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Trends in Cancer Aug 2021Biguanides are a class of antidiabetic drugs that includes phenformin and metformin; however, the former was withdrawn from approval in many countries due to its... (Review)
Review
Biguanides are a class of antidiabetic drugs that includes phenformin and metformin; however, the former was withdrawn from approval in many countries due to its toxicity. Findings from retrospective epidemiological studies in diabetic populations and preclinical laboratory models have demonstrated that biguanides possess antitumor activities that suggest their repurposing for cancer prevention and treatment. However, a better understanding of how these biguanides behave as antitumor agents is needed to guide their improved applications in cancer therapy, spurring increased interest in their pharmacology. Here, we present evidence for proposed mechanisms of action related to their antitumor activity, including their effects on central carbon metabolism in cancer cells and immune-modulating activity, and then review progress on biguanide repurposing in cancer therapeutics and the possible re-evaluation of phenformin as a cancer therapeutic agent.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Biguanides; Cell Line, Tumor; Clinical Trials as Topic; Disease Models, Animal; Drug Repositioning; Drug Synergism; Humans; Immune Checkpoint Inhibitors; Neoplasms; Oxidative Phosphorylation; Protein Kinase Inhibitors; Tumor Microenvironment; Xenograft Model Antitumor Assays
PubMed: 33865798
DOI: 10.1016/j.trecan.2021.03.001 -
Indian Journal of Ophthalmology Apr 2024This is a comprehensive review after a thorough literature search in PubMed-indexed journals, incorporating current information on the pathophysiology, clinical... (Review)
Review
This is a comprehensive review after a thorough literature search in PubMed-indexed journals, incorporating current information on the pathophysiology, clinical features, diagnosis, medical and surgical therapy, as well as outcomes of Acanthamoeba keratitis (AK). AK is a significant cause of ocular morbidity, and early diagnosis with timely institution of appropriate therapy is the key to obtaining good outcomes. The varied presentations result in frequent misdiagnosis, and co-infections can increase the morbidity of the disease. The first line of therapy continues to be biguanides and diamidines, with surgery as a last resort.
Topics: Humans; Acanthamoeba Keratitis; Pentamidine; Biguanides
PubMed: 38454853
DOI: 10.4103/IJO.IJO_2627_23 -
British Medical Journal Dec 1977
Topics: Acidosis; Diabetes Mellitus; Humans; Lactates; Metformin; Phenformin
PubMed: 589254
DOI: 10.1136/bmj.2.6100.1436 -
Cancer Prevention Research... Sep 2010Retrospective studies that may be impractical to confirm prospectively suggest that diabetics treated with metformin have a substantially reduced cancer burden compared... (Review)
Review
Retrospective studies that may be impractical to confirm prospectively suggest that diabetics treated with metformin have a substantially reduced cancer burden compared with other diabetics. It is unclear if this reflects a chemopreventive effect, an effect on transformed cells, or both. It also remains to be established if these data have relevance to people without diabetes. Laboratory models, however, provide independent impressive evidence for the activity of metformin and other biguanides in both cancer treatment and chemoprevention. Investigations of mechanisms of action of biguanides have revealed considerable complexity and have identified important gaps in knowledge that should be addressed to ensure the optimal design of clinical trials of these agents. Such trials may define important new indications for biguanides in the prevention and/or treatment of many common cancers.
Topics: Animals; Antineoplastic Agents; Biguanides; Biomedical Research; Humans; Hypoglycemic Agents; Medical Oncology; Metformin; Neoplasms
PubMed: 20810670
DOI: 10.1158/1940-6207.CAPR-10-0175 -
Biochemical Pharmacology Sep 2023Metformin has been used for ages to treat diabetes mellitus due to its safety profile and low cost. However, metformin has variable pharmacokinetics in patients, and due... (Review)
Review
Metformin has been used for ages to treat diabetes mellitus due to its safety profile and low cost. However, metformin has variable pharmacokinetics in patients, and due to its poor oral absorption, the therapeutic doses are relatively high, causing unpleasant gastrointestinal adverse effects. Therefore, novel derivatives of metformin have been synthesized during the past decades. Particularly, after the mid-2000 s, when organic cation transporters were identified as the main metformin carriers, metformin derivatives have been under intensive investigation. Nevertheless, due to the biguanide structure, derivatives of metformin have been challenging to synthesize. Moreover, the mechanisms of metformin's action are not fully understood to date, and since it has multifunctional properties, the interests have switched to re-purposing for other diseases. Indeed, metformin derivatives have been demonstrated in many cases to be more effective than metformin itself and have the potential to be used in different diseases, including several types of cancers and neurodegenerative diseases. On the other hand, the pleiotropic nature of metformin and its derivatives can also create challenges. Not all properties are fit for all diseases. In this review, the history of the development of metformin-like compounds is summarized, and insights into their potential for future drug discovery are discussed.
Topics: Humans; Metformin; Drug Discovery; Drug-Related Side Effects and Adverse Reactions
PubMed: 37591450
DOI: 10.1016/j.bcp.2023.115743 -
The Cochrane Database of Systematic... Feb 2015Acanthamoeba are microscopic, free-living, single-celled organisms which can infect the eye and lead to Acanthamoeba keratitis (AK). AK can result in loss of vision in... (Review)
Review
BACKGROUND
Acanthamoeba are microscopic, free-living, single-celled organisms which can infect the eye and lead to Acanthamoeba keratitis (AK). AK can result in loss of vision in the infected eye or loss of eye itself; however, there are no formal guidelines or standards of care for the treatment of AK.
OBJECTIVES
To evaluate the relative effectiveness and safety of medical therapy for the treatment of AK.
SEARCH METHODS
We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015, Issue 1), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to January 2015), EMBASE (January 1980 to January 2015), PubMed (1948 to January 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to January 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 9 January 2015.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) of medical therapy for AK, regardless of the participants' age, sex, or etiology of disease. We included studies that compared either anti-amoeba therapy (drugs used alone or in combination with other medical therapies) with no anti-amoeba therapy or one anti-amoeba therapy with another anti-amoeba therapy.
DATA COLLECTION AND ANALYSIS
Two authors independently screened search results and full-text reports, assessed risk of bias, and abstracted data. We used standard methodological procedures as set forth by the Cochrane Collaboration.
MAIN RESULTS
We included one RCT (56 eyes of 55 participants) in this review. The study compared two types of topical biguanides for the treatment of AK: chlorhexidine 0.02% and polyhexamethylene biguanide (PHMB) 0.02%. All participants were contact lens wearers with a median age of 31 years. Treatment duration ranged from 51 to 145 days. The study, conducted in the UK, was well-designed and had low risk of bias overall.Outcome data were available for 51 (91%) of 56 eyes. Follow-up times for outcome measurements in the study were not reported. Resolution of infection, defined as control of ocular inflammation, relief of pain and photosensitivity, and recovery of vision, was 86% in the chlorhexidine group compared with 78% in the PHMB group (relative risk (RR) 1.10, 95% confidence intervals (CI) 0.84 to 1.42). In the chlorhexidine group, 20 of 28 eyes (71%) had better visual acuity compared with 13 of 23 eyes (57%) in the PHMB group at final follow-up (RR 1.26, 95% CI 0.82 to 1.94). Five participants required therapeutic keratoplasty: 2 in the chlorhexidine group compared with 3 in the PHMB group (RR 0.55, 95% CI 0.10 to 3.00). No serious adverse event related to drug toxicity was observed in the study.
AUTHORS' CONCLUSIONS
There is insufficient evidence to evaluate the relative effectiveness and safety of medical therapy for the treatment of AK. Results from the one included study yielded no difference with respect to outcomes reported between chlorhexidine and PHMB. However, the sample size was inadequate to detect clinically meaningful differences between the two groups as indicated by the wide confidence intervals of effect estimates.
Topics: Acanthamoeba Keratitis; Anti-Infective Agents, Local; Biguanides; Chlorhexidine; Humans; Randomized Controlled Trials as Topic
PubMed: 25710134
DOI: 10.1002/14651858.CD010792.pub2 -
International Journal of Molecular... Jan 2022Biguanides, particularly the widely prescribed drug metformin, have been marketed for many decades and have well-established absorption profiles. They are commonly... (Review)
Review
Biguanides, particularly the widely prescribed drug metformin, have been marketed for many decades and have well-established absorption profiles. They are commonly administered via the oral route and, despite variation in oral uptake, remain commonly prescribed for diabetes mellitus, typically type 2. Studies over the last decade have focused on the design and development of advanced oral delivery dosage forms using bio nano technologies and novel drug carrier systems. Such studies have demonstrated significantly enhanced delivery and safety of biguanides using nanocapsules. Enhanced delivery and safety have widened the potential applications of biguanides not only in diabetes but also in other disorders. Hence, this review aimed to explore biguanides' pharmacokinetics, pharmacodynamics, and pharmaceutical applications in diabetes, as well as in other disorders.
Topics: Biguanides; Bile Acids and Salts; Chronic Disease; Drug Carriers; Drug Compounding; Drug Delivery Systems; Drug Development; Humans; Hypoglycemic Agents; Metformin; Theranostic Nanomedicine
PubMed: 35055022
DOI: 10.3390/ijms23020836 -
Journal of Vascular Surgery Mar 2020Abdominal aortic aneurysm (AAA) is a life-threatening disease and pharmacologic agents to treat the disease remain lacking for clinical practice. Epidemiologic studies... (Review)
Review
Abdominal aortic aneurysm (AAA) is a life-threatening disease and pharmacologic agents to treat the disease remain lacking for clinical practice. Epidemiologic studies have highlighted a negative association between the use of antidiabetic drugs, including metformin, and AAA. Metformin is well-known for its blood glucose-lowering effect, but its action on both metabolism and inflammatory response has led to propose it as a potential therapeutic target in several cardiovascular diseases. In this review, we summarize the current knowledge on the link between metformin and AAA. Based on the known effects of the drug on the aortic wall, translational applications and clinical trials investigating the interest of metformin in the management of patients with AAA are discussed.
Topics: Aortic Aneurysm, Abdominal; Humans; Hypoglycemic Agents; Metformin
PubMed: 31727461
DOI: 10.1016/j.jvs.2019.08.270 -
The Journal of Clinical Investigation Sep 2013Metformin is widely prescribed for the treatment of type II diabetes. Recently, it has been proposed that this compound or related biguanides may have antineoplastic... (Review)
Review
Metformin is widely prescribed for the treatment of type II diabetes. Recently, it has been proposed that this compound or related biguanides may have antineoplastic activity. Biguanides may exploit specific metabolic vulnerabilities of transformed cells by acting on them directly, or may act by indirect mechanisms that involve alterations of the host environment. Preclinical data suggest that drug exposure levels are a key determinant of proposed direct actions. With respect to indirect mechanisms, it will be important to determine whether recently demonstrated metformin-induced changes in levels of candidate systemic mediators such as insulin or inflammatory cytokines are of sufficient magnitude to achieve therapeutic benefit. Results of the first generation of clinical trials now in progress are eagerly anticipated. Ongoing investigations may justify a second generation of trials that explore pharmacokinetic optimization, rational drug combinations, synthetic lethality strategies, novel biguanides, and the use of predictive biomarkers.
Topics: Antimetabolites, Antineoplastic; Biguanides; Clinical Trials as Topic; Drug Resistance, Neoplasm; Drug Synergism; Energy Metabolism; Humans; Molecular Targeted Therapy; Neoplasms
PubMed: 23999444
DOI: 10.1172/JCI67232 -
Tidsskrift For Den Norske Laegeforening... May 2016BACKGROUND Polyhexamethylene biguanide hydrochloride/polyhexanide/polyaminopropyl biguanide (PHMB) is used as a disinfectant and antiseptic. This article discusses the... (Review)
Review
BACKGROUND Polyhexamethylene biguanide hydrochloride/polyhexanide/polyaminopropyl biguanide (PHMB) is used as a disinfectant and antiseptic. This article discusses the use of the substance as an antiseptic. We summarise published data on its antimicrobial effect in vitro and its clinical effect and safety when used on skin, wounds and mucosa.MATERIAL AND METHOD A literature search was conducted in PubMed for articles published in the last five years. Articles available as of June 2014 were considered.RESULTS Of 332 articles identified, 27 were included. In vitro studies have demonstrated an antimicrobial effect on Gram-negative bacteria, Gram-positive bacteria and Candida albicans. The clinical studies are small, not well controlled and frequently sponsored by industry. Few adverse effects from the substance were reported.INTERPRETATION Better designed, larger-scale clinical studies of effect and safety are needed in order to give recommendations on the use of polyhexanide on skin, wounds and mucosa.
Topics: Anti-Infective Agents, Local; Biguanides; Candida albicans; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; In Vitro Techniques; Wound Infection
PubMed: 27143460
DOI: 10.4045/tidsskr.14.1041