Preclinical studies show that activation of AMP kinase by phenformin can augment the cytotoxic effect and RAF inhibitors in BRAF V600-mutated melanoma. We conducted a phase Ib dose-escalation trial of phenformin with standard dose dabrafenib/trametinib in patients with metastatic BRAF V600-mutated melanoma.
We used a 3+3 dose-escalation design which explored phenformin doses between 50 and 200 mg twice daily. Patients also received standard dose dabrafenib/trametinib. We measured phenformin pharmacokinetics and assessed the effect of treatment on circulating myeloid-derived suppressor cells (MDSC).
A total of 18 patients were treated at dose levels ranging from 50 to 200 mg twice daily. The planned dose-escalation phase had to be cancelled because of the COVID 19 pandemic. The most common toxicities were nausea/vomiting; there were two cases of reversible lactic acidosis. Responses were seen in 10 of 18 patients overall (56%) and in 2 of 8 patients who had received prior therapy with RAF inhibitor. Pharmacokinetic data confirmed drug bioavailability. MDSCs were measured in 7 patients treated at the highest dose levels and showed MDSC levels declined on study drug in 6 of 7 patients.
We identified the recommended phase II dose of phenformin as 50 mg twice daily when administered with dabrafenib/trametinib, although some patients will require short drug holidays. We observed a decrease in MDSCs, as predicted by preclinical studies, and may enhance immune recognition of melanoma cells.
This is the first trial using phenformin in combination with RAF/MEK inhibition in patients with BRAF V600-mutated melanoma. This is a novel strategy, based on preclinical data, to increase pAMPK while blocking the MAPK pathway in melanoma. Our data provide justification and a recommended dose for a phase II trial.

BACKGROUND: Chronic inflammation is a risk factor for diabetes, but it can also be a complication of diabetes, leading to severe diabetes and causing many other clinical manifestations. Inflammation is a major emerging complication in both type I and type II diabetes, which causes increasing interest in targeting inflammation to improve and control diabetes. Diabetes with insulin resistance and impaired glucose utilization in humans and their underlying mechanism is not fully understood. But a growing understanding of the intricacy of the insulin signaling cascade in diabetic inflammatory cells reveals potential target genes and their proteins responsible for severe insulin resistance. With this baseline concept, the current project explores the binding affinities of the hyaluronic acid anti-diabetic compounds conjugates to such target proteins in diabetic inflammatory cells and their molecular geometries. A range of 48 anti-diabetic compounds was screened against aldose reductase binding pocket 3 protein target through in silico molecular docking, and results revealed that three compounds viz, metformin (CID:4091), phenformin (CID:8249), sitagliptin (CID:4,369,359), possess significant binding affinity out of 48 chosen drugs. Further, these three anti-diabetic compounds were conjugated with hyaluronic acid (HA), and their binding affinity and their molecular geometrics towards aldose reductase enzyme were screened compared with the free form of the drug. The molecular geometries of three shortlisted drugs (metformin, phenformin, sitagliptin) and their HA conjugates were also explored through density functional theory studies, and it proves their good molecular geometry towards pocket 3 of aldose reductase target. Further, MD simulation trajectories affirm that HA conjugates possess good binding affinity and simulation trajectories with protein target aldose reductase than a free form of the drug. Our current study unravels the new mechanism of drug targeting for diabetes through HA conjugation for inflammatory diabetes. HA conjugates act as novel drug candidates for treating inflammatory diabetes; however, it needs further human clinical trials.
METHODS: For ligand structure, PubChem, ACD chem sketch, and online structure file generator platform are utilized for ligand preparation. Target protein aldose reductase obtained from protein database (PDB). For molecular docking analysis, AutoDock Vina (Version 4) was utilized. pKCSM online server used to predict ADMET properties of the above three shortlisted drugs from the docking study. Using mol-inspiration software (version 2011.06), three shortlisted compounds\' bioactivity scores were predicted. DFT analysis for three shortlisted anti-diabetic drugs and their hyaluronic acid conjugates were calculated using a functional B3LYP set of Gaussian 09 software. Molecular dynamics simulation calculations for six chosen protein-ligand complexes were done through YASARA dynamics software and AMBER14 force field.

The results presented in this paper confirm the beneficial role of an easy-to-use and low-cost thin-layer chromatography (TLC) technique for describing the retention behavior and the experimental lipophilicity parameter of two biguanide derivatives, metformin and phenformin, in both normal-phase (NP) and reversed-phase (RP) TLC systems. The retention parameters (RF, RM) obtained under different chromatographic conditions, i.e., various stationary and mobile phases in the NP-TLC and RP-TLC systems, were used to determine the lipophilicity parameter (RMW) of metformin and phenformin. This study confirms the poor lipophilicity of both metformin and phenformin. It can be stated that the optimization of chromatographic conditions, i.e., the kind of stationary phase and the composition of mobile phase, was needed to obtain the reliable value of the chromatographic lipophilicity parameter (RMW) in this study. The fewer differences in the RMW values of both biguanide derivatives were ensured by the RP-TLC system composed of RP2, RP18, and RP18W plates and the mixture composed of methanol, propan-1-ol, and acetonitrile as an organic modifier compared to the NP-TLC analysis. The new calculation procedures for logP of drugs based on topological indices 0χν, 0χ, 1χν, M, and Mν may be a certain alternative to other algorithms as well as the TLC procedure performed under optimized chromatographic conditions. The knowledge of different lipophilicity parameters of the studied biguanides can be useful in the future design of novel and more therapeutically effective metformin and phenformin formulations for antidiabetic and possible anticancer treatment. Moreover, the topological indices presented in this work may be further used in the QSAR study of the examined biguanides.

Extensive in vitro studies have been conducted to evaluate the anticancer activity of oral hypoglycemic agents. Many of these studies experienced detrimental limitations, since they were conducted on cancer cells commonly grown in culture media consisting of extremely high concentrations of growth factors and glucose. The present study was aimed at exploring the antiproliferative effects of the commonly studied metformin and the less frequently reported phenformin oral hypoglycemic agents on different molecular subtypes of breast cancer under rich glucose and glucose deprived conditions. Our results indicate that under glucose deprived conditions, which better reflect the factual glucose-starved solid tumors in vivo, biguanides exert more antiproliferative activities against the three molecular subtypes of breast cancer cell lines examined in this study. In addition, the observed antiproliferative activities of biguanides appear to be mediated by apoptosis induction in breast cancer cells. This induction is significantly augmented under glucose deprived conditions.

Observational studies have shown conflicting results on the potential protecting effect of biguanide use with the risk of colorectal neoplasms. In addition, the cellular mechanism can either support or oppose biguanides influence on colorectal carcinoma. Our objective was to evaluate the association between biguanide use and colorectal carcinoma. A population-based cohort study using healthcare data from the Danish National database (1996-2007), was conducted. Oral antidiabetic drug users (n = 177,281) were matched 1:3 with a population-based reference group. Cox proportional hazard models estimated hazard ratios (HRs) of colorectal carcinoma. Stratification was performed to analyse the risk of colorectal cancer in current biguanide users. Two sub-analyses were performed, to investigate the risk of colorectal cancer associated with discontinuous and prolonged use of biguanides. Instead of a protective effect, we found that current biguanide users had a 1.2-fold increased risk of colorectal cancer (HR = 1.19, 95% CI = 1.08-1.30) as compared with the non-diabetes reference group. Prolonged use was not inversely associated with colorectal cancer either. When studying colorectal risk with biguanides, the underlying T2DM should be taken into account since a 1.3-1.6-fold increased risk was found in oral antidiabetic drug users compared to controls unexposed to diabetic medication. This study could not detect a protective effect of biguanide use with colorectal cancer. Therefore, this study does not support a further investigation of the effectiveness of biguanides to prevent colorectal carcinoma in clinical studies.

A fast, sensitive and specific high-performance liquid chromatography tandem mass spectrometry method was developed for simultaneous determination of metformin and rosiglitazone in human plasma. With phenformin as an internal standard, the analysis was carried out on a C(18) column (50 mm × 2.1 mm, 3.5 μm) using a mobile phase consisting of acetonitrile-10 mM ammonium acetate (20:80, v/v). The detection was performed by tandem mass spectrometry via electrospray ionization. Linear calibration curves were obtained in the concentration of 1.054-263.5 ng/mL for rosiglitazone and 4.040-5050 ng/mL for metformin. The method was applicable to clinical pharmacokinetic study of metformin and rosiglitazone in healthy volunteers following oral administration.

OBJECTIVE: To assess the feasibility of administering at the same time low doses of five probe drugs, metoprolol (25 mg), chlorzoxazone (250 mg), tolbutamide (250 mg), dapsone (100 mg) and caffeine (100 mg) to determine simultaneously the activities of CYP2D6, CYP2E1, CYP2C9, CYP3A4, CYP1A2, N-acetyltransferase-2 and xanthine oxidase.
METHODS: Ten healthy young non-smoking males received the following drugs or combinations of drugs over a 5-week period: week 1) metoprolol; 2) tolbutamide; 3) caffeine, chlorzoxazone and dapsone; 4) caffeine, chlorzoxazone, dapsone and metoprolol; 5) caffeine, chlorzoxazone, dapsone, metoprolol and tolbutamide. The drugs were self-administered at bedtime and urine was collected for the following 8 h.
RESULTS: Mean molar phenotypic ratios obtained after administering metoprolol (mean change of -11%) or tolbutamide (mean change of -0.3%) alone, were not significantly different from those obtained when other drugs were co-administered (P > 0.05). The mean within-subject coefficients of variation were 33%, 18%, 22%, 13%, 16%, 13% and 5% for CYP3A4, CYP2D6, CYP2C9, CYP2E1, CYP1A2, N-acetyltransferase 2 and xanthine oxidase metabolic ratios, respectively. No significant interactions (P > 0.5) were observed during the simultaneous administration of various combinations of the five probe drugs.
CONCLUSIONS: We propose that this cocktail, composed of five widely available drugs, constitutes a promising means of simultaneously determining the activities of the major CYP enzymes in large populations.

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