Metformin: new applications for an old drug.

Metformin is a biguanide, evolved as one of the most widely used medicines. The applications of this component include but are not limited to reducing blood glucose, weight loss, and polycystic ovary syndrome. Studies about other probable indications have emerged, indicating that this agent can also be utilized for other purposes. In this review, applications of metformin are noticed based on the current evidence. Metformin commonly is used as an off-label drug in non-alcoholic fatty liver disease (NAFLD), but it worsens inflammation and should not be used for this purpose, according to the latest research. Metformin decreased the risk of death in patients with liver cirrhosis. It is an effective agent in the prevention and improvement of survival in patients suffering hepatocellular carcinoma. There is evidence of the beneficial effects of metformin in colorectal cancer, early-stage prostate cancer, breast cancer, urothelial cancer, blood cancer, melanoma, and bone cancer, suggesting metformin as a potent anti-tumor agent. Metformin shows neuroprotective effects and provides a potential therapeutic benefit for mild cognitive impairment and Alzheimer's disease (AD). It also has been shown to improve mental function and reduce the incidence of dementia. Another condition that metformin has been shown to slow the progression of is Duchenne muscular dystrophy. Regarding infectious diseases, tuberculosis (TB) and coronavirus disease (COVID-19) are among the conditions suggested to be affected by metformin. The beneficial effects of metformin in cardiovascular diseases were also reported in the literature. Concerning renal function, studies showed that daily oral administration of metformin could ameliorate kidney fibrosis and normalize kidney structure and function. This study reviewed the clinical and preclinical evidence about the possible benefits of metformin based on recent studies. Numerous questions like whether these probable indications of metformin can be observed in non-diabetics, need to be described by future basic experiments and clinical studies.

Biological Properties of Transition Metal Complexes with Metformin and Its Analogues.

Metformin is a widely prescribed medication for the treatment and management of type 2 diabetes. It belongs to a class of biguanides, which are characterized by a wide range of diverse biological properties, including anticancer, antimicrobial, antimalarial, cardioprotective and other activities. It is known that biguanides serve as excellent N-donor bidentate ligands and readily form complexes with virtually all transition metals. Recent evidence suggests that the mechanism of action of metformin and its analogues is linked to their metal-binding properties. These findings prompted us to summarize the existing data on the synthetic strategies and biological properties of various metal complexes with metformin and its analogues. We demonstrated that coordination of biologically active biguanides to various metal centers often resulted in an improved pharmacological profile, including reduced drug resistance as well as a wider spectrum of activity. In addition, coordination to the redox-active metal centers, such as Au(III), allowed for various activatable strategies, leading to the selective activation of the prodrugs and reduced off-target toxicity.

Does metformin affect outcomes in COVID-19 patients with new or pre-existing diabetes mellitus? A systematic review and meta-analysis.

AIMS: The COVID-19 pandemic is a global public health emergency and patients with diabetes mellitus (DM) are disproportionately affected, exhibiting more severe outcomes. Recent studies have shown that metformin is associated with improved outcomes in patients with COVID-19 and DM and may be a potential candidate for drug repurposing. We aimed to investigate the effects of metformin on outcomes in patients with COVID-19 and DM. METHODS: Databases (PubMed, Scopus, Web of Science, EMBASE, Clinicaltrials.gov and Cochrane library) were searched up to 10 April 2021 for studies reporting data on metformin use in COVID-19 patients with DM. The risk of bias was assessed using the Newcastle-Ottawa scale. Certainty of evidence was rated using the GRADE approach. The primary outcome was mortality reported as odds ratio (OR). A random-effects meta-analysis was carried out on both unadjusted and adjusted ORs. This study is registered with PROSPERO, CRD42020221842. RESULTS: In total, 2 916 231 patients from 32 cohort studies were included in the quantitative and qualitative synthesis. The meta-analysis showed that metformin was significantly associated with lower mortality in COVID-19 patients with DM in both unadjusted (OR 0.61 [95% confidence interval: 0.53-0.71], P < .00001, I2  = 70%) and adjusted (OR 0.78 [95% confidence interval: 0.69-0.88], P < .00001, I2  = 67%) models. CONCLUSION: Poor outcomes in COVID-19 patients with DM can be attributed to inadequate glycaemic control and weakened immune responses. Metformin has multiple effects that can improve outcomes in patients with DM and our findings highlight a possible role of its use. However, robust randomised trials are needed to thoroughly assess its use.

Update on the role of antiseptics in the management of chronic wounds with critical colonisation and/or biofilm.

Biofilms play a major role in delaying chronic wounds from healing. A wound infiltrated with biofilm, or "critically colonised" wound, may become clinically infected if the number of microbes exceeds a critical level. Chronic wound biofilms represent a significant treatment challenge by demonstrating recalcitrance towards antimicrobial agents. However, a "window of opportunity" may exist after wound debridement when biofilms are more susceptible to topical antiseptics. Here, we discuss the role of antiseptics in the management of chronic wounds and biofilm, focusing on povidone-iodine (PVP-I) in comparison with two commonly used antiseptics: polyhexanide (PHMB) and silver. This article is based on the literature reviewed during a focus group meeting on antiseptics in wound care and biofilm management, and on a PubMed search conducted in March 2020. Compared with PHMB and silver, PVP-I has a broader spectrum of antimicrobial activity, potent antibiofilm efficacy, no acquired bacterial resistance or cross-resistance, low cytotoxicity, good tolerability, and an ability to promote wound healing. PVP-I represents a viable therapeutic option in wound care and biofilm management, with the potential to treat biofilm-infiltrated, critically colonised wounds. We propose a practical algorithm to guide the management of chronic, non-healing wounds due to critical colonisation or biofilm, using PVP-I.

Inhaled biguanides and mTOR inhibition for influenza and coronavirus (Review).

The mammalian target of rapamycin (mTOR) signaling pathway senses and responds to nutrient availability, energy sufficiency, stress, hormones and mitogens to modulate protein synthesis. Rapamycin is a bacterial product that can inhibit mTOR via the PI3K/AKT/mTOR pathway. mTOR signaling is necessary for the development of influenza and modulates the antibody response to provide cross-protective immunity to lethal infection with influenza virus. In one human study, it was found that the treatment of severe H1N1 influenza­related pneumonia with rapamycin and steroids improved the outcome. However, in other studies, immunosuppression with systemic steroids, and possibly rapamycin as well, was associated with an increased morbidity/mortality and a prolonged viral replication. In order to avoid the systemic side-effects, some investigators have postulated that the inhalation of rapamycin would be desirable. However, the inhalation of rapamycin, with its well-documented lung toxicity, could be contraindicated. Another class of drug, biguanides, can also inhibit mTOR, but have no lung toxicity. Biguanides are widely used small molecule drugs prescribed as oral anti-diabetics that have exhibited considerable promise in oncology. During the 1971 outbreak of influenza, diabetic patients treated with the biguanides, phenformin and buformin, had a lower incidence of infection than diabetics treated with sulfonylureas or insulin. Both buformin and phenformin reduce the mortality of influenza in mice; phenformin is less effective than buformin. The inhalation of buformin or phenformin for influenza may be an effective novel treatment strategy that would limit the risk of systemic side-effects associated with biguanides due to the low inhaled dose. Coronavirus disease 2019 (COVID-19) is an infectious disease caused by SARS-CoV-2, a virus closely related to the SARS virus. The disease is the cause of the 2019-2020 coronavirus outbreak. It is primarily spread between individuals via small droplets emitted from infected individuals when breathing or coughing. PI3K/AKT/mTOR signaling responses play important roles in MERS-CoV infection and may represent a novel drug target for therapeutic intervention strategies. The present review article discusses the effects of biguanides on influenza and coronavirus.