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Dimakos J, Cui Y, Platt RW, Renoux C, Filion KB, Douros A. Fluoroquinolones and the risk of severe hypoglycaemia among sulphonylurea users: Population-based cohort study. Diabetes Obes Metab 2024; 26:3088-3098. [PMID: 38698651 DOI: 10.1111/dom.15627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 04/13/2024] [Accepted: 04/15/2024] [Indexed: 05/05/2024]
Abstract
AIM Fluoroquinolone-related hypoglycaemia is rare but may become clinically relevant in individuals at high baseline hypoglycaemic risk, such as patients with diabetes using sulphonylureas. Our population-based cohort study assessed whether fluoroquinolones are associated with an increased risk of severe hypoglycaemia compared with amoxicillin among patients treated with sulphonylureas. MATERIALS AND METHODS Using the UK's Clinical Practice Research Datalink Aurum linked to hospitalization and vital statistics data, we assembled a base cohort of patients who initiated second-generation sulphonylureas (1998-2020). The study cohort included patients initiating either fluoroquinolones or amoxicillin while on sulphonylureas. Using an intent-to-treat exposure definition, we assessed the 30-day risk of severe hypoglycaemia (hospitalization with or death because of hypoglycaemia) associated with fluoroquinolones compared with amoxicillin. Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) of severe hypoglycaemia after 1:5 matching on previous sulphonylurea use and propensity scores. Secondary analyses were stratified by demographics and glycated haemoglobin. RESULTS Overall, 143 417 patients initiated fluoroquinolones (n = 13 123) or amoxicillin (n = 130 294) while on sulphonylureas. Compared with amoxicillin, fluoroquinolones were not associated with the risk of severe hypoglycaemia (HR, 1.17; 95% CI, 0.91-1.50). Fluoroquinolones were associated with an increased risk in patients <65 years (HR, 2.90; 95% CI, 1.41-5.97) but not in those ≥65 years (HR, 1.03; 95% CI, 0.79-1.35) in stratified analyses. There was no evidence of effect modification by sex or glycated haemoglobin. CONCLUSIONS In patients using second-generation sulphonylureas, fluoroquinolones were not associated with an increased risk of severe hypoglycaemia compared with amoxicillin. An increased risk among younger adults is possible.
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Affiliation(s)
- Jenny Dimakos
- Department of Medicine, McGill University, Montreal, Canada
| | - Ying Cui
- Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Canada
| | - Robert W Platt
- Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Canada
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada
- Department of Pediatrics, McGill University, Montreal, Canada
| | - Christel Renoux
- Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Canada
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada
- Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
| | - Kristian B Filion
- Department of Medicine, McGill University, Montreal, Canada
- Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Canada
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada
| | - Antonios Douros
- Department of Medicine, McGill University, Montreal, Canada
- Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Canada
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada
- Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Berlin, Germany
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Dogheim GM, Werida RH. Drug Utilization Evaluation Study of Ciprofloxacin Use and Adverse Events Occurrence: Role of Community Pharmacists. J Pharm Technol 2024; 40:15-22. [PMID: 38318258 PMCID: PMC10838536 DOI: 10.1177/87551225231216328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2024] Open
Abstract
Background: Antimicrobial resistance is a global health crisis threatening optimal management of infectious diseases. Ciprofloxacin is a widely used fluoroquinolone in various disease conditions. Resistance against ciprofloxacin is increasing, leading to nonoptimal management of patients. Thus, the aim of this study was to assess ciprofloxacin use in the community setting in terms of appropriate prescribing, dosing, frequency, and duration of use. Methods: A cross-sectional, retrospective study was conducted by community pharmacists in 5 community pharmacies in Egypt from September 2021 to February 2022. Patients prescribed oral ciprofloxacin during the period of the study were included. Data on demographics, indications for ciprofloxacin, dosing regimen, adverse events, and drug interactions were collected. Results: A total of 151 patients' record indicated for ciprofloxacin were included in the study, of whom 44.4% were men and 55.6% were women who were neither pregnant nor lactating. Based on international guidelines, 96.69% ciprofloxacin prescriptions were appropriate; 96.03% contained correct ciprofloxacin dosing whereas 3.97% were overdose. A total of 90. 73% had correct frequency of administration and 96.03% records had correct durations. Only 1.99% of patients were ≤18 years of age, which is an absolute contraindication. Interacting drugs with ciprofloxacin were 28.5% with acetaminophen, 31.1% with ibuprofen, 16.6% with antacids, 21.2% with chlorpheniramine, and 7.9% with prednisolone. Adverse events included 1.32% hypoglycemia, 0.66% hyperglycemia, 3.97% tendinitis, and 2.65% QTc (heart rate-corrected QT interval) prolongation. Conclusion and relevance: Ciprofloxacin use in community pharmacies is appropriate according to international guidelines. Ongoing drug utilization evaluation is necessary to ensure rational drug use, which in turn can decrease resistance rates.
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Affiliation(s)
- Gaidaa M. Dogheim
- Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Rehab H. Werida
- Department of Clinical Pharmacy & Pharmacy Practice, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt
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3
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Maines E, Urru SAM, Leonardi L, Fancellu E, Campomori A, Piccoli G, Maiorana A, Soffiati M, Franceschi R. Drug-induced hyperinsulinemic hypoglycemia: An update on pathophysiology and treatment. Rev Endocr Metab Disord 2023; 24:1031-1044. [PMID: 37552352 DOI: 10.1007/s11154-023-09828-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/28/2023] [Indexed: 08/09/2023]
Abstract
The initial step for the differential diagnosis of hypoglycemia is to determine whether it is hyperinsulinemic or non hyperinsulinemic. Existing literature discusses drug-related hypoglycemia, but it misses a focus on drug-induced hyperinsulinemic hypoglycemia (DHH). Here we reviewed the association existing between drugs and hyperinsulinemic hypoglycemia. We primarily selected on the main electronic databases (MEDLINE, EMBASE, Web of Science, and SCOPUS) the reviews on drug-induced hypoglycemia. Among the drugs listed in the reviews, we selected the ones linked to an increase in insulin secretion. For the drugs missing a clear association with insulin secretion, we investigated the putative mechanism underlying hypoglycemia referring to the original papers. Our review provides a list of the most common agents associated with hyperinsulinemic hypoglycemia (HH), in order to facilitate both the recognition and the prevention of DHH. We also collected data about the responsiveness of DHH to diazoxide or octreotide.
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Affiliation(s)
- Evelina Maines
- Department of Women's and Children's Health, Pediatric Unit, Azienda Provinciale per i Servizi Sanitari APSS, Largo Medaglie d'oro 9, Trento, Italy.
| | - Silvana Anna Maria Urru
- Hospital Pharmacy Unit, Azienda Provinciale per i Servizi Sanitari APSS, Largo Medaglie d'oro 9, Trento, Italy
| | - Letizia Leonardi
- Department of Women's and Children's Health, Pediatric Unit, Azienda Provinciale per i Servizi Sanitari APSS, Largo Medaglie d'oro 9, Trento, Italy
| | | | - Annalisa Campomori
- Hospital Pharmacy Unit, Azienda Provinciale per i Servizi Sanitari APSS, Largo Medaglie d'oro 9, Trento, Italy
| | - Giovanni Piccoli
- CIBIO - Department of Cellular, Computational and Integrative Biology, Università degli Studi di Trento, Trento, Italy
| | - Arianna Maiorana
- Division of Metabolism and Research Unit of Metabolic Biochemistry, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Massimo Soffiati
- Department of Women's and Children's Health, Pediatric Unit, Azienda Provinciale per i Servizi Sanitari APSS, Largo Medaglie d'oro 9, Trento, Italy
| | - Roberto Franceschi
- Department of Women's and Children's Health, Pediatric Unit, Azienda Provinciale per i Servizi Sanitari APSS, Largo Medaglie d'oro 9, Trento, Italy
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4
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Singh P, Walia V, Verma PK. Hypoglycemia and anxiolysis mediated by levofloxacin treatment in diabetic rats. J Diabetes Metab Disord 2023; 22:1197-1209. [PMID: 37975146 PMCID: PMC10638278 DOI: 10.1007/s40200-023-01234-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 05/03/2023] [Indexed: 11/19/2023]
Abstract
Purpose The present study was designed to determine the effect of levofloxacin (LVX) treatment on the blood glucose level, insulin sensitivity, anxiety level, nitrite and MDA level of STZ induced diabetic rats. Methods Wistar rats were used in the present study. The rats were made diabetic by the administration of single dose of STZ (45 mg/kg, i.p.) and NAD (50 mg/kg, i.p.). The rats with the blood glucose level greater than 200 mg/dl were considered as diabetic (confirmed at day-3 of STZ-NAD administration). The non-diabetic rats were considered as control and received saline.Diabetic rats received metformin (50 mg/kg, p.o.) and LVX (20, 25, 30 and 35 mg/kg, i.p.) daily for 14 days (starting from the day at which STZ was injected). Following administration on 14th day,the blood sample was collected and the rats were subjected to behavioral assays for the determination of locomotor activity and anxiety level. Plasma was separated and used for the estimation ofnitrite and malondialdehyde (MDA)level. On 15th day OGTT was performed in the overnight fasted rats for the assessment of insulin sensitivity. Results The results obtained suggested that the administration of STZ-NAD induced the hyperglycemia at day-3 of administration. Diabetic rats displayed the significant increase in blood glucose, anxiety related behavior, MDA level while significant decrease in the insulin sensitivity and plasma nitrite level. Daily administration of metformin to the diabetic rats decreased the blood glucose level, increased the time spent at the center of open field, reversed the anxiety related behavior in LDT and EPM, did not affect the plasma nitrite level, decreased the plasma MDA level, decreased the fasting glucose level and AUC in OGTT assay. LVX (30 and 35 mg/kg) treatment significantly decreased the blood glucose level of diabetic rats. LVX (20, 25 and 30 mg/kg) treatment significantly decreased the number of square crossing while LVX (20, 25, 30 and 35) treatment significantly increased the time spent at the center of the field by the diabetic rats. LVX (20 and 35 mg/kg) treatment significantly reversed the STZ induced anxiety in LDT while LVX (20, 30 and 35 mg/kg) treatment significantly reversed the STZ induced anxiety in EPM test. LVX (20, 25 and 35 mg/kg) treatment significantly increased the plasma nitrite level and LVX (20-35 mg/kg) treatment significantly decreased the MDA level of diabetic rats. Further only LVX (35 mg/kg) treatment significantly decreased the fasting glucose level and increased the AUC of diabetic rats. Conclusion In conclusion, STZ-NAD administration increased the blood glucose level, anxiety related behavior, decreased the plasma nitrite and increased the MDA level. LVX administration potentiated the diabetogenic effects of STZ-NAD in rats. Daily administration of LVX decreased the blood glucose level of diabetic rats. LVX administration alleviated the STZ induced anxiety in OFT, LDT and EPM test. LVX administration increased the plasma nitrite level and decreased the lipid peroxidation in diabetic rats. Supplementary Information The online version contains supplementary material available at 10.1007/s40200-023-01234-0.
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Affiliation(s)
- Poonam Singh
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, 124001 Haryana India
| | - Vaibhav Walia
- SGT College of Pharmacy, SGT University, Gurugram, Haryana India
| | - Prabhakar Kumar Verma
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, 124001 Haryana India
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Watson CJ, Edlow JA. Managing Adults With Hypoglycemia. Ann Emerg Med 2023; 82:705-712. [PMID: 37632497 DOI: 10.1016/j.annemergmed.2023.07.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/19/2023] [Accepted: 07/20/2023] [Indexed: 08/28/2023]
Affiliation(s)
- Christopher James Watson
- Tufts University School of Medicine, Boston, MA; Division of Medical Toxicology, Department of Emergency Medicine, Maine Medical Center, Portland, ME
| | - Jonathan A Edlow
- Harvard Medical School, Boston, MA; Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA.
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Lafita López A, Ocabo Buil P, Arche Banzo MJ. [Severe quinolone-induced hypoglycemia]. Med Clin (Barc) 2023; 161:229. [PMID: 37236836 DOI: 10.1016/j.medcli.2023.04.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/25/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023]
Affiliation(s)
- Alberto Lafita López
- Servicio de Medicina Intensiva, Hospital Universitario San Jorge, Huesca, España.
| | - Paula Ocabo Buil
- Servicio de Medicina Intensiva, Hospital Universitario San Jorge, Huesca, España
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Ayodele O, Khanye S, Mothibe M, Sibiya N. Fluoroquinolone-induced Glycaemic Aberrations: Could Quinolones be Repurposed to Serve as New Antidiabetic Agents? Curr Rev Clin Exp Pharmacol 2023; 18:12-21. [PMID: 35184708 DOI: 10.2174/2772432817666220218101050] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 01/13/2022] [Accepted: 01/17/2022] [Indexed: 02/08/2023]
Abstract
Nalidixic acid is a synthetic antibiotic discovered in the 1960s during the synthesis of chloroquine, an effective drug for treating malaria. Nalidixic acid became the backbone for developing quinolones that are now widely used clinically for the treatment of various bacterial infections. The mechanism of action of quinolone involves the inhibition of topoisomerase II and topoisomerase IV. In attempts to improve the potency of fluoroquinolones, modifications were made; these modifications resulted in the emergence of newer generations of fluoroquinolones. Also, due to these modifications, several side effects were noted, including blood glucose control aberrations. Among fluoroquinolones that disrupt glucose homeostasis is gatifloxacin, which is in the third-generation category. Fluoroquinolones have been demonstrated to induce glycaemic aberrations by enhancing pancreatic cells' insulin secretion and interaction with antidiabetic agents via inhibition of cytochrome P450 enzymes. Considering their ability to induce hypoglycaemia, few studies have reported repurposing of quinolones as antidiabetic agents. Hyperglycaemia has also been reported to often precede hypoglycaemia. Due to the ability to decrease blood glucose, it is not surprising that some authors have reported novel quinolone derivates with antidiabetic properties in experimental studies. However, there is still a paucity of data regarding the effect of quinolones derivatives on glycaemic control. Understanding how fluoroquinolones lower blood glucose concentration could serve as the basis for developing novel quinolone derivatives with the sole purpose of lowering blood glucose concentrations. Although there are various conventional anti-hyperglycaemic agents, due to their associated shortfalls as well as an increase in the prevalence of diabetes, the discovery and development of new antidiabetics are warranted.
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Affiliation(s)
- Omobonlale Ayodele
- Division of Pharmacology, Faculty of Pharmacy, Rhodes University, Makhanda 6140, South Africa
| | - Setshaba Khanye
- Division of Pharmaceutical Chemistry, Faculty of Pharmacy, Rhodes University, Makhanda 6140, South Africa
| | - Mamosheledi Mothibe
- Division of Pharmacology, Faculty of Pharmacy, Rhodes University, Makhanda 6140, South Africa
| | - Ntethelelo Sibiya
- Division of Pharmacology, Faculty of Pharmacy, Rhodes University, Makhanda 6140, South Africa
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8
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Juhl CR, Burgdorf J, Knudsen C, Lubberding AF, Veedfald S, Isaksen JL, Hartmann B, Frikke-Schmidt R, Mandrup-Poulsen T, Holst JJ, Kanters JK, Torekov SS. A randomized, double-blind, crossover study of the effect of the fluoroquinolone moxifloxacin on glucose levels and insulin sensitivity in young men and women. Diabetes Obes Metab 2023; 25:98-109. [PMID: 36054143 PMCID: PMC10087839 DOI: 10.1111/dom.14851] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 08/15/2022] [Accepted: 08/22/2022] [Indexed: 12/14/2022]
Abstract
AIM The voltage-gated potassium channel Kv 11.1 is important for repolarizing the membrane potential in excitable cells such as myocytes, pancreatic α- and β-cells. Moxifloxacin blocks the Kv 11.1 channel and increases the risk of hypoglycaemia in patients with diabetes. We investigated glucose regulation and secretion of glucoregulatory hormones in young people with and without moxifloxacin, a drug known to block the Kv 11.1 channel. MATERIALS AND METHODS The effect of moxifloxacin (800 mg/day for 4 days) or placebo on glucose regulation was assessed in a randomized, double-blind, crossover study of young men and women (age 20-40 years and body mass index 18.5-27.5 kg/m2 ) without chronic disease, using 6-h oral glucose tolerance tests and continuous glucose monitoring. RESULTS Thirty-eight participants completed the study. Moxifloxacin prolonged the QTcF interval and increased heart rate. Hypoglycaemia was more frequently observed with moxifloxacin, both during the 8 days of continuous glucose monitoring and during the oral glucose tolerance tests. Hypoglycaemia questionnaire scores were higher after intake of moxifloxacin. Moxifloxacin reduced the early plasma-glucose response (AUC0-30 min ) by 7% (95% CI: -9% to -4%, p < .01), and overall insulin response (AUC0-360 min ) decreased by 18% (95% CI: -24% to -11%, p < .01) and plasma glucagon increased by 17% (95% CI: 4%-33%, p = .03). Insulin sensitivity calculated as the Matsuda index increased by 11%, and MISI, an index of muscle insulin sensitivity, increased by 34%. CONCLUSIONS In young men and women, moxifloxacin, a drug known to block the Kv 11.1 channel, increased QT interval, decreased glucose levels and was associated with increased muscle insulin sensitivity and more frequent episodes of hypoglycaemia.
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Affiliation(s)
- Christian R Juhl
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Josephine Burgdorf
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Cecilie Knudsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anniek F Lubberding
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Simon Veedfald
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jonas L Isaksen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ruth Frikke-Schmidt
- Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Thomas Mandrup-Poulsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jørgen K Kanters
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Signe S Torekov
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Shahbazi F, Shojaei L, Farvadi F, Kadivarian S. Antimicrobial safety considerations in critically ill patients: part II: focused on anti-microbial toxicities. Expert Rev Clin Pharmacol 2022; 15:563-573. [PMID: 35734938 DOI: 10.1080/17512433.2022.2093716] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Antibiotic prescription is a challenging issue in critical care settings. Different pharmacokinetic and pharmacodynamic properties, polypharmacy, drug interactions, and high incidence of multidrug-resistant microorganisms in this population can influence the selection, safety, and efficacy of prescribed antibiotics. AREAS COVERED In the current article we searched PubMed, Scopus and Google Scholar for neurotoxicities, hematologic toxicity and fluid stewardship in intensive care units. EXPERT OPINION Critically ill patients who receive antimicrobial agents should be monitored for neurological, hematologic toxicities especially seizure, thrombocytopenia, and clostridioides infections. Other toxicities including QTc prolongation, electrolyte disturbances, liver enzyme elevation, and infusion-related reactions were being considered. Other changes, including fluid overload, hypoalbuminemia, augmented renal clearance, increased cardiac outputs in septic shock, and acute kidney injury, may influence treatment efficiency and patient outcome.
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Affiliation(s)
- Foroud Shahbazi
- Department of Clinical Pharmacy, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Lida Shojaei
- Department of Clinical Pharmacy, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fakhrossadat Farvadi
- Center for nanotechnology in drug delivery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sara Kadivarian
- Department of Clinical Pharmacy, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Liao SH, Hu SY, How CK, Hsieh VCR, Chan CM, Chiu CS, Hsieh MS. Risk for hypoglycemic emergency with levofloxacin use, a population-based propensity score matched nested case-control study. PLoS One 2022; 17:e0266471. [PMID: 35377912 PMCID: PMC8979446 DOI: 10.1371/journal.pone.0266471] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 03/21/2022] [Indexed: 11/19/2022] Open
Abstract
Potential association between oral levofloxacin use and hypoglycemic emergency (HE) have been established. However, a large epidemiological study is required to verify this observation. This study aimed to determine if use of oral levofloxacin increased the risk of HE. The nationwide database between 1999 and 2013, including 1.6 million patients with type 2 diabetes (T2D), was used to conduct a nested case-control study. Cases and controls comprised of patients with and without HE, respectively. To avoid indication bias the control subjects were chosen through propensity score matching with cases in a 10-fold ratio. T2D severity was classified based on the adjusted diabetic complication severity index score. 26,695 and 266,950 matched patients with T2D, were finally used as cases and controls, respectively, for the analysis. Multivariate logistic regression analysis showed that antibiotic use was associated with an increased risk for HE (adjusted odds ratio (aOR) = 6.08, 95% confidence interval (95% CI): 5.79–6.38). When compared with antibiotic non-users, those who used fluoroquinolones and sulfonamides displayed the highest (aOR = 12.05, 95% CI: 10.66–13.61) and second highest (aOR = 7.20, 95% CI: 6.29–8.24) risks of HE, respectively. The associated risk for HE was significantly higher with levofloxacin than that with cephalosporins (aOR = 5.13, 95% CI: 2.28–11.52) and penicillin (aOR = 9.40, 95% CI: 2.25–39.24). In the joint effect analyses, the risk for HE increased with the combination of levofloxacin with insulin (aOR = 8.42, 95% CI: 1.91–37.00) or sulfonylurea (aOR = 3.56, 95% CI: 1.12–11.33). Use of oral levofloxacin, compared to that of other antibiotics, was found to be significantly associated with HE in T2D patients. Clinicians should exercise caution while prescribing levofloxacin, especially when combined with insulin or sulfonylurea.
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Affiliation(s)
- Shu-Hui Liao
- Department of Pathology and Laboratory, Taipei Veterans General Hospital, Taoyuan Branch, Taoyuan, Taiwan
| | - Sung-Yuan Hu
- Department of Emergency Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- Chung Shan Medical University, Taichung, Taiwan
| | - Chorng-Kuang How
- Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Kinmen Hospital, Ministry of Health and Welfare, Kinmen, Taiwan
| | - Vivian Chia-Rong Hsieh
- Department of Health Services Administration, China Medical University, Taichung, Taiwan
| | - Chia-Ming Chan
- Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chien-Shan Chiu
- Department of Dermatology, Taichung Veterans General Hospital, Taichung, Taiwan
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Ming-Shun Hsieh
- Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Emergency Medicine, Taipei Veterans General Hospital, Taoyuan Branch, Taoyuan, Taiwan
- * E-mail:
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Dogan H, Ocal H, Safak T, Kilinc MA, Risvanli A. Dose related inhibitor effect of enrofloxacin on in vitro feline spontaneous myometrial contractility. Anim Reprod Sci 2022; 239:106972. [DOI: 10.1016/j.anireprosci.2022.106972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 03/16/2022] [Accepted: 03/20/2022] [Indexed: 11/29/2022]
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Insulinotropic Potential of Moxifloxacin and Gemifloxacin: An In Vivo Rabbits Model Study Followed by Randomized Phase I Clinical Trial. Antibiotics (Basel) 2022; 11:antibiotics11020148. [PMID: 35203750 PMCID: PMC8868483 DOI: 10.3390/antibiotics11020148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/20/2022] [Accepted: 01/20/2022] [Indexed: 02/01/2023] Open
Abstract
Fluoroquinolones (FQs) have been reported to cause dysglycemia in both diabetic and non-diabetic patients. However, diabetic patients are usually on polypharmacy, so we cannot attribute the dysglycemia specifically to FQs. To answer the question as to whether Moxifloxacin and Gemifloxacin influence blood glucose levels and serum insulin levels or otherwise, rabbits were used as experimental animals in an in vivo model followed by a phase I randomized clinical trial in euglycemic healthy volunteers. The effects on the serum insulin and blood glucose levels in the Moxifloxacin and Gemifloxacin treated groups were, respectively, determined on the fifth day in both the in-vivo rabbits model and in the test subjects of the phase I clinical trial. The effects of these drugs were also checked on the histomorphology of the pancreas in the rabbits. The findings of our study suggest that Moxifloxacin and Gemifloxacin significantly (p < 0.05) reduced the blood glucose levels via a subsequent significant shift in the serum insulin levels both in the in vivo animal model and in the test subjects of the phase I clinical trial. No prominent effects on the beta cells histomorphology were noted in this study. Moxifloxacin showed a more significant effect than Gemifloxacin. The insulinotropic effect was comparable to the effect of Glibenclamide. It is concluded that Moxifloxacin and Gemifloxacin have a significant blood glucose lowering effect mediated through insulinotropic action. (Clinical Trials.gov identifier: NCT04692623).
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Hegazy WAH, Rajab AAH, Abu Lila AS, Abbas HA. Anti-diabetics and antimicrobials: Harmony of mutual interplay. World J Diabetes 2021; 12:1832-1855. [PMID: 34888011 PMCID: PMC8613656 DOI: 10.4239/wjd.v12.i11.1832] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/26/2021] [Accepted: 10/25/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes is one of the four major non-communicable diseases, and appointed by the world health organization as the seventh leading cause of death worldwide. The scientists have turned over every rock in the corners of medical sciences in order to come up with better understanding and hence more effective treatments of diabetes. The continuous research on the subject has elucidated the role of immune disorders and inflammation as definitive factors in the trajectory of diabetes, assuring that blood glucose adjustments would result in a relief in the systemic stress leading to minimizing inflammation. On a parallel basis, microbial infections usually take advantage of immunity disorders and propagate creating a pro-inflammatory environment, all of which can be reversed by antimicrobial treatment. Standing at the crossroads between diabetes, immunity and infection, we aim in this review at projecting the interplay between immunity and diabetes, shedding the light on the overlapping playgrounds for the activity of some antimicrobial and anti-diabetic agents. Furthermore, we focused on the anti-diabetic drugs that can confer antimicrobial or anti-virulence activities.
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Affiliation(s)
- Wael A H Hegazy
- Department of Microbiology and Immunology, Zagazig University, Zagzig 44519, Egypt
| | - Azza A H Rajab
- Department of Microbiology and Immunology, Zagazig University, Zagzig 44519, Egypt
| | - Amr S Abu Lila
- Department of Pharmaceutics, Zagazig University, Faculty of Pharmacy, Zagzig 44519, Egypt
- Department of Pharmaceutics, College of Pharmacy, University of Hail, Hail 81442, Saudi Arabia
| | - Hisham A Abbas
- Department of Microbiology and Immunology, Zagazig University, Zagzig 44519, Egypt
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Han J, Kiss L, Mei H, Remete AM, Ponikvar-Svet M, Sedgwick DM, Roman R, Fustero S, Moriwaki H, Soloshonok VA. Chemical Aspects of Human and Environmental Overload with Fluorine. Chem Rev 2021; 121:4678-4742. [PMID: 33723999 PMCID: PMC8945431 DOI: 10.1021/acs.chemrev.0c01263] [Citation(s) in RCA: 186] [Impact Index Per Article: 46.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Indexed: 12/24/2022]
Abstract
Over the last 100-120 years, due to the ever-increasing importance of fluorine-containing compounds in modern technology and daily life, the explosive development of the fluorochemical industry led to an enormous increase of emission of fluoride ions into the biosphere. This made it more and more important to understand the biological activities, metabolism, degradation, and possible environmental hazards of such substances. This comprehensive and critical review focuses on the effects of fluoride ions and organofluorine compounds (mainly pharmaceuticals and agrochemicals) on human health and the environment. To give a better overview, various connected topics are also discussed: reasons and trends of the advance of fluorine-containing pharmaceuticals and agrochemicals, metabolism of fluorinated drugs, withdrawn fluorinated drugs, natural sources of organic and inorganic fluorine compounds in the environment (including the biosphere), sources of fluoride intake, and finally biomarkers of fluoride exposure.
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Affiliation(s)
- Jianlin Han
- Jiangsu
Co-Innovation Center of Efficient Processing and Utilization of Forest
Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China
| | - Loránd Kiss
- University
of Szeged, Institute of Pharmaceutical Chemistry
and Interdisciplinary Excellence Centre, Eötvös u. 6, 6720 Szeged, Hungary
| | - Haibo Mei
- Jiangsu
Co-Innovation Center of Efficient Processing and Utilization of Forest
Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China
| | - Attila Márió Remete
- University
of Szeged, Institute of Pharmaceutical Chemistry
and Interdisciplinary Excellence Centre, Eötvös u. 6, 6720 Szeged, Hungary
| | - Maja Ponikvar-Svet
- Department
of Inorganic Chemistry and Technology, Jožef
Stefan Institute, Jamova
cesta 39, 1000 Ljubljana, Slovenia
| | - Daniel Mark Sedgwick
- Departamento
de Química Orgánica, Universidad
de Valencia, 46100 Burjassot, Valencia Spain
| | - Raquel Roman
- Departamento
de Química Orgánica, Universidad
de Valencia, 46100 Burjassot, Valencia Spain
| | - Santos Fustero
- Departamento
de Química Orgánica, Universidad
de Valencia, 46100 Burjassot, Valencia Spain
| | - Hiroki Moriwaki
- Hamari
Chemicals Ltd., 1-19-40, Nankokita, Suminoe-ku, Osaka 559-0034, Japan
| | - Vadim A. Soloshonok
- Department
of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, 20018 San Sebastian, Spain
- IKERBASQUE,
Basque Foundation for Science, 48011 Bilbao, Spain
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Swart F, Bianchi G, Lenzi J, Iommi M, Maestri L, Raschi E, Zoli M, Ponti FD, Poluzzi E. Risk of hospitalization from drug-drug interactions in the Elderly: real-world evidence in a large administrative database. Aging (Albany NY) 2020; 12:19711-19739. [PMID: 33024058 PMCID: PMC7732312 DOI: 10.18632/aging.104018] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 08/22/2020] [Indexed: 01/24/2023]
Abstract
The aim of this study was to assess the risk of hospitalization associated with the concomitant prescription of 10 highly prevalent drug-drug interactions (DDIs) among all individuals aged ≥65 residing in Bologna's area, Italy. We used incidence density sampling, and the effect of current (last month) and past (≥30 days before) exposure to DDI was investigated through conditional multivariable logistic regression analysis. Two DDIs were associated with increased hospitalization due to DDI related conditions: ACE-inhibitors/ diuretics plus glucocorticoids (current DDI: OR 2.36, 95% CI 1.94-2.87; past DDI: OR 1.36, 95% CI 1.12-1.65) and antidiabetic therapy plus current use of fluoroquinolones (OR 4.43, 95% CI 1.61-11.2). Non-Steroidal Anti-inflammatory Drugs (NSAIDs) increased the risk of re-bleeding in patients taking Selective Serotonin Reuptake Inhibitors (OR 5.56, 95% CI 1.24-24.9), while no significant effect was found in those without a history of bleeding episodes. Concomitant prescription of NSAIDs and ACE-inhibitors/diuretics in patients with a history of high-risk conditions was infrequent. Within the pattern of drug prescriptions in the older population of Bologna's area, we distinguished DDIs with actual clinical consequences from others that might be considered generally safe. Observed prescribing habits of clinicians reflect awareness of potential interactions in patients at risk.
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Affiliation(s)
- Floor Swart
- School of Medicine, Vrije University of Amsterdam, Amsterdam, The Netherlands
| | - Giampaolo Bianchi
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy,Centre of Studies and Research on the Elderly, University of Bologna, Bologna, Italy
| | - Jacopo Lenzi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Marica Iommi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Lorenzo Maestri
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Emanuel Raschi
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Marco Zoli
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy,Centre of Studies and Research on the Elderly, University of Bologna, Bologna, Italy
| | - Fabrizio De Ponti
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy,Centre of Studies and Research on the Elderly, University of Bologna, Bologna, Italy
| | - Elisabetta Poluzzi
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy,Centre of Studies and Research on the Elderly, University of Bologna, Bologna, Italy
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Iguchi T, Goto K, Watanabe K, Hashimoto K, Suzuki T, Kishino H, Fujimoto K, Mori K. Fluoroquinolones suppress gluconeogenesis by inhibiting fructose 1,6-bisphosphatase in primary monkey hepatocytes. Toxicol In Vitro 2020; 65:104786. [PMID: 32004540 DOI: 10.1016/j.tiv.2020.104786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 01/08/2020] [Accepted: 01/26/2020] [Indexed: 11/17/2022]
Abstract
Dysglycemia is one of the most serious adverse events associated with the clinical use of certain fluoroquinolones. The purpose of this study was to investigate the effects of the representative fluoroquinolones moxifloxacin and gatifloxacin on hepatic gluconeogenesis using primary monkey hepatocytes. Glucose production was induced after the cells were incubated for 4 h with 10 mM sodium lactate and 1 mM sodium pyruvate as gluconeogenic substrates. Under these conditions, moxifloxacin and gatifloxacin dose-dependently suppressed gluconeogenesis at concentrations of 100 μM or higher. Transcriptome analysis of rate-limiting enzymes involved in hepatic gluconeogenesis revealed that moxifloxacin and gatifloxacin at a concentration of 1000 μM did not affect the expression of key gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase, glucose 6-phosphatase, and fructose 1,6-bisphosphatase. Furthermore, metabolome analysis, in vitro glucose production assay using additional gluconeogenic substrates, and fructose 1,6-bisphosphatase assay using the cell extracts showed that fluoroquinolones enzymatically suppressed hepatic gluconeogenesis by inhibiting fructose 1,6-bisphosphatase. These inhibitory effects may involve in the clinically relevant dysglycemia associated with fluoroquinolones in human.
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Affiliation(s)
- Takuma Iguchi
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan.
| | - Koichi Goto
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan.
| | - Kyoko Watanabe
- Biomarker & Translational Research Department, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-0005, Japan.
| | - Kazuyuki Hashimoto
- Biomarker & Translational Research Department, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-0005, Japan.
| | - Takami Suzuki
- Oncology Research Laboratories I, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-0005, Japan.
| | - Hiroyuki Kishino
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan.
| | - Kazunori Fujimoto
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan.
| | - Kazuhiko Mori
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan.
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Kennedy KE, Teng C, Patek TM, Frei CR. Hypoglycemia Associated with Antibiotics Alone and in Combination with Sulfonylureas and Meglitinides: An Epidemiologic Surveillance Study of the FDA Adverse Event Reporting System (FAERS). Drug Saf 2019; 43:363-369. [PMID: 31863282 DOI: 10.1007/s40264-019-00901-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
INTRODUCTION Fluoroquinolones, clarithromycin, linezolid, tigecycline, cefditoren, doxycycline, and trimethoprim-sulfamethoxazole are known to be associated with hypoglycemia, but few studies have considered concomitant glucose-lowering medications. OBJECTIVE The objective of this study was to evaluate the association between hypoglycemia and antibiotics using the US Food and Drug Administration Adverse Event Reporting System (FAERS), while accounting for concomitant glucose-lowering medications including sulfonylureas and meglitinides. METHODS FAERS reports from 1 January 2004 to 31 December 2017 were included in the study. Reporting odds ratios (RORs) and corresponding 95% confidence intervals (CIs) for the association between antibiotics and hypoglycemia were calculated. An association was considered to be statistically significant when the lower limit of the 95% CI was > 1.0. RESULTS A total of 2,334,959 reports (including 18,466 hypoglycemia reports) were considered, after inclusion criteria were applied. Statistically significant hypoglycemia RORs (95% CI) for antibiotics were: cefditoren 14.03 (8.93-22.03), tigecycline 3.32 (1.95-5.65), clarithromycin 2.41 (1.89-3.08), ertapenem 2.07 (1.14-3.75), moxifloxacin 2.06 (1.59-2.65), levofloxacin 1.66 (1.37-2.01), and linezolid 1.54 (1.07-2.20). After adjusting for concomitant sulfonylureas and meglitinides, the following antibiotics were still significantly associated with hypoglycemia: cefditoren 14.25 (9.08-22.39), tigecycline 3.34 (1.96-5.68), ertapenem 1.93 (1.03-3.60), and clarithromycin 1.56 (1.15-2.11). CONCLUSION In many patients, antibiotics, including fluoroquinolones, are associated with hypoglycemia when they are also taking sulfonylureas or meglitinides. Cefditoren, tigecycline, ertapenem, and clarithromycin are associated with hypoglycemia even if not taken with sulfonylureas or meglitinides. The association between ertapenem and hypoglycemia has not been previously reported.
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Affiliation(s)
- Kaitlin E Kennedy
- Pharmacotherapy Division, College of Pharmacy, The University of Texas at Austin, San Antonio, TX, USA
- Pharmacotherapy Education and Research Center, Long School of Medicine, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., MSC-6220, San Antonio, TX, 78229, USA
| | - Chengwen Teng
- Pharmacotherapy Division, College of Pharmacy, The University of Texas at Austin, San Antonio, TX, USA
- Pharmacotherapy Education and Research Center, Long School of Medicine, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., MSC-6220, San Antonio, TX, 78229, USA
| | - Taylor M Patek
- Pharmacotherapy Division, College of Pharmacy, The University of Texas at Austin, San Antonio, TX, USA
- Pharmacotherapy Education and Research Center, Long School of Medicine, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., MSC-6220, San Antonio, TX, 78229, USA
| | - Christopher R Frei
- Pharmacotherapy Division, College of Pharmacy, The University of Texas at Austin, San Antonio, TX, USA.
- Pharmacotherapy Education and Research Center, Long School of Medicine, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., MSC-6220, San Antonio, TX, 78229, USA.
- South Texas Veterans Health Care System, San Antonio, TX, USA.
- University Health System, San Antonio, TX, USA.
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19
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Ciprofloxacin and risk of hypolycemia in non-diabetic patients. J Med Case Rep 2019; 13:142. [PMID: 31078137 PMCID: PMC6511658 DOI: 10.1186/s13256-019-2083-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 04/12/2019] [Indexed: 11/24/2022] Open
Abstract
Background Fluoroquinolones have been associated with hypoglycemia in patients taking diabetic medications, most commonly due to drug-drug interactions and other associated risk factors. Except for four published case reports, there are no studies that have found positive associations between ciprofloxacin and hypoglycemia. In all but one of the cases, ciprofloxacin was taken with other hypoglycemic drugs. Recently, the Eritrean National Pharmacovigilance Centre received a serious case of hypoglycemia with recurrent episodes in a young and healthy patient without diabetes following use of oral ciprofloxacin. The aim of the present study is therefore to assess the causal relationship between ciprofloxacin and hypoglycemia in patients without diabetes using the World Health Organization-Uppsala Monitoring Centre global adverse drug reaction database (VigiBase®). Methods A search was made on the World Health Organization global adverse drug reaction database (August 15, 2018) using “ciprofloxacin” as the drug substance and “hypoglycemia” as the reaction term. Cases that used hypoglycemic drugs (patients with diabetes) concurrently with ciprofloxacin and those with a completeness score below 50% were excluded to control for confounders and to improve the strength of the data. Hill criteria were used to assess causation. Results A total of 35 cases of hypoglycemia reported since 1989 from 17 countries in patients without diabetes associated with ciprofloxacin use with a median time to onset of 4 days were retrieved. The cases have a median age of 64 years (interquartile range, 50–85) with a similar male–to-female ratio. Ciprofloxacin was the only suspect and the sole drug administered in 48.5% of the cases. In ten cases, hypoglycemia abated following withdrawal of ciprofloxacin, and reaction recurred in one case on the subsequent rechallenge. Hypoglycemia was marked as “serious” in 20 cases, and the outcome was fatal in two cases. Conclusions This assessment found a suggestive causal link between use of ciprofloxacin and hypoglycemia in patients without diabetes.
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Successful Use of Octreotide Therapy for Refractory Levofloxacin-Induced Hypoglycemia: A Case Report and Literature Review. Case Rep Crit Care 2019; 2019:3560608. [PMID: 31210993 PMCID: PMC6532307 DOI: 10.1155/2019/3560608] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 04/17/2019] [Accepted: 04/21/2019] [Indexed: 12/05/2022] Open
Abstract
Fluoroquinolones are commonly prescribed antimicrobials that have been implicated in alterations of glucose metabolism. We report a case of refractory fluoroquinolone-induced hypoglycemia in a patient with type-2 diabetes mellitus on glipizide that was successfully treated with octreotide. A patient was admitted with hypoglycemia after having been initiated on levofloxacin therapy. Despite treating the hypoglycemia supportively with multiple boluses of 25 g of dextrose, a continuous dextrose infusion, and glucagon, the patient experienced repeated episodes of rebound hypoglycemia. The persistent hypoglycemia was eventually reversed with the administration of subcutaneous octreotide. Clinicians should be cognizant of this adverse effect of fluoroquinolones, as well as predisposing risk factors, and consider octreotide as an adjunctive therapy for refractory hypoglycemia cases.
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Yabe K, Yamamoto Y, Suzuki T, Takada S, Mori K. Functional and Morphological Characteristics of Pancreatic Islet Lesions Induced by Quinolone Antimicrobial Agent Gatifloxacin in Rats. Toxicol Pathol 2018; 47:35-43. [PMID: 30407147 DOI: 10.1177/0192623318809062] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
We characterized pancreatic islet lesions induced by several quinolones using functional and morphological examinations of the pancreatic islets in male rats orally administered gatifloxacin, lomefloxacin, or levofloxacin at 300 mg/kg for 14 consecutive days. Consequently, in contrast to lomefloxacin or levofloxacin, gatifloxacin increased serum glucose and glycosylated albumin on day 14 and elevated serum glucose tended to decrease insulin in the intravenous glucose tolerance test. Microscopically, only gatifloxacin induced cytoplasmic vacuoles containing eosinophilic homogenous contents in islet cells. Immunohistochemical examination revealed that vacuolated islet cells were positively stained for insulin, demonstrating they were pancreatic β cells. Electron microscopy showed that the cytoplasmic vacuoles represented dilated cisterna of the rough endoplasmic reticulum filled with electron-lucent materials in pancreatic β cells. Moreover, insulin secretory granules were drastically decreased in vacuolated islet cells, suggesting impaired insulin synthesis and/or transport. This gatifloxacin-induced pancreatic toxicity in rats was considered to be associated with high pancreatic drug distribution. These results demonstrated that gatifloxacin provoked functional and morphological pancreatic β cell alteration associated with impaired insulin synthesis and/or transport, leading to hyperglycemia.
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Affiliation(s)
- Koichi Yabe
- 1 Pharmacovigilance Department, Daiichi Sankyo Co., Ltd., Tokyo, Japan
| | - Yuka Yamamoto
- 2 Biological Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan
| | - Takami Suzuki
- 3 Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan
| | - Sanae Takada
- 3 Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan
| | - Kazuhiko Mori
- 3 Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo, Japan
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Kondo M, Miyoshi Y, Tarumoto K, Hirayama N, Sasaki T, Yamashita K, Yamashita S, Hatao K. Severe and Recurrent Hypoglycemia Caused by Garenoxacin in a Patient not Taking Hypoglycemic Drugs. Intern Med 2018; 57:2041-2043. [PMID: 29491302 PMCID: PMC6096026 DOI: 10.2169/internalmedicine.0366-17] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Quinolones are known to induce hypoglycemia, although there is no written report of garenoxacin-induced hypoglycemia. We herein report a case of garenoxacin-induced hypoglycemia in a patient not taking hypoglycemic drugs. An 89-year-old Japanese woman with type 2 diabetes and chronic renal insufficiency requiring hemodialysis was admitted to the emergency department in a comatose state. Her serum glucose measured 1 mg/dL on arrival. The patient had not taken any hypoglycemic drugs recently and had never experienced a hypoglycemic episode. She had received a four-day course of garenoxacin treatment before the emergency admission. Clinicians should therefore recognize the potential risk of hypoglycemia during garenoxacin therapy.
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Affiliation(s)
- Manabu Kondo
- Department of Endocrinology and Hematology, Tokuyama Central Hospital, Japan
| | - Yuka Miyoshi
- Department of Endocrinology and Hematology, Tokuyama Central Hospital, Japan
| | - Kohji Tarumoto
- Department of Emergency and Critical Care Medicine, Tokuyama Central Hospital, Japan
| | - Norie Hirayama
- Department of Pharmacy, Tokuyama Central Hospital, Japan
| | - Takahiro Sasaki
- Department of Endocrinology and Hematology, Tokuyama Central Hospital, Japan
| | - Kohji Yamashita
- Department of Endocrinology and Hematology, Tokuyama Central Hospital, Japan
| | - Susumu Yamashita
- Department of Emergency and Critical Care Medicine, Tokuyama Central Hospital, Japan
| | - Katsuhiro Hatao
- Department of Endocrinology and Hematology, Tokuyama Central Hospital, Japan
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Real J, Miranda C, Olofsson CS, Smith PA. Lipophilicity predicts the ability of nonsulphonylurea drugs to block pancreatic beta-cell K ATP channels and stimulate insulin secretion; statins as a test case. Endocrinol Diabetes Metab 2018; 1:e00017. [PMID: 30815553 PMCID: PMC6354820 DOI: 10.1002/edm2.17] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 01/18/2018] [Accepted: 02/18/2018] [Indexed: 12/26/2022] Open
Abstract
AIMS KATP ion channels play a key role in glucose-stimulated insulin secretion. However, many drugs block KATP as "off targets" leading to hyperinsulinaemia and hypoglycaemia. As such drugs are often lipophilic, the aim was to examine the relationship between drug lipophilicity (P) and IC 50 for KATP block and explore if the IC 50's of statins could be predicted from their lipophilicity and whether this would allow one to forecast their acute action on insulin secretion. MATERIALS AND METHODS A meta-analysis of 26 lipophilic, nonsulphonylurea, blockers of KATP was performed. From this, the IC 50's for pravastatin and simvastatin were predicted and then tested experimentally by exploring their effects on KATP channel activity via patch-clamp measurement, calcium imaging and insulin secretion in murine beta cells and islets. RESULTS Nonsulphonylurea drugs inhibited KATP channels with a Log IC 50 linearly related to their logP. Simvastatin blocked KATP with an IC 50 of 25 nmol/L, a value independent of cytosolic factors, and within the range predicted by its lipophilicity (21-690 nmol/L). 10 μmol/L pravastatin, predicted IC 50 0.2-12 mmol/L, was without effect on the KATP channel. At 10-fold therapeutic levels, 100 nmol/L simvastatin depolarized the beta-cell membrane potential and stimulated Ca2+ influx but did not affect insulin secretion; the latter could be explained by serum binding. CONCLUSIONS The logP of a drug can aid prediction for its ability to block beta-cell KATP ion channels. However, although the IC 50 for the block of KATP by simvastatin was predicted, the difference between this and therapeutic levels, as well as serum sequestration, explains why hypoglycaemia is unlikely to be observed with acute use of this statin.
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Affiliation(s)
- Joana Real
- Department of Physiology/Metabolic PhysiologyInstitute of Neuroscience and PhysiologyGöteborgSweden
| | - Caroline Miranda
- Department of Physiology/Metabolic PhysiologyInstitute of Neuroscience and PhysiologyGöteborgSweden
| | - Charlotta S. Olofsson
- Department of Physiology/Metabolic PhysiologyInstitute of Neuroscience and PhysiologyGöteborgSweden
| | - Paul A. Smith
- School of Life Sciences University of NottinghamNottinghamUK
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Yoshimatsu Y, Ishizaka T, Chiba K, Mori K. Usefulness of simultaneous and sequential monitoring of glucose level and electrocardiogram in monkeys treated with gatifloxacin under conscious and nonrestricted conditions. Exp Anim 2018; 67:281-290. [PMID: 29311442 PMCID: PMC5955759 DOI: 10.1538/expanim.17-0136] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Drug-induced cardiac electrophysiological abnormalities accompanied by hypoglycemia or
hyperglycemia increase the risk for life-threatening arrhythmia. To assess the
drug-induced cardiotoxic potential associated with extraordinary blood glucose (GLU)
levels, the effect of gatifloxacin (GFLX) which was frequently associated with GLU
abnormality and QT/QTc prolongations in the clinic on blood GLU and electrocardiogram
(ECG) parameters was investigated in cynomolgus monkeys (n=4) given GFLX orally in an
ascending dose regimen (10, 30, 60 and 100 mg/kg). Simultaneous and sequential GLU and ECG
monitoring with a continuous GLU monitoring system and Holter ECG, respectively, were
conducted for 24 h under free-moving conditions. Consequently, GFLX at 30 and 60 mg/kg
dose-dependently induced a transient decrease in GLU without any ECG abnormality 2–4 h
postdose. Highest dose of 100 mg/kg caused severe hypoglycemia with a mean GLU of <30
mg/dL, accompanied by remarkable QT/QTc prolongations by 20–30% in all animals. In
contrast, hyperglycemia without QT/QTc prolongations was noted 24 h after dosing in one
animal. A close correlation between GLU and QTc values was observed in animals treated
with 100 mg/kg, suggesting that GFLX-induced hypoglycemia enhanced QT/QTc prolongations.
Furthermore, the 24-h sequential GLU monitoring data clearly distinguished between
GFLX-induced GLU abnormality and physiological GLU changes influenced by feeding
throughout the day. In conclusion, the combined assessment of continuous GLU and ECG
monitoring is valuable in predicting the drug-induced cardio-electrophysiological risk
associated with both GLU and ECG abnormalities.
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Affiliation(s)
- Yu Yoshimatsu
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan
| | - Tomomichi Ishizaka
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan
| | - Katsuyoshi Chiba
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan
| | - Kazuhiko Mori
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan
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Tomita T. [Research on Insufficient Information for Pharmaceutical Products]. YAKUGAKU ZASSHI 2017; 137:1497-1504. [PMID: 29199258 DOI: 10.1248/yakushi.17-00164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Several issues concerning medicines remain unclear, including the availability of known, but not easily recognizable information. This review evaluates the mechanisms of side effects and the various risk indications included in package inserts. The results can be summarized as follows. 1) Short-term exposure to gatifloxacin significantly induced insulin secretion and increased the cytosolic Ca2+ concentration of islet cells by augmenting extracellular Ca2+ influx and its release from the endoplasmic reticulum. Alternatively, there was a decline in the cellular insulin level and reactivity to sulfonylurea after prolonged exposure. The insulin depletion was greater than that produced by other fluoroquinolones. 2) The elution of di(2-ethylhexyl)phthalate (DEHP) from the infusion set could be associated with the solubilizers in the injection medicines. The package inserts of several products containing polysorbate or ethanol had no warning about DEHP. Although there was a slight correlation between polysorbate content and descriptions on package inserts, the use of DEHP-containing devices was prohibited for some products, even with limited amounts of polysorbate. Therefore, the package insert statements should be reviewed to reflect appropriately the extent of DEHP elution. 3) Risk management plan consists of strategies to minimize the potential risks of medicines. One approach could be to introduce reminders on package inserts; however, of 268 potential risks associated with 81 products, 56 were not mentioned in package inserts. Because most postmarketing pharmacovigilance plans depend on spontaneous reporting by healthcare personnel, the descriptions on package inserts should be reexamined.
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Affiliation(s)
- Takashi Tomita
- Department of Pharmaceutical Services, Hiroshima University Hospital
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Zhanel GG, Fontaine S, Adam H, Schurek K, Mayer M, Noreddin AM, Gin AS, Rubinstein E, Hoban DJ. A Review of New Fluoroquinolones : Focus on their Use in Respiratory Tract Infections. ACTA ACUST UNITED AC 2016; 5:437-65. [PMID: 17154673 DOI: 10.2165/00151829-200605060-00009] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
The new respiratory fluoroquinolones (gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, and on the horizon, garenoxacin) offer many improved qualities over older agents such as ciprofloxacin. These include retaining excellent activity against Gram-negative bacilli, with improved Gram-positive activity (including Streptococcus pneumoniae and Staphylococcus aureus). In addition, gatifloxacin, moxifloxacin and garenoxacin all demonstrate increased anaerobic activity (including activity against Bacteroides fragilis). The new fluoroquinolones possess greater bioavailability and longer serum half-lives compared with ciprofloxacin. The new fluoroquinolones allow for once-daily administration, which may improve patient adherence. The high bioavailability allows for rapid step down from intravenous administration to oral therapy, minimizing unnecessary hospitalization, which may decrease costs and improve quality of life of patients. Clinical trials involving the treatment of community-acquired respiratory infections (acute exacerbations of chronic bronchitis, acute sinusitis, and community-acquired pneumonia) demonstrate high bacterial eradication rates and clinical cure rates. In the treatment of community-acquired respiratory tract infections, the various new fluoroquinolones appear to be comparable to each other, but may be more effective than macrolide or cephalosporin-based regimens. However, additional data are required before it can be emphatically stated that the new fluoroquinolones as a class are responsible for better outcomes than comparators in community-acquired respiratory infections. Gemifloxacin (except for higher rates of hypersensitivity), levofloxacin, and moxifloxacin have relatively mild adverse effects that are more or less comparable to ciprofloxacin. In our opinion, gatifloxacin should not be used, due to glucose alterations which may be serious. Although all new fluoroquinolones react with metal ion-containing drugs (antacids), other drug interactions are relatively mild compared with ciprofloxacin. The new fluoroquinolones gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin have much to offer in terms of bacterial eradication, including activity against resistant respiratory pathogens such as penicillin-resistant, macrolide-resistant, and multidrug-resistant S. pneumoniae. However, ciprofloxacin-resistant organisms, including ciprofloxacin-resistant S. pneumoniae, are becoming more prevalent, thus prudent use must be exercised when prescribing these valuable agents.
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Affiliation(s)
- George G Zhanel
- Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, CanadaDepartment of Clinical Microbiology, Health Sciences Centre, Winnipeg, Manitoba, CanadaDepartment of Medicine, Health Sciences Centre, Winnipeg, Manitoba, Canada
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Qiu HY, Yuan SS, Yang FY, Shi TT, Yang JK. HERG Protein Plays a Role in Moxifloxacin-Induced Hypoglycemia. J Diabetes Res 2016; 2016:6741745. [PMID: 26649323 PMCID: PMC4663361 DOI: 10.1155/2016/6741745] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 08/06/2015] [Indexed: 11/17/2022] Open
Abstract
The purpose of this study was to investigate the effect of moxifloxacin on HERG channel protein and glucose metabolism. HERG expression was investigated using immunohistochemistry. The whole-cell patch clamp method was used to examine the effect of moxifloxacin on HERG channel currents. A glucose tolerance test was used to analyze the effects of moxifloxacin on blood glucose and insulin concentrations in mice. Results show that HERG protein was expressed in human pancreatic β-cells. Moxifloxacin inhibited HERG time-dependent and tail currents in HEK293 cells in a concentration-dependent manner. The IC50 of moxifloxacin inhibition was 36.65 μmol/L. Moxifloxacin (200 mg/kg) reduced blood glucose levels and increased insulin secretion in wild-type mice at 60 min after the start of the glucose tolerance test. In contrast, moxifloxacin did not significantly alter blood glucose and insulin levels in HERG knockout mice. Serum glucose levels increased and insulin concentrations decreased in HERG knockout mice when compared to wild-type mice. The moxifloxacin-induced decrease in blood glucose and increase in insulin secretion occurred via the HERG protein; thus, HERG protein plays a role in insulin secretion.
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Affiliation(s)
- Hai-Yan Qiu
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing 100730, China
| | - Sha-Sha Yuan
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing 100730, China
| | - Fang-Yuan Yang
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing 100730, China
| | - Ting-Ting Shi
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing 100730, China
| | - Jin-Kui Yang
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing 100730, China
- *Jin-Kui Yang:
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Liu N, Zhao Z, Tan Y, Lu L, Wang L, Liao Y, Beloglazova N, De Saeger S, Zheng X, Wu A. Simultaneous Raising of Rabbit Monoclonal Antibodies to Fluoroquinolones with Diverse Recognition Functionalities via Single Mixture Immunization. Anal Chem 2015; 88:1246-52. [DOI: 10.1021/acs.analchem.5b03637] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Na Liu
- Key
Laboratory of Food Safety Research, Institute for Nutritional Sciences,
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai 200031, P. R. China
- Key
Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, 100021, China
- School
of Biosystems Engineering and Food Science, Zhejiang University, 388 Yuhangtang Road, Hangzhou 310058, P. R. China
| | - Zhiyong Zhao
- Key
Laboratory of Food Safety Research, Institute for Nutritional Sciences,
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai 200031, P. R. China
- Key
Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, 100021, China
| | - Yanglan Tan
- Key
Laboratory of Food Safety Research, Institute for Nutritional Sciences,
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai 200031, P. R. China
- Key
Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, 100021, China
| | - Lei Lu
- School
of Biosystems Engineering and Food Science, Zhejiang University, 388 Yuhangtang Road, Hangzhou 310058, P. R. China
| | - Lin Wang
- School
of Biosystems Engineering and Food Science, Zhejiang University, 388 Yuhangtang Road, Hangzhou 310058, P. R. China
| | - Yucai Liao
- College
of Plant Science and Technology, Huazhong Agricultural University, No. 1 Shizishan Street, Hongshan District, Wuhan, Hubei 430070, PR China
| | - Natalia Beloglazova
- Laboratory
of Food Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg
460, 9000 Ghent, Belgium
| | - Sarah De Saeger
- Laboratory
of Food Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg
460, 9000 Ghent, Belgium
| | - Xiaodong Zheng
- School
of Biosystems Engineering and Food Science, Zhejiang University, 388 Yuhangtang Road, Hangzhou 310058, P. R. China
| | - Aibo Wu
- Key
Laboratory of Food Safety Research, Institute for Nutritional Sciences,
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai 200031, P. R. China
- Key
Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, 100021, China
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Abstract
Patients with diabetes mellitus are often susceptible to hypoglycemic episodes while on therapy. Most of these are attributed to inappropriate dosing of hypoglycemic agents, dietary indiscretion, or acute illness. Medications being used concomitantly should be reviewed closely when the etiology of hypoglycemia is unclear. A fifty-six-year-old woman with a history of diabetes mellitus (on metformin monotherapy) was found unresponsive at home. Her fingerstick glucose was 15 mg/dL for which she received 50% dextrose intravenously. The patient never had any previous documented hypoglycemic episodes. She had recently been diagnosed with pneumonia and was prescribed oral levofloxacin therapy. The patient had taken 4 doses of levofloxacin before the onset of hypoglycemia. These episodes recurred over the next 2 days needing close intensive care unit monitoring, dextrose infusion, and glucagon administration. Basic blood/urine investigations, cortisol and thyroid profile were normal except for low blood glucose and renal insufficiency (serum creatinine 1.4 mg/dL and creatinine clearance 42 mL/min). HbA1c was 6.8% (4.4%-6.4%), insulin 51.3 μU/mL (2.6-24.9 μU/mL), IGF-1 301 ng/mL (27-223 ng/mL), and C peptide 9.3 ng/mL (0.8-3.5 ng/mL). These levels were elevated but were deemed nondiagnostic because of fluctuating glucose values after glucagon administration. A blood screen for sulfonylureas and metaglinides was negative. A seventy-two-hour fast was performed to rule out hyperinsulinemic hypoglycemic syndromes; however, blood glucose values remained consistently above 120 mg/dL during this period. Thus, after exclusion of other causes, we utilized the adverse drug reaction probability scale and concluded that hypoglycemia was probably related to recent use of levofloxacin.
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Kabbara WK, Ramadan WH, Rahbany P, Al-Natour S. Evaluation of the appropriate use of commonly prescribed fluoroquinolones and the risk of dysglycemia. Ther Clin Risk Manag 2015; 11:639-47. [PMID: 25960658 PMCID: PMC4410896 DOI: 10.2147/tcrm.s81280] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background Fluoroquinolones are among the most widely prescribed antibiotics. However, concerns about increasing resistant microorganisms and the risk of dysglycemia associated with the use of these agents have emerged. Objective The primary objective of the study was to evaluate the appropriate use of commonly prescribed fluoroquinolones, including appropriate indication, dose, dose adjustment in renal impairment, and duration of treatment. The secondary objective was to investigate the dysglycemic effect of fluoroquinolone use (hypoglycemia and/or hyperglycemia) in diabetic and nondiabetic patients. Methods A prospective observational study at a teaching hospital in Lebanon was conducted over a 6-month period. A total of 118 patients receiving broad-spectrum fluoroquinolones (levofloxacin, ciprofloxacin, and moxifloxacin) were identified. Patients were mainly recruited from internal medicine floors and intensive care units. Results The final percentage for the appropriate indication, dose, and duration of fluoroquinolone therapy was 93.2%, 74.6%, and 57.6%, respectively. A total of 57.1% of the patients did not receive the appropriate dose adjustment according to their level of renal impairment. In addition, dysglycemia occurred in both diabetic and nondiabetic patients. Dysglycemia was more frequently encountered with ciprofloxacin (50.0%), followed by levofloxacin (42.4%) and moxifloxacin (7.6%). Hyperglycemia was more common than hypoglycemia in all groups. The highest incidence of hyperglycemia occurred with levofloxacin (70.0%), followed by ciprofloxacin (39.0%) and moxifloxacin (33.3%). In contrast, hypoglycemia did not occur in the ciprofloxacin group, but it was more common with moxifloxacin (11.1%) and levofloxacin (6.0%). Conclusion The major clinical interventions for the future will adjust the dose and duration of therapy with commonly prescribed fluoroquinolones. The incidence of hypoglycemia was less common than hyperglycemia.
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Affiliation(s)
- Wissam K Kabbara
- Department of Pharmacy Practice, School of Pharmacy, Lebanese American University, Byblos, Lebanon
| | - Wijdan H Ramadan
- Department of Pharmacy Practice, School of Pharmacy, Lebanese American University, Byblos, Lebanon
| | - Peggy Rahbany
- Children's National Medical Center, Washington, DC, USA
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Ghaly H, Jörns A, Rustenbeck I. Effect of fluoroquinolones on mitochondrial function in pancreatic beta cells. Eur J Pharm Sci 2013; 52:206-14. [PMID: 24284031 DOI: 10.1016/j.ejps.2013.11.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Revised: 11/04/2013] [Accepted: 11/12/2013] [Indexed: 11/19/2022]
Abstract
Hyper- and hypoglycaemias are known side effects of fluoroquinolone antibiotics, resulting in a number of fatalities. Fluoroquinolone-induced hypoglycaemias are due to stimulated insulin release by the inhibition of the KATP channel activity of the beta cell. Recently, it was found that fluoroquinolones were much less effective on metabolically intact beta cells than on open cell preparations. Thus the intracellular effects of gatifloxacin, moxifloxacin and ciprofloxacin were investigated by measuring NAD(P)H- and FAD-autofluorescence, the mitochondrial membrane potential, and the adenine nucleotide content of isolated pancreatic islets and beta cells. 100 μM of moxifloxacin abolished the NAD(P)H increase elicited by 20mM glucose, while gatifloxacin diminished it and ciprofloxacin had no significant effect. This pattern was also seen with islets from SUR1 Ko mice, which have no functional KATP channels. Moxifloxacin also diminished the glucose-induced decrease of FAD-fluorescence, which reflects the intramitochondrial production of reducing equivalents. Moxifloxacin, but not ciprofloxacin or gatifloxacin significantly reduced the effect of 20mM glucose on the ATP/ADP ratio. The mitochondrial hyperpolarization caused by 20mM glucose was partially antagonized by moxifloxacin, but not by ciprofloxacin or gatifloxacin. Ultrastructural analyses after 20 h tissue culture showed that all three compounds (at 10 and 100 μM) diminished the number of insulin secretory granules and that gatifloxacin and ciprofloxacin, but not moxifloxacin induced fission/fusion configurations of the beta cell mitochondria. In conclusion, fluoroquinolones affect the function of the mitochondria in pancreatic beta cells which may diminish the insulinotropic effect of KATP channel closure and contribute to the hyperglycaemic episodes.
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Affiliation(s)
- Hany Ghaly
- Institute of Pharmacology and Toxicology, University of Braunschweig, D-38106 Braunschweig, Germany
| | - Anne Jörns
- Institute of Clinical Biochemistry, Hannover Medical School, 30623 Hannover, Germany
| | - Ingo Rustenbeck
- Institute of Pharmacology and Toxicology, University of Braunschweig, D-38106 Braunschweig, Germany.
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Bito M, Tomita T, Komori M, Taogoshi T, Kimura Y, Kihira K. The mechanisms of insulin secretion and calcium signaling in pancreatic β-cells exposed to fluoroquinolones. Biol Pharm Bull 2013; 36:31-5. [PMID: 23302634 DOI: 10.1248/bpb.b12-00425] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Fluoroquinolones reportedly induce hypoglycemia through stimulation of insulin secretion from pancreatic β-cells via inhibition of K(ATP) channels and activation of L-type voltage-dependent Ca(2+) channels. In physiological condition, the cytosolic Ca(2+) concentration ([Ca(2+)](c)) is also regulated by release of Ca(2+) from intracellular Ca(2+) stores. In this study, we investigated the mechanism of insulin secretion induced by fluoroquinolones, with respect to intracellular Ca(2+) stores. Even where the absence of supplemental extracellular Ca(2+), insulin secretion and [Ca(2+)](c) were increased by gatifloxacin, levofloxacin or tolbutamide. Insulin secretion and the rise of [Ca(2+)](c) induced by fluoroquinolones were reduced by depleting of Ca(2+) in endoplasmic reticumum (ER) by thapsigargin, and inhibiting ryanodine receptor of ER by dantrolene. Inhibition of inositol 1,4,5-triphosphate receptor of ER by xestospongin C suppressed insulin secretion induced by fluoroquinolones, whereas it did not affect [Ca(2+)](c). Destruction of acidic Ca(2+) stores such as lysosome and lysosome-related organelles by glycyl-L-phenylalanine-2-nephthylamide (GPN) did not affect insulin secretion and the rise of [Ca(2+)](c) induced by fluoroquinolones. The increase in insulin and [Ca(2+)](c) induced by tolbutamide were reduced by thapsigargin, dantrolene, and GPN but not by xestospongin C. In conclusion, fluoroquinolones induces Ca(2+) release from ER mediated by the ryanodine receptor, and the reaction might involve in insulin secretion. Sulfonylureas induce Ca(2+) release from GPN-sensitive acidic Ca(2+) stores, but fluoroquinolones did not.
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Affiliation(s)
- Motoki Bito
- Division of Clinical Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Hiroshima University, 1–2–3 Kasumi, Minami-ku, Hiroshima 734–8551, Japan
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Rafat C, Debrix I, Hertig A. Levofloxacin for the treatment of pyelonephritis. Expert Opin Pharmacother 2013; 14:1241-53. [DOI: 10.1517/14656566.2013.792805] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Zhang X, Overholser BR, Kays MB, Sowinski KM. Gatifloxacin Pharmacokinetics in Healthy Men and Women. J Clin Pharmacol 2013; 46:1154-62. [PMID: 16988204 DOI: 10.1177/0091270006291840] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The sex-based pharmacokinetics of gatifloxacin were investigated. Healthy subjects (6 men, 6 women) received a single oral dose of gatifloxacin 400 mg. Blood and urine samples were collected, and gatifloxacin concentrations were determined by high-performance liquid chromatography. Pharmacokinetic parameters were estimated by fitting appropriate models to the serum concentration-time data using ADAPT II. Linear regression analysis was used to determine the influence of sex and weight on the oral clearance (CL(s)/F) and apparent steady-state volume of distribution (V(ss)/F) of gatifloxacin. Women had a significantly smaller V(ss)/F compared to men (93.5 +/- 21.3 L vs 128.8 +/- 16.2 L, P = .009); however, there was no significant difference when normalized for total body weight (TBW) or lean body weight (LBW). Neither CL(s)/F nor peak serum concentration (C(max)) was significantly different between sexes, although C(max) was 25% higher in women (P = .06). Regression analyses revealed that TBW (R(2) = .63) and LBW (R(2) = .65) were strong predictors of V(ss)/F. Given the smaller V(ss)/F, women may have slightly higher maximum concentrations, but these differences are unlikely to have clinical significance.
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Affiliation(s)
- Xin Zhang
- Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Purdue University, Indianapolis, Indiana 46202, USA
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35
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Ishiwata Y, Takahashi Y, Nagata M, Yasuhara M. Effects of Moxifloxacin on Serum Glucose Concentrations in Rats. Biol Pharm Bull 2013; 36:686-90. [DOI: 10.1248/bpb.b12-00930] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Yasuyoshi Ishiwata
- Department of Pharmacy, University Hospital of Medicine, Tokyo Medical and Dental University
| | - Yutaka Takahashi
- Department of Pharmacy, University Hospital of Medicine, Tokyo Medical and Dental University
| | - Masashi Nagata
- Department of Pharmacy, University Hospital of Medicine, Tokyo Medical and Dental University
| | - Masato Yasuhara
- Department of Pharmacy, University Hospital of Medicine, Tokyo Medical and Dental University
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Combined contributions of over-secreted glucagon-like peptide 1 and suppressed insulin secretion to hyperglycemia induced by gatifloxacin in rats. Toxicol Appl Pharmacol 2012. [PMID: 23200776 DOI: 10.1016/j.taap.2012.11.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Accumulating evidences have showed that gatifloxacin causes dysglycemia in both diabetic and non-diabetic patients. Our preliminary study demonstrated that gatifloxacin stimulated glucagon-like peptide 1 (GLP-1) secretion from intestinal cells. The aim of the study was to investigate the association between gatifloxacin-stimulated GLP-1 release and dysglycemia in both normal and streptozotocin-induced diabetic rats and explore the possible mechanisms. Oral administration of gatifloxacin (100 mg/kg/day and 200 mg/kg/day) for 3 and 12 days led to marked elevation of GLP-1 levels, accompanied by significant decrease in insulin levels and increase in plasma glucose. Similar results were found in normal rats treated with 3-day gatifloxacin. Gatifloxacin-stimulated GLP-1 release was further confirmed in NCI-H716 cells, which was abolished by diazoxide, a K(ATP) channel opener. QT-PCR analysis showed that gatifloxacin also upregulated expression of proglucagon and prohormone convertase 3 mRNA. To clarify the contradiction on elevated GLP-1 without insulinotropic effect, effects of GLP-1 and gatifloxacin on insulin release were investigated using INS-1 cells. We found that short exposure (2h) to GLP-1 stimulated insulin secretion and biosynthesis, whereas long exposure (24 h and 48 h) to high level of GLP-1 inhibited insulin secretion and biosynthesis. Moreover, we also confirmed gatifloxacin acutely stimulated insulin secretion while chronically inhibited insulin biosynthesis. All the results gave an inference that gatifloxacin stimulated over-secretion of GLP-1, in turn, high levels of GLP-1 and gatifloxacin synergistically impaired insulin release, worsening hyperglycemia.
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Abstract
INTRODUCTION Hypoglycaemia is a side effect caused by some therapies for type 2 diabetes, which can cause physical, social and psychological harm. Hypoglycaemia also prevents attainment of treatment goals and satisfactory glycaemic control. AREAS COVERED The risk of hypoglycaemia associated with commonly prescribed therapies, including metformin, sulphonylureas, dipeptidyl peptidase-4 enzyme (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists and thiazolidinediones, is reviewed in this paper (insulin-induced hypoglycaemia is not included). Other medications that are frequently co-prescribed in type 2 diabetes are also discussed, including anti-hypertensive drugs, antibiotics and fibrates, along with various important patient-related risk factors. EXPERT OPINION Hypoglycaemia is a common and potentially dangerous side effect of some medications used for type 2 diabetes. The risk of hypoglycaemia should always be considered when selecting and implementing a therapy, with a focus on the individual. Future research into new therapies should measure the frequency of hypoglycaemia prospectively and accurately. Hypoglycaemia has been shown to be a potentially life-threatening metabolic stress; therefore therapies that effectively manage diabetes without the risk of hypoglycaemia are likely to be favoured in the future.
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Affiliation(s)
- Berit Inkster
- Royal Infirmary of Edinburgh, Department of Diabetes, 51 Little France Crescent, Edinburgh, EH16 4SA, UK
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38
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Abstract
Hypoglycemia is a common finding in both daily clinical practice and acute care settings. The causes of severe hypoglycemia (SH) are multi-factorial and the major etiologies are iatrogenic, infectious diseases with sepsis and tumor or autoimmune diseases. With the advent of aggressive lowering of HbA1c values to achieve optimal glycemic control, patients are at increased risk of hypoglycemic episodes. Iatrogenic hypoglycemia can cause recurrent morbidity, sometime irreversible neurologic complications and even death, and further preclude maintenance of euglycemia over a lifetime of diabetes. Recent studies have shown that hypoglycemia is associated with adverse outcomes in many acute illnesses. In addition, hypoglycemia is associated with increased mortality among elderly and non-diabetic hospitalized patients. Clinicians should have high clinical suspicion of subtle symptoms of hypoglycemia and provide prompt treatment. Clinicians should know that hypoglycemia is associated with considerable adverse outcomes in many acute critical illnesses. In order to reduce hypoglycemia-associated morbidity and mortality, timely health education programs and close monitoring should be applied to those diabetic patients presenting to the Emergency Department with SH. ED disposition strategies should be further validated and justified to achieve balance between the benefits of euglycemia and the risks of SH. We discuss relevant issues regarding hypoglycemia in emergency and critical care settings.
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Affiliation(s)
- Shih-Hung Tsai
- Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Yen-Yue Lin
- Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chin-Wang Hsu
- Department of Critical & Emergency Medicine, Cheng-Hsin General Hospital, Taipei, Taiwan
| | - Chien-Sheng Cheng
- Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Der-Ming Chu
- Peng-Hu Branch, Tri-Service General Hospital, National Defense Medical Center, Peng-Hu, Taiwan
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Kasuya F, Miwa Y, Kazumi M, Inoue H, Ohta H. Effect of enoxacin, felbinac, and sparfloxacin on fatty acid metabolism and glucose concentrations in rat tissues. Int J Toxicol 2011; 30:367-76. [PMID: 21633127 DOI: 10.1177/1091581810397619] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Multiple changes in metabolic levels could be useful for understanding physiological toxicity. To explore further risk factors for the convulsions induced by the interaction of nonsteroidal anti-inflammatory and new quinolone antimicrobial drugs, the effect of sparfloxacin, enoxacin, and felbinac on fatty acid metabolism and glucose concentrations in the liver, brain, and blood of rats was investigated. The levels of long-chain acyl-CoAs (C(18:1) and C(20:4)) in the liver and brain were decreased at the onset of convulsions induced by the coadministration of enoxacin with felbinac. Then, glucose concentrations in the liver and blood were decreased, whereas they were increased in a dose-dependant manner in the brain. However, the formation of acyl-CoAs and glucose levels in the liver, brain, and blood was not significantly influenced by enoxacin, felbinac, and sparfloxacin alone, respectively. The disturbance of both fatty acid metabolism and glucose levels might be associated with the increased susceptibility to convulsions, which may contribute to further understanding of the toxic effects associated with these drugs.
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Affiliation(s)
- Fumiyo Kasuya
- Biochemical Toxicology Laboratory, Faculty of Pharmaceutical Sciences, Kobegakuin University, 1-1-3, Minatojima, chuo-ku, Kobe, 651-2180, Japan.
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40
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Koeppe MO, Cristofoletti R, Fernandes EF, Storpirtis S, Junginger HE, Kopp S, Midha KK, Shah VP, Stavchansky S, Dressman JB, Barends DM. Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Levofloxacin. J Pharm Sci 2011; 100:1628-36. [DOI: 10.1002/jps.22413] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2010] [Revised: 11/02/2010] [Accepted: 11/02/2010] [Indexed: 11/06/2022]
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Abstract
Drugs are the most frequent cause of hypoglycaemia in adults. Although hypoglycaemia is a well known adverse effect of antidiabetic agents, it may occasionally develop in the course of treatment with drugs used in everyday clinical practice, including NSAIDs, analgesics, antibacterials, antimalarials, antiarrhythmics, antidepressants and other miscellaneous agents. They induce hypoglycaemia by stimulating insulin release, reducing insulin clearance or interfering with glucose metabolism. Several drugs may also potentiate the hypoglycaemic effect of antidiabetic agents. Administration of these agents to individuals with diabetes mellitus is of most concern. Many of these drugs, and depending on clinical setting, may also induce hyperglycaemia. Drug-induced hepatotoxicity and nephrotoxicity may lead in certain circumstances to hypoglycaemia. Some drugs may also induce hypoglycaemia by causing pancreatitis. Drug-induced hypoglycaemia is usually mild but may be severe. Effective clinical management can be handled through awareness of this drug-induced adverse effect on blood glucose levels. Herein, we review pertinent clinical information on the incidence of drug-induced hypoglycaemia and discuss the underlying pathophysiological mechanisms, and prevention and management.
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Affiliation(s)
- Chaker Ben Salem
- Department of Clinical Pharmacology, Faculty of Medicine of Sousse, and Medical Intensive Care Unit, Sahloul University Hospital, Sousse, Tunisia.
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K. Suresh K, D. Bhosale S, V. Thulasiram H, J. Kulkarni M. Comparative and chemical proteomic approaches reveal gatifloxacin deregulates enzymes involved in glucose metabolism. J Toxicol Sci 2011; 36:787-96. [DOI: 10.2131/jts.36.787] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Affiliation(s)
- Kesavan K. Suresh
- Proteomics Facility, Division of Biochemical Sciences, CSIR-National Chemical Laboratory, India
| | - Santosh D. Bhosale
- Proteomics Facility, Division of Biochemical Sciences, CSIR-National Chemical Laboratory, India
| | - Hirekodathakallu V. Thulasiram
- Chemistry Biology Unit, Division of Organic Chemistry, CSIR- National Chemical Laboratory, India
- CSIR-Institute of Genomics and Integrative Biology, India
| | - Mahesh J. Kulkarni
- Proteomics Facility, Division of Biochemical Sciences, CSIR-National Chemical Laboratory, India
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43
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Ishiwata Y, Yasuhara M. Gatifloxacin-induced histamine release and hyperglycemia in rats. Eur J Pharmacol 2010; 645:192-7. [DOI: 10.1016/j.ejphar.2010.07.032] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2009] [Revised: 06/07/2010] [Accepted: 07/15/2010] [Indexed: 10/19/2022]
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Abstract
The fluoroquinolone class of antibacterial agents are among the most frequently prescribed drugs, with utility in a broad range of bacterial infections. Although very useful agents, the fluoroquinolones as a class are associated with a number of adverse events, some with considerable clinical significance. In the past 15-20 years, tolerability concerns have led to restrictions on the use of the fluoroquinolones and, in some instances, the withdrawal of agents from the market. This review focuses on the safety and tolerability of levofloxacin, a third-generation fluoroquinolone, relative to other fluoroquinolones. A literature search was performed of the MEDLINE database encompassing the dates 1980-2009, using as keywords the drug names levofloxacin and concurrently marketed fluoroquinolones combined with the words 'safety', 'adverse effect' or 'adverse drug reaction', or the name of the specific adverse effect. Adverse events commonly associated with the fluoroquinolones include gastrointestinal and CNS toxicity (most frequently headache and dizziness), as well as other adverse events including ECG abnormalities (for example QT interval prolongation), disrupted glucose metabolism, phototoxicity, tendon and joint disorders, hypersensitivity and skin disorders, and hepatic toxicity. Package inserts for the fluoroquinolones in Europe and the US contain warnings regarding these risks. US package inserts also carry 'black-box' warnings regarding the risk of tendon rupture and joint disorders with these agents; however, there is a substantial body of evidence to indicate that there are marked differences in the tolerability profiles of the individual agents within the fluoroquinolone class. These differences may be explained, at least in part, by structural differences: all fluoroquinolones share a basic quinolone core, with differences in specific side chains underlying the adverse event relationships. Furthermore, many of the fluoroquinolone-associated adverse effects and toxicities occur more frequently in patients with pre-existing risk factors, or in certain subpopulations. Notably, package inserts for the fluoroquinolones carry warnings regarding use in the elderly, paediatric patients and patients with pre-existing, or factors predisposing to, seizure disorders. Because of this, many adverse reactions with these agents could be prevented by improving patient screening and education. The recent withdrawal of gatifloxacin due to dysglycaemia makes it timely to review the safety and tolerability of the individual agents in this class. Overall, it appears that levofloxacin is relatively well tolerated, with low rates of clinically important adverse events such as CNS toxicity, cardiovascular toxicity and dysglycaemia.
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Affiliation(s)
- Hans H Liu
- Bryn Mawr Medical Specialists, Bryn Mawr, Pennsylvania, USA
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Abstract
The fluoroquinolones ciprofloxacin, levofloxacin, moxifloxacin and gemifloxacin are widely used for the treatment of various types of bacterial infections. Overall, these antibacterial agents can be considered safe and well tolerated drugs. Comparative studies have evaluated the use of quinolones in elderly and younger populations. Although age per se does not seem to decrease their tolerability, specific adverse effects of the quinolones must be considered when they are chosen for antibacterial treatment. Renal function declines consistently with age and doses of renally excreted quinolones (e.g. ofloxacin, levofloxacin, gatifloxacin) need to be adjusted if a clinically relevant reduction of creatinine clearance is identified. Reactions of the gastrointestinal tract, such as nausea, dyspepsia, vomiting or diarrhoea, are among the most often registered adverse drug reactions during therapy with fluoroquinolones. Treatment with a quinolone causes diarrhoea less frequently than treatment with other classes of antimicrobials. Conflicting data have been published with respect to the incidence of Clostridium difficile-associated diarrhoea in quinolone-treated patients. Hypersensitivity reactions, often manifested on the skin, occur less commonly during therapy with quinolones than, for example, during therapy with beta-lactam antibacterials. Adverse reactions of the CNS are of particular concern in the elderly population. Given the CNS excitatory effects of quinolones, elderly patients should be monitored carefully for such symptoms. It is likely that many signs of possible adverse reactions, such as confusion, weakness, loss of appetite, tremor or depression, are often mistakenly attributed to old age and remain unreported. Quinolones should be used with caution in patients with known or suspected CNS disorders that predispose to seizures (e.g. severe cerebral arteriosclerosis or epilepsy). Quinolones can cause QT interval prolongation. They should be avoided in patients with known prolongation of the QT interval, patients with uncorrected hypokalaemia or hypomagnesaemia and patients receiving class IA (e.g. quinidine, procainamide) or class III (e.g. amiodarone, sotalol) antiarrhythmic agents. Tendinitis and tendon ruptures are recognized as quinolone-induced adverse effects that can occur during treatment or as late as several months after treatment. Chronic renal diseases, concomitant use of corticosteroids and age >60 years are known risk factors for quinolone-induced tendopathies. Overall, the specific adverse-effect profile of quinolones must be considered when they are chosen for treatment of bacterial infections. Because of physiological changes in renal function and when certain co-morbidities are present, some special considerations are necessary when elderly patients are treated with these drugs.
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Affiliation(s)
- Ralf Stahlmann
- Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
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Szollosi A, Nenquin M, Henquin JC. Pharmacological stimulation and inhibition of insulin secretion in mouse islets lacking ATP-sensitive K+ channels. Br J Pharmacol 2010; 159:669-77. [PMID: 20128805 DOI: 10.1111/j.1476-5381.2009.00588.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND AND PURPOSE ATP-sensitive potassium channels (K(ATP) channels) in beta cells are a major target for insulinotropic drugs. Here, we studied the effects of selected stimulatory and inhibitory pharmacological agents in islets lacking K(ATP) channels. EXPERIMENTAL APPROACH We compared insulin secretion (IS) and cytosolic calcium ([Ca(2+)](c)) changes in islets isolated from control mice and mice lacking sulphonylurea receptor1 (SUR1), and thus K(ATP) channels in their beta cells (Sur1KO). KEY RESULTS While similarly increasing [Ca(2+)](c) and IS in controls, agents binding to site A (tolbutamide) or site B (meglitinide) of SUR1 were ineffective in Sur1KO islets. Of two non-selective blockers of potassium channels, quinine was inactive, whereas tetraethylammonium was more active in Sur1KO compared with control islets. Phentolamine, efaroxan and alinidine, three imidazolines binding to K(IR)6.2 (pore of K(ATP) channels), stimulated control islets, but only phentolamine retained weaker stimulatory effects on [Ca(2+)](c) and IS in Sur1KO islets. Neither K(ATP) channel opener (diazoxide, pinacidil) inhibited Sur1KO islets. Calcium channel blockers (nimodipine, verapamil) or diphenylhydantoin decreased [Ca(2+)](c) and IS in both types of islets, verapamil and diphenylhydantoin being more efficient in Sur1KO islets. Activation of alpha(2)-adrenoceptors or dopamine receptors strongly inhibited IS while partially (clonidine > dopamine) lowering [Ca(2+)](c) (control > Sur1KO islets). CONCLUSIONS AND IMPLICATIONS Those drugs retaining effects on IS in islets lacking K(ATP) channels, also affected [Ca(2+)](c), indicating actions on other ionic channels. The greater effects of some inhibitors in Sur1KO than in control islets might be relevant to medical treatment of congenital hyperinsulinism caused by inactivating mutations of K(ATP) channels.
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Affiliation(s)
- A Szollosi
- Unité d'Endocrinologie et Métabolisme, Faculty of Medicine, University of Louvain, Brussels, Belgium
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Parker HE, Reimann F, Gribble FM. Molecular mechanisms underlying nutrient-stimulated incretin secretion. Expert Rev Mol Med 2010; 12:e1. [PMID: 20047700 DOI: 10.1017/s146239940900132x] [Citation(s) in RCA: 107] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from enteroendocrine cells in the intestinal epithelium in response to nutrient ingestion. The actions of GLP-1 and GIP - not only on local gut physiology but also on glucose homeostasis, appetite control and fat metabolism - have made these hormones an attractive area for drug discovery programmes. The potential range of strategies to target the secretion of these hormones therapeutically has been limited by an incomplete understanding of the mechanisms underlying their release. The use of organ and whole-animal perfusion techniques, cell line models and primary L- and K-cells has led to the identification of a variety of pathways involved in the sensing of carbohydrate, fat and protein in the gut lumen. This review focuses on our current understanding of these signalling mechanisms that might underlie nutrient responsiveness of L- and K-cells.
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Affiliation(s)
- Helen E Parker
- Cambridge Institute for Medical Research and Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, UK
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NAGAI M, NAGATA S, YAMAGISHI N, SATOH H, FURUHAMA K. Clinicopathological Aspect of Dysglycemia in Naive and Diabetic Rats induced by the Fluoroquinolone Antibacterial Gatifloxacin. J Vet Med Sci 2010; 72:567-73. [DOI: 10.1292/jvms.09-0465] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- Mikiko NAGAI
- Department of Veterinary Basic Medicine, Iwate University
| | - Saori NAGATA
- Department of Veterinary Basic Medicine, Iwate University
| | - Norio YAMAGISHI
- Department of Veterinary Clinical Medicine, Iwate University
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Report and recommendations of the workshop of the European Centre for the Validation of Alternative Methods for Drug-Induced Cardiotoxicity. Cardiovasc Toxicol 2009; 9:107-25. [PMID: 19572114 DOI: 10.1007/s12012-009-9045-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2009] [Accepted: 04/17/2009] [Indexed: 10/20/2022]
Abstract
Cardiotoxicity is among the leading reasons for drug attrition and is therefore a core subject in non-clinical and clinical safety testing of new drugs. European Centre for the Validation of Alternative Methods held in March 2008 a workshop on "Alternative Methods for Drug-Induced Cardiotoxicity" in order to promote acceptance of alternative methods reducing, refining or replacing the use of laboratory animals in this field. This review reports the outcome of the workshop. The participants identified the major clinical manifestations, which are sensitive to conventional drugs, to be arrhythmias, contractility toxicity, ischaemia toxicity, secondary cardiotoxicity and valve toxicity. They gave an overview of the current use of alternative tests in cardiac safety assessments. Moreover, they elaborated on new cardiotoxicological endpoints for which alternative tests can have an impact and provided recommendations on how to cover them.
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50
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Garber SM, Pound MW, Miller SM. Hypoglycemia associated with the use of levofloxacin. Am J Health Syst Pharm 2009; 66:1014-9. [DOI: 10.2146/ajhp080105] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Affiliation(s)
- Seth M. Garber
- Southwest Health Center, Unity Health, Inc., Washington, DC; at the time of writing he was Chief Resident, Family Medicine Residency, Duke/Southern Regional Area Health Education Center (AHEC), Fayetteville, NC
| | | | - Susan M. Miller
- School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, and Director of Pharmacotherapy Education, Duke/Southern Regional AHEC
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