Future treatments of cirrhosis

Cirrhosis can be sub-classified in clinical stages with distinct differences in prognosis and can even be reversed in some cases with successful etiological treatment. In this article, we review potential future therapies of cirrhosis, mainly focusing in the expansion of indications of currently licensed drugs. We strongly advocate that future therapies should focus on preventing the advent of complications and further progression of liver disease and should involve both primary and secondary care physicians. Such strategies could be based on the combination of currently licensed, relatively safe and inexpensive drugs and such randomized controlled trials should be prioritized in patients with advanced liver disease. The paradigm should be similar to that of prevention in cardiovascular diseases and long-term follow-up trials are needed.     

A systematic review of the safety of probiotics

Introduction: Gestational diabetes mellitus (GDM), the most frequent medical complication of pregnancy, is associated with several adverse outcomes over the short- and long-term for both mother and offspring. Standard treatment for GDM consists of insulin injections. Oral hypoglycemic agents (OHAs), on the other hand, are still the subject of controversy. Although OHAs are seemingly as efficient as insulin and may provide better quality of life, congenital malformations and unknown long-term effects are still feared.

Areas covered: Recent data on the pharmacokinetics of two OHAs (glyburide and metformin) and their clinical use for GDM are reviewed, with a focus on clinical trials and observational studies comparing insulin with glyburide or metformin (1960 – 2010). The review will provide a comprehensive overview of the pros and cons of OHA usage, an appreciation of OHAs' efficiency for the purpose of controlling glycemia and embryogenetic basics relating to congenital malformations.

Expert opinion: While insulin treatment is an effective therapy for controlling maternal glycemia, it nevertheless requires sufficient education and skills on the part of the patient to manage properly and may cause hypoglycemia, fear and anxiety. Oral treatment as a more user-friendly alternative may thus facilitate the control of GDM in some patients.     

Drug-induced hypoglycaemia in type 2 diabetes

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.     

Metformin in the treatment of non-alcoholic fatty liver disease: safety,efficacy and mechanism

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease etiology worldwide. It encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis. Although the physiopathology of NAFLD is partly known. Insulin-resistance plays a central role in the development and progression of NAFLD. Several studies have indicated that metformin, as an insulin sensitizer, effectively improves NAFLD and its related metabolic status. Metformin was effective in reducing enzyme levels in the short period, but very limited and controversial information are available on liver histology. Larger randomized controlled trials of sufficient duration using clearly defined histological endpoints are needed to fully assess the efficacy of this drug in modifying the natural history of NAFLD.     

Glucose starvation induces resistance to metformin through the elevation of mitochondrial multidrug resistance protein 1

Metformin, a drug for type 2 diabetes mellitus, has shown therapeutic effects for various cancers. However, it had no beneficial effects on the survival rate of human malignant mesothelioma (HMM) patients. The present study was performed to elucidate the underlying mechanism of metformin resistance in HMM cells. Glucose‐starved HMM cells had enhanced resistance to metformin, demonstrated by decreased apoptosis and autophagy and increased cell survival. These cells showed abnormalities in mitochondria, such as decreased ATP synthesis, morphological elongation, altered mitochondrial permeability transition pore and hyperpolarization of mitochondrial membrane potential (MMP). Intriguingly, Mdr1 was significantly upregulated in mitochondria but not in cell membrane. The upregulated mitochondrial Mdr1 was reversed by treatment with carbonyl cyanide m‐chlorophenyl hydrazone, an MMP depolarization inducer. Furthermore, apoptosis and autophagy were increased in multidrug resistance protein 1 knockout HMM cells cultured under glucose starvation with metformin treatment. The data suggest that mitochondrial Mdr1 plays a critical role in the chemoresistance to metformin in HMM cells, which could be a potential target for improving its therapeutic efficacy.