orally under fasting conditions in healthy Chinese subjects.

Method

A single-center open two-cycle trial was conducted on 12 healthy subjects who received a single oral dose of 120 mg of bismuth potassium citrate. The plasma concentration of bismuth was determined using a validated inductively coupled plasma mass spectrometry (ICP‒MS) method. The pharmacokinetic parameters, including maximum serum concentration (Cmax) and area under the curve concentration–time curve (AUC0–t and AUC0–), and safety were evaluated via noncompartment analysis.

Results

The ratios of the least square geometric mean ratio between the test (T) and reference (R) formulations for Cmax, AUC0–t, and AUC0– were 44.8%, 55.5%, and 64.4%, respectively; the bilateral 95% confidence intervals (Cis) for these parameters were 20.2–99.6%, 24.1–127.5%, and 23.7–175.0%, respectively, and the non-inferior limits for these parameters were 169.4%, 198.8%, and 200.5%, respectively. The upper limits of the one-sided 97.5% confidence interval for the least squares geometric mean ratio (T/R) were lower than the non-inferior limits. No serious adverse reactions or adverse reactions leading to detachment were observed among the subjects.

Conclusion

The concentration of bismuth in the blood of healthy subjects in the T formulation was not greater than that in the R formulation. Similarly, the safety of oral administration of 120 mg of bismuth potassium citrate formulations to healthy subjects was good. The trial registration number (TRN) was [2018] 013, 6 December 2018.
Hinweise

Supplementary Information

The online version contains supplementary material available at https://​doi.​org/​10.​1007/​s40268-024-00455-9.
Hong-Yu Luo, Shuo-Guo Xu have contributed equally to this study.
Key Points
Pharmacokinetic study of 120mg bismuth potassium citrate formulations administered orally under fasting conditions in healthy Chinese subjects.
The concentration of bismuth in the T formulation was not greater than that in the R formulation.
120 mg of bismuth potassium citrate formulations to healthy subjects was good.

1 Introduction

Gastritis refers to inflammation of the gastric lining caused by damage to the gastric mucosa. The duration of mucositis can be used to distinguish acute from chronic active gastritis. Most acute gastritis cases progress to chronic active gastritis [17]. Chronic gastritis is a chronic inflammation of the gastric mucosa and is highly prevalent in China. Chronic gastritis manifests as either nonatrophic or atrophic. However, the morphological manifestations and sequelae of chronic gastritis are very similar across the world. The prevalence of chronic gastritis has been underestimated worldwide. Chronic gastritis is one of the most common severe epidemic infections and is associated with serious and fatal sequelae, such as peptic ulcers or gastric cancer. It is estimated that millions of people worldwide die prematurely each year due to cancer and ulcers caused by chronic gastritis [4, 13]. Helicobacter pylori is the most common cause of chronic gastritis, and the different pathologies of H. pylori infection are caused by complex interactions among bacterial virulence, host genetics, and environmental factors. According to experimental research, clearing H. pylori and protecting the gastric mucosa are effective methods for treating gastritis [10, 17].
Bismuth salt has long been of therapeutic value in the treatment of chronic gastritis and peptic ulcers. Potassium bismuth citrate is a type of bismuth salt, and its solubility can be improved through citric acid addition [7, 12, 16]. Bismuth potassium citrate is a commonly used drug for treating acute peptic ulcers and can affect mucosal defense. Previous results indicate that the cure rate after 4 weeks of treatment is 78–84%. When used in acute course treatment, this approach may lead to a decrease in the recurrence rate [6, 11]. After oral administration, bismuth is rapidly absorbed, causing H. pylori to shed bacterial walls, degrade structures, and undergo vacuolization. Lu Weifeng’s research report at the eighth National Symposium on Biochemistry and Pharmacology and the seventh Servier Award Ceremony showed that the blood bismuth concentration reaches maximum serum concentration (Cmax) within ~ 20–30 min, with an average Cmax of 17.2 ± 12.7 ng/ml. At half-life (T1/2) of ~ 5–10 h, and after long-term medication, the blood bismuth concentration reached a steady state after ~ 8–10 days. Bismuth is excreted from the body through urine and feces [9]. It has also been observed that many enzymes produced by H. pylori, including urease, catalase, and lipase, are inhibited, which may affect the local environment and growth. Studies have shown that bismuth complexes bind to the bacterial walls and periplasmic spaces of H. pylori, ultimately leading to bacterial expansion and disintegration [8]. Thus, it can be seen that bismuth potassium citrate can also inhibit the growth of H. pylori.
To date, few studies have examined the pharmacokinetics and safety of bismuth potassium citrate capsules. Therefore, the aim of this trial was to study the pharmacokinetic characteristics and safety of a single oral administration of bismuth potassium citrate capsules.

2 Materials and Methods

2.1 Study Design

This single-center randomized open double-cycle crossover single oral administration phase I trial was performed in healthy fasting Chinese volunteers. This trial was conducted at the Phase I Clinical Research Center of Changsha Central Hospital Affiliated with South China University. This trial is a comparative study on the pharmacokinetics of a single administration in healthy fasting subjects. This study was approved by the ethics committee of Changsha Central Hospital. All participants provided written informed consent.

2.2 Study Population

According to the Technical Guidelines for Clinical Pharmacokinetic Research of Chemical Drugs issued by the CFDA, the number of subjects in each group should be 8–12. Therefore, this study enrolled 12 subjects. The inclusion criteria were as follows: (1) age ≥ 18 years of age, both male and female, and (2) weight ≥ 50.0 kg, for males, and weight ≥ 45.0 kg, for females, with a body mass index (BMI) of ~ 19.0–26.0 kg/m2 (including boundary values).
Drugs, diseases, and physiological factors that may have affected the results of this trial. Therefore, according to the medication manual for bismuth potassium citrate, the exclusion criteria were as follows: (1) patients with any clinically severe diseases, such as circulatory system diseases, endocrine system diseases, nervous system diseases, digestive system diseases, respiratory system diseases, hematological diseases, immunological diseases, psychiatric disorders, metabolic abnormalities, or patients with any other diseases that can interfere with the test results, such as known severe bleeding tendencies or gastric ulcers; (2) patients who were allergic to any component of the investigational drug, food, or other substances; (3) patients who underwent surgery within 4 weeks prior to the trial or who planned to have an operation during the trial period; (4) those who have used any medication or health products (including Chinese herbal medicine) within 14 days before the trial; (5) patients who have used any clinical trial drug or were enrolled in any drug clinical trial within the first 3 months prior to the trial; (6) patients who donated or lost blood more than 400 mL of blood within 3 months before the trial; (7) patients who were unable to take one or more non-pharmacological contraceptive measures during the trial period or women during pregnancy or lactation; (8) those who have special dietary requirements and cannot follow a unified diet; (9) drinking excessive amounts of tea, coffee, or caffeinated beverages (over 2000 mL) every day for the first 3 months prior to the trial; (10) patients who had consumed or planned to consume any food or drink containing caffeine (such as coffee, strong tea, or chocolate) or substances rich in xanthine (such as sardine or beef liver) within 48 h before taking the study drug for the first time; (11) patients who smoked more than five cigarettes per day in the 3 months prior to the trial; (12) alcoholics or those who frequently drank alcohol within the 6 months prior to the trial, that is, those who drank more than 5040 mL of beer or 630 mL of 40% alcohol or 2100 mL of wine per week; (13) patients who were drug abusers or had used marijuana drugs within 3 months prior to the trial, or who had taken drugs such as cocaine and phencyclidine within 1 year prior to the trial; (14) patients who had irregular bowel movements within the week before the trial; (15) subjects with clinically significant abnormalities in vital signs, such as blood pressure and pulse or physical examination, electrocardiogram, laboratory examination, alcohol testing, or drug abuse screening; and (16) subjects who may not be able to complete this trial for other reasons or because the researchers believe that they should not be included.

2.3 Study Preparation and Procedures

The test (T) formulation was produced by Hunan Warrant Pharmaceutical Co., Ltd., and the reference (R) formulation was produced by Astellas Pharma Ltd. The doses were all 120 mg. On the morning of the trial day, a single oral administration of the T or R formulation was administered with 240 mL of water; drinking water was prohibited before and within 1 h after administration, and standard meals were consumed 4 or 10 h after administration.

2.4 Blood Sample Collection and Determination

According to US Food and Drug Administration (FDA) guidelines, 5 mL of venous blood was collected before administration (0 h) and at 0.08, 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, and 36 h after administration. The commonly used clinical anticoagulant K2EDTA was selected for surgery. Blood samples were collected from all subjects at each sampling point. After the blood sample was collected, it was placed in a numbered K2EDTA anticoagulant tube, gently inverted and mixed, and centrifuged (1200g at 2–8 °C for 10 min), after which the separated plasma was transferred to a 2-mL storage tube labeled accordingly. The blood sample was centrifuged within 60 min after the start of collection, after which the sample was frozen at − 20 °C for 120 min and subsequently transferred to − 70 °C after the sample was completely frozen. Blood bioanalysis was performed at Changsha du Zheng Biotechnology Co., Ltd.

2.5 Pharmacokinetic Assessment

The blood drug concentration data were estimated and analyzed using Phoenix WinNonlin 7.0 software for non-compartmental analysis of pharmacokinetic parameters, and the main pharmacokinetic parameters were calculated to comprehensively reflect the characteristics of drug absorption, distribution, metabolism, and excretion in the bodies of the healthy subjects. The main pharmacokinetic parameters included time taken to reach Cmax (Tmax), Cmax, area under the concentration–time curve (AUC)0–t, AUC0–, and λz. For the pharmacokinetic parameters (Cmax, AUC0–t, and AUC0–), a mixed linear model was used for multivariate analysis of variance after logarithmic conversion of the data; furthermore, a t-test was used to analyze differences between the two formulations. Based on the research objectives and noninferiority testing methods, the following pharmacokinetic evaluation criteria were used: if the upper limit of the one-sided 95% confidence interval (CI) of the least squares geometric mean ratio (test formulation/reference formulation) of each pharmacokinetic parameter (Cmax, AUC0–t, and AUC0–) is less than e[0.15*In(μ)] (μR is the point estimate of the least squares geometric mean of the R formulation), then the concentration of bismuth in the human blood of the T formulation was not greater than that of the R formulation, and the safety of the T formulation was considered to meet the requirements. The bioanalytical methods and methodological validation results for bismuth potassium citrate are listed in Supplementary Material 1 and Table S1.

2.6 Safety Assessment

Vital signs were measured during the check-in, before administration (0 h), and at 1, 2, 4, 6, 8, 12, 24, and 36 h after administration. During the screening period and group physical examination laboratory test indicators, including routine blood, routine urine, liver and kidney function, blood glucose, blood lipids, serum electrolytes, coagulation function, blood transfusion, and blood pregnancy indices, were also evaluated. All adverse events were recorded during the trial. Throughout the entire research process, the severity of adverse events and reactions was evaluated in relation to the investigational drug.

3 Results

3.1 Subject Characteristics

A total of 65 subjects were screened via the fasting test, and 12 subjects ultimately completed two cycles of the experiment. The mean age of the 12 participants was 25 ± 5 years old, with a mean weight of 60.0 ± 8.2 kg, a mean height of 165.0 ± 7.0 cm, and a mean body mass index of 22.0 ± 2.2 kg/m2. The demographic information of the subjects is shown in Table 1.
Table 1
Demographic characteristics
Characteristic
Fasting condition (N = 12)
Age (year)
25 ± 5
Gender
 Male
9 (75.0%)
 Female
3 (25.0%)
Nationality
 Han nationality
11 (91.7%)
 Minority nationality
1 (8.3%)
 Height (cm)
165.0 ± 7.0
 Weight (kg)
60.0 ± 8.2
 BMI (kg/m2)
22.0 ± 2.2

3.2 Pharmacokinetics

Pharmacokinetic evaluations were also conducted on 12 subjects. The average concentration–time curves of the T and R formulations under fasting conditions were similar (Fig. 1). The main pharmacokinetic parameters of the T formulation treatment were as follows: Cmax = 25.6 ± 29.4 ng/mL, AUC0–t = 96.3 ± 123.8 h·ng/mL, and AUC0– = 117.8 ± 136.2 h·ng/mL. The Cmax, AUC0–t, and AUC0– of the R formulation were 46.6 ± 39.6 ng/mL, 137.8 ± 121.3 h·ng/mL, and 147.6 ± 126.9 h·ng/mL, respectively (Table 2). The mean plasma concentration–time curve of a single dose of bismuth potassium citrate is shown in Fig. 1. There was no significant difference in the Cmax, AUC0–t, or AUC0– between the T and R formulations. The upper limits values of the one-sided 97.5% confidence intervals for the least squares geometric mean ratios of Cmax, AUC0–t, and AUC0– of the T and R formulations were lower than the noninferiority margin values, respectively (Table 3). The results indicate that the concentration of bismuth in the blood of healthy subjects in the T formulation was not greater than that in the R formulation, and, thus, the safety of the T formulation met the established requirements. Moreover, analysis of variance (ANOVA) was used to analyze the pharmacokinetic (PK) parameters, as shown in Table S2. The results showed that the administration sequence factor was related to the pharmacokinetic parameters.
Table 2
Summary of pharmacokinetic parameters of bismuth potassium citrate
Parameters
Mean ± SD (CV%)
Test drug (T) (N = 12)
Reference drug (R) (N = 12)
Cmax (ng/mL)
25.6 ± 29.4 (114.6)
46.6 ± 39.6 (84.9)
Tmax (h)
0.5 (0.3, 1.0)
0.33 (0.2, 0.5)
AUC0–t(h·ng/mL)
96.3 ± 123.8 (128.6)
137.8 ± 121.3 (88.0)
AUC0–(h·ng/mL)
117.8 ± 136.2 (115.6)
147.6 ± 126.9 (86.0)
λz(1/h)
0.1 ± 0.1 (38.5)
0.1 ± 0.1 (52.8)
T1/2(h)
6.6 ± 2.3 (34.6)
9.0 ± 3.4 (38.2)
CL/F(mL/h)
2,555,924.1 ± 2,452,106.5 (95.9)
1,641,034.2 ± 1,806,484.0 (110.1)
Vd/F(mL)
18,989,119.2 ± 11,977,349.4 (63.1)
16,285,240.6 ± 9,838,921.9 (60.4)
Table 3
Comparative evaluation of pharmacokinetics of pharmacokinetic parameters
Parameter
T
R
GMR (%)
95% CI
97.5% CIa
Non-inferiority margin
CV (%)
Cmax (ng/mL)
15.0
33.6
44.8
~20.2–99.6
99.6
169.4
107.7
AUC0–t (h·ng/mL)
54.2
97.7
55.5
~24.1–127.5
127.5
198.8
114.5
AUC0– (h·ng/mL)
66.5
103.3
64.4
~23.7–175.0
175.0
200.5
121.1
GMR the geometric mean ratio of T over R PK metric, CV the intraindividual variation
aCalculate 95% CI of the ratio on the basis of the difference and standard error of the least squares mean. The 97.5% CI is the upper limit value of 95% CI

3.3 Safety

In this clinical trial, four adverse events occurred in two patients after treatment with the T formulation, yielding an incidence rate of 16.7%. One subject developed hypertriglyceridemia, and one subject experienced three adverse events, namely, an elevated white blood cell (WBC) count, an elevated monocyte count, and an elevated lymphocyte count. The severity of adverse events was level 1 for all patients. No adverse reactions occurred. Among the subjects treated with the R formulation, three subjects experienced a total of four adverse events, yielding an incidence rate of 25.0%. One subject suffered from hyperuricemia, one subject suffered from ST segment elevation, and one subject suffered from hypoglycemia and hyperuricemia The severity of adverse events was level 1 for all patients. Two patients experienced a total of two adverse reactions, yielding an incidence rate of 16.7%. The severity of adverse reactions was level 1 for all patients. No serious adverse events occurred in any of the subjects (Table 4).
Table 4
Summary of adverse events and relationship with drugs
 
Test drug n (%) E
Reference drug n (%) E
Number of subjects with AEs
2 (16.7%) 4
3 (25.0%) 4
Severity
 Mild
2 (16.7%) 4
3 (25.0%) 4
 Moderate
0 (0) 0
0 (0) 0
 Severe
0 (0) 0
0 (0) 0
Correlation with drugs
 Definitely related
0 (0) 0
0 (0) 0
 Probably related
0 (0) 0
2 (16.7%) 2
 Possibly related
0 (0) 0
0 (0) 0
 Possibly unrelated
2 (16.7%) 4
1 (8.3%) 1
 Definitely unrelated
0 (0) 0
1 (8.3%) 1
Adverse events
Hypertriglyceridemia
1 (8.3%) 1
0 (0) 0
Hyperuricemia
0 (0) 0
2 (16.7%) 2
Hypoglycemia
0 (0) 0
1 (8.3%) 1
ST segment lifting
0 (0) 0
1 (8.3%) 1
Elevated white blood cells
1 (8.3%) 1
0 (0) 0
Elevated blood monocyte count
1 (8.3%) 1
0 (0) 0
Elevated blood lymphocyte count
1 (8.3%) 1
0 (0) 0

4 Discussion

Nearly 4.4 billion people worldwide have been infected by H. pylori, which is highly prevalent in China; nearly 50% of Chinese people are carriers of H. pylori [1]. H. pylori is similar to a malignant tumor. Chronic gastritis cannot be eliminated without the eradication of H. pylori. In recent years, the incidence of gastric cancer has been high, and H. pylori infection is one of the biggest risk factors for gastric cancer. H. pylori carriers also have a severalfold greater risk of developing gastric cancer than noncarriers, with approximately 90% of gastric cancer cases being induced by H. pylori [10]. Therefore, the early detection and treatment of H. pylori are highly important. Bismuth quadruple therapy is currently a common experiential therapy in clinical practice, with a clinical satisfaction rate > 90%. This treatment method can reduce antibiotic resistance and improve treatment effectiveness [14, 15].
Currently, there is a lack of detailed pharmacokinetic data on bismuth potassium citrate. The lack of pharmacokinetic data can limit clinical treatment and increase the risk of adverse events. Therefore, this study was the first to compare the pharmacokinetics of bismuth potassium citrate for the first time. The results showed that the half-life of the T formulation of bismuth potassium citrate capsules was 6.6 h, and the maximum plasma concentration reached 0.5 h after administration, with a maximum plasma concentration of 25.6 ng/mL. The AUC0–t and AUC0– were 96.3 and 117.8 h·ng/mL, respectively. Compared with those of the R formulation, the plasma concentration–time curves of the two formulations were similar in shape; however, the mean Cmax and AUC values of the two formulations were different, but there was no evidence that they were significantly different. This study used bismuth potassium citrate tablets as a positive control drug and demonstrated that the efficacy and safety of bismuth potassium citrate capsule formulations are comparable to those of tablets. Determination of the drug concentration facilitates adjustment of the drug dosage and treatment plan. Drug dosage forms, patient’s disease status, concomitant medication, and food may all affect blood drug concentrations. No influence of dosage form factors was found in this study. Therefore, the effects of food and patient disease status on the use of bismuth potassium citrate need to be further evaluated.
No adverse reactions were found in the subjects after treatment with the T formulation in this trial. Bismuth potassium citrate capsules have three safe effects: relieving stomach pain, resisting H. pylori, and repairing gastric mucosa. Previous studies have shown that when the blood bismuth concentration is less than 100 ng/mL, no toxic effects occur, and the incidence of serious adverse events is relatively low [2, 5]. In our pharmacokinetic studies, the blood bismuth concentration was not greater than 100 ng/mL within the measured time range. Therefore, our results also indicate that a blood bismuth concentration of 100 ng/mL is safe, and this concentration can be used as a predictor of clinical toxicity in patients treated with bismuth potassium citrate.
However, the mechanism by which bismuth causes bactericidal damage to H. pylori is still unclear, and bismuth seems to exert its bactericidal effect through multiple mechanisms. The results of network pharmacology analysis indicated that bismuth preparations downregulated the expression of the H. pylori virulence factors CagA and VacA and regulated the expression of catalase and fatty acid metabolism in H. pylori. However, previous studies have not shown that the CYP2C19 gene polymorphism in bismuth-containing quadruple therapy affects the efficacy of bismuth potassium citrate for the treatment of H. pylori [3]. The target of action of bismuth potassium citrate has not been elucidated, so it is still difficult to explore the mechanism of individual differences presented in pharmacokinetic evaluations. This study provides a theoretical reference and direction for in-depth research and clinical application of bismuth potassium citrate.
One limitation of this study is the small sample size. Another limitation is that this study did not compare the effects of food on the study drug under fasting versus postprandial conditions. Furthermore, future experiments should be conducted to explore whether the efficacy of the T formulation is superior to that of the R formulation.

5 Conclusion

The concentration of bismuth in the human blood was not greater in the T drug group than in the R drug group. No adverse events related to the T drug were found. The safety of the T formulation meets the established criteria. No serious adverse reactions or adverse reactions leading to detachment were observed in the subjects after taking the T or R formulation.

Acknowledgments

The work was supported by the Phase I Clinical Trial Centre, Changsha Central Hospital affiliated with the University of South China, Changsha, Hunan. We thank Professor Gao for his guidance in writing this paper. We also thank to all the researchers and nurses for their support and dedication.

Declarations

Conflict of Interest

The authors declare no conflicts of interest in this work.

Ethics Statement

The study involving participants was registered on the Platform for Bioequivalence and Clinical Trials prior to the trial and approved by the ethics committee of Changsha Central Hospital affiliated with the University of South China. All the subjects provided informed consent.

Funding

This work was supported by Changsha Central Hospital Affiliated with the University of South China Foundation of Key Program (YNKY202205), a project supported by the Scientific Research Fund of the Hunan Provincial Education Department (22A0320), by the Hunan Provincial Natural Science Foundation of China (2021JJ30753), and by the Hunan Provincial Health High-Level Talents Support Program.

Data Availability Statement

All data generated or analyzed during this trial are included in this published article.

Author Contributions

All authors made substantial contributions in drafting the article or revising it critically for important intellectual content; gave final approval of the version to be published; and agree to be accountable for all the work.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creativecommons.​org/​licenses/​by-nc/​4.​0/​.
Anhänge

Supplementary Information

Below is the link to the electronic supplementary material.
Literatur
1.
Zurück zum Zitat Bi H, Chen X, Chen Y, et al. Efficacy and safety of high-dose esomeprazole–amoxicillin dual therapy for Helicobacter pylori rescue treatment: a multicenter, prospective, randomized, controlled trial. Chin Med J. 2022;135(14):1707–15.CrossRefPubMedPubMedCentral Bi H, Chen X, Chen Y, et al. Efficacy and safety of high-dose esomeprazole–amoxicillin dual therapy for Helicobacter pylori rescue treatment: a multicenter, prospective, randomized, controlled trial. Chin Med J. 2022;135(14):1707–15.CrossRefPubMedPubMedCentral
2.
Zurück zum Zitat Cao Y, Zhang J, Liu Y, et al. The efficacy and safety of different bismuth agents in Helicobacter pylori first-line eradication: a multicenter, randomized, controlled clinical trial. Medicine (Baltimore). 2021;100(50): e27923.CrossRefPubMed Cao Y, Zhang J, Liu Y, et al. The efficacy and safety of different bismuth agents in Helicobacter pylori first-line eradication: a multicenter, randomized, controlled clinical trial. Medicine (Baltimore). 2021;100(50): e27923.CrossRefPubMed
3.
Zurück zum Zitat Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19. N Engl J Med. 2020;383(21):2041–52.CrossRefPubMed Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19. N Engl J Med. 2020;383(21):2041–52.CrossRefPubMed
5.
Zurück zum Zitat Ford AC, Malfertheiner P, Giguere M, et al. Adverse events with bismuth salts for Helicobacter pylori eradication: systematic review and meta-analysis. World J Gastroenterol. 2008;14(48):7361–70.CrossRefPubMedPubMedCentral Ford AC, Malfertheiner P, Giguere M, et al. Adverse events with bismuth salts for Helicobacter pylori eradication: systematic review and meta-analysis. World J Gastroenterol. 2008;14(48):7361–70.CrossRefPubMedPubMedCentral
6.
Zurück zum Zitat Gavey CJ, Szeto ML, Nwokolo CU, et al. Bismuth accumulates in the body during treatment with Tripotassium dicitrato bismuthate. Aliment Pharmacol Ther. 2010;3(1):21–8.CrossRef Gavey CJ, Szeto ML, Nwokolo CU, et al. Bismuth accumulates in the body during treatment with Tripotassium dicitrato bismuthate. Aliment Pharmacol Ther. 2010;3(1):21–8.CrossRef
7.
Zurück zum Zitat Guevara B, Cogdill AG. Helicobacter pylori: A review of current diagnostic and management strategies. Dig Dis Sc. 2020;65(7):1917–31.CrossRef Guevara B, Cogdill AG. Helicobacter pylori: A review of current diagnostic and management strategies. Dig Dis Sc. 2020;65(7):1917–31.CrossRef
8.
Zurück zum Zitat Lambert JR, Midolo P. The actions of bismuth in the treatment of Helicobacter pylori infection. Aliment Pharmacol Ther. 1997;11(Suppl 1):27–33.CrossRefPubMed Lambert JR, Midolo P. The actions of bismuth in the treatment of Helicobacter pylori infection. Aliment Pharmacol Ther. 1997;11(Suppl 1):27–33.CrossRefPubMed
9.
Zurück zum Zitat Lambert JR. Pharmacology of bismuth-containing compounds. Rev Infect Dis. 1991;13(Suppl 8):S691-695.CrossRefPubMed Lambert JR. Pharmacology of bismuth-containing compounds. Rev Infect Dis. 1991;13(Suppl 8):S691-695.CrossRefPubMed
10.
Zurück zum Zitat Malfertheiner P, Camargo MC, El-Omar E, et al. Helicobacter pylori infection. Nat Rev Dis Primers. 2023;9(1):19.CrossRefPubMed Malfertheiner P, Camargo MC, El-Omar E, et al. Helicobacter pylori infection. Nat Rev Dis Primers. 2023;9(1):19.CrossRefPubMed
11.
Zurück zum Zitat Porro GB, Lazzaroni M, Barbara L. Tripotassium dicitrate bismuthate and ranitidine in duodenal ulcer Healing and influence on recurrence. Scand J Gastroenterol. 1988;23(10):1232–6.CrossRef Porro GB, Lazzaroni M, Barbara L. Tripotassium dicitrate bismuthate and ranitidine in duodenal ulcer Healing and influence on recurrence. Scand J Gastroenterol. 1988;23(10):1232–6.CrossRef
12.
Zurück zum Zitat Rokkas T, Sladen GE. Bismuth: effects on gastritis and peptic ulcer. Scand J Gastroenterol. 1988;142:82–6.CrossRef Rokkas T, Sladen GE. Bismuth: effects on gastritis and peptic ulcer. Scand J Gastroenterol. 1988;142:82–6.CrossRef
14.
Zurück zum Zitat Song Z, Suo B, Zhang L, et al. Rabeprazole, minocycline, amoxicillin, and bismuth as first-line and second-line regimens for Helicobacter pylori eradication. Helicobacter. 2016;21(6):462–70.CrossRefPubMed Song Z, Suo B, Zhang L, et al. Rabeprazole, minocycline, amoxicillin, and bismuth as first-line and second-line regimens for Helicobacter pylori eradication. Helicobacter. 2016;21(6):462–70.CrossRefPubMed
15.
Zurück zum Zitat Song ZQ, Zhou LY. Esomeprazole, minocycline, metronidazole and bismuth as first-line and second-line regimens for Helicobacter pylori eradication. J Dig Dis. 2016;17(4):260–7.CrossRefPubMed Song ZQ, Zhou LY. Esomeprazole, minocycline, metronidazole and bismuth as first-line and second-line regimens for Helicobacter pylori eradication. J Dig Dis. 2016;17(4):260–7.CrossRefPubMed
16.
Zurück zum Zitat Vogt K, Warrelmann M, Hahn H. Effect of bismuth subcarbonate against Campylobacter pylori: do citrate ions improve antibacterial activity? Zentralblatt für Bakteriologie. 1990;273(1):33–5.CrossRefPubMed Vogt K, Warrelmann M, Hahn H. Effect of bismuth subcarbonate against Campylobacter pylori: do citrate ions improve antibacterial activity? Zentralblatt für Bakteriologie. 1990;273(1):33–5.CrossRefPubMed
17.
Zurück zum Zitat Watari J. Helicobacter pylori associated chronic gastritis, clinical syndromes, precancerous lesions, and pathogenesis of gastric cancer development. World J Gastroenterol. 2014;20(18):5461–73.CrossRefPubMedPubMedCentral Watari J. Helicobacter pylori associated chronic gastritis, clinical syndromes, precancerous lesions, and pathogenesis of gastric cancer development. World J Gastroenterol. 2014;20(18):5461–73.CrossRefPubMedPubMedCentral
Metadaten
Titel
Pharmacokinetic and Safety Study of Bismuth Potassium Citrate Formulations in Healthy Subjects
verfasst von
Hong-Yu Luo
Shuo-Guo Xu
Li-Chen Gao
Hui-Zhi Long
Zi-Wei Zhou
Feng-Jiao Li
Shang-Ming Dai
Jin-Da Hu
Yu Su
Yan Cheng
Publikationsdatum
12.02.2024
Verlag
Springer International Publishing
Erschienen in
Drugs in R&D
Print ISSN: 1174-5886
Elektronische ISSN: 1179-6901
DOI
https://doi.org/10.1007/s40268-024-00455-9