Clinical Trials Of New Drugs Research Articles

A Brief Report of the Status of Central Nervous System Metastasis Enrollment Criteria for Advanced Non–Small Cell Lung Cancer Clinical Trials: A Review of the ClinicalTrials.gov Trial Registry

IntroductionCentral nervous system (CNS) metastases are common in non–small cell lung cancer (NSCLC), yet clinical trials of new drugs in advanced NSCLC have varying inclusion and exclusion criteria for CNS disease. The true extent of variation in CNS-related enrollment criteria in NSCLC clinical trials has not been documented. MethodsWe performed a systematic search of the ClinicalTrials.gov website to characterize interventional drug trials enrolling adult patients with advanced NSCLC. ResultsOf 413 open trials, 78 (19%) strictly excluded patients with leptomeningeal disease (LMD). Separate from LMD, patients with any history of CNS metastases were strictly excluded in 59 trials (14%), allowed after local treatment in 169 (41%), and allowed with no prior treatment in 106 (26%). No explicit mention of CNS disease was made in 79 trials (19%). In multivariate analysis looking at trial phase, location, sponsor, and treatment type, only sponsor was statistically significant, with pharmaceutical industry-sponsored trials having higher odds of excluding patients with brain metastases than did university or investigator-initiated trials (OR = 2.262, 95% confidence interval: 1.063–4.808, p = 0.0342) ConclusionsWith 14% to 19% of trials excluding any history of LMD or CNS parenchymal metastatic disease and 41% of trials permitting CNS disease only after prior CNS-directed treatment, direct evidence of activity of a treatment on CNS disease cannot be reliably generated in most NSCLC trials. Given the high frequency of CNS disease in NSCLC and only sponsor being associated with specific CNS exclusion criteria, sponsors should consider tailoring trial designs to explore CNS benefit more explicitly.

Idiopathic pulmonary fibrosis in BRIC countries: the cases of Brazil, Russia, India, and China.

Idiopathic pulmonary fibrosis (IPF), the prototype of interstitial lung diseases, has the worst prognosis and is the only interstitial lung disease for which approved pharmacological treatments are available. Despite being considered a rare disease, IPF patients pose major challenges to both physicians and healthcare systems. It is estimated that a large number of IPF patients reside in BRIC countries (Brazil, Russia, India, and China) given their overall total population of approximately 3 billion inhabitants. Nevertheless, the limited availability of chest imaging in BRIC countries is considered a chief obstacle to diagnosis, since high-resolution computed tomography of the chest is the key diagnostic test for IPF. Further, obtaining reliable lung function tests and providing treatment access is difficult in the more rural areas of these countries. However, IPF might represent an opportunity for BRIC countries: the exponentially increasing demand for the enrollment of IPF patients in clinical trials of new drugs is predicted to face a shortage of patients – BRIC countries may thus play a crucial role in advancing towards a cure for IPF.

Primary Myelofibrosis Brazilian Patient Journey: From Initial Symptoms to Treatment

Rationale for Study Primary Myelofibrosis (PMF) mainly affects individuals in their sixth decade of life or older. It is the most difficult myeloproliferative neoplasm to be defined, as the phenotype mimics a variety of hematological and non-hematological diseases. No symptom or sign is specific for PMF. Many patients are asymptomatic at presentation and the disease is usually detected by the discovery of a splenomegaly or abnormal blood counts during a routine examination. The only treatment with curative potential for PMF is allogeneic stem cell transplantation. This should be reserved only for high-risk patients, after careful consideration, taking into account the option for participation in clinical trials of new drugs. It is therefore extremely important the early identification of poor prognosis patients, to offer the best therapy. In Brazil, we do not have sufficient data to assess a patient's journey between the first symptoms and diagnosis of PMF. Moreover, the real incidence/ prevalence of this disease is unknown and a sub-diagnosis rate is speculated in our country. Objectives Understand and identify the journey of patients with PMF (clinical characteristics, diagnosis process and therapeutics interventions) and the problems between the first symptoms and initiation of treatment. Methods Given the observational nature of the study and the lack of a specific hypothesis to be tested, the statistical analysis is descriptive. This partial analysis includes descriptive results of contents of the database. Categorical data are presented as frequencies and percentages. For continuous data, mean, standard deviation, median, minimum, and maximum values are presented. Results 103 patient disposition (2008-2012); all of them met WHO criteria 2008: median age: 69; 58% male and 13.6% had died. Based on medical history, professional or environmental exposure was related in 4%, but this information was lack in 25% of the medical charts. In almost 42% of the medical records, the family history was not available. Two patients had a positive family history (brother of one and sister from another one with the same disease). Most frequent reason (63,1%) for medical evaluation seeking was symptoms and fatigue happened in 67% of them. Time from symptoms onset date until the confirmed diagnosis took a median of 9.7 months. General physician was the most frequent specialist to do the first evaluation of the patient until confirmed or suspected diagnosis. Bone marrow aspiration and bone marrow biopsy were performed in all patients; mutation status for JAK V617F in 82.5%, PCR for BCR-ABL in 71.8% and bone marrow cytogenetics in 64.1%. According to IPSS (78 patients), 8.5 % were low risk, 63.4% intermediate-1 63.4%, intermediate-2 28.1% and none high risk. Anemia was the most frequent laboratorial finding (67%) and most of the patients were treated with hydroxiurea (75.7%). Conclusions Although most of the patients have apparently the diagnosis of PMF, it took almost 10 months to be done. An expressive number of medical reports do not show a complete history, while 20-30% of them don’t have all the laboratory tools for a precise diagnosis. It is important to know Brazilian needs to improve diagnostic and provide a better treatment, since we are facing new drugs for PMF. Disclosures: No relevant conflicts of interest to declare.

Development and validation of a patient-reported outcome measure for stroke patients.

BackgroundFamily support and patient satisfaction with treatment are crucial for aiding in the recovery from stroke. However, current validated stroke-specific questionnaires may not adequately capture the impact of these two variables on patients undergoing clinical trials of new drugs. Therefore, the aim of this study was to develop and evaluate a new stroke patient-reported outcome measure (Stroke-PROM) instrument for capturing more comprehensive effects of stroke on patients participating in clinical trials of new drugs.MethodsA conceptual framework and a pool of items for the preliminary Stroke-PROM were generated by consulting the relevant literature and other questionnaires created in China and other countries, and interviewing 20 patients and 4 experts to ensure that all germane parameters were included. During the first item-selection phase, classical test theory and item response theory were applied to an initial scale completed by 133 patients with stroke. During the item-revaluation phase, classical test theory and item response theory were used again, this time with 475 patients with stroke and 104 healthy participants. During the scale assessment phase, confirmatory factor analysis was applied to the final scale of the Stroke-PROM using the same study population as in the second item-selection phase. Reliability, validity, responsiveness and feasibility of the final scale were tested.ResultsThe final scale of Stroke-PROM contained 46 items describing four domains (physiology, psychology, society and treatment). These four domains were subdivided into 10 subdomains. Cronbach’s α coefficients for the four domains ranged from 0.861 to 0.908. Confirmatory factor analysis supported the validity of the final scale, and the model fit index satisfied the criterion. Differences in the Stroke-PROM mean scores were significant between patients with stroke and healthy participants in nine subdomains (P < 0.001), indicating that the scale showed good responsiveness.ConclusionsThe Stroke-PROM is a patient-reported outcome multidimensional questionnaire developed especially for clinical trials of new drugs and is focused on issues of family support and patient satisfaction with treatment. Extensive data analyses supported the validity, reliability and responsiveness of the Stroke-PROM.Electronic supplementary materialThe online version of this article (doi:10.1186/s12955-015-0246-0) contains supplementary material, which is available to authorized users.

Cytosine modifications in myeloid malignancies.

Aberrant DNA methylation is a hallmark of many cancers, including the myeloid malignancies acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The discovery of TET-mediated demethylation of 5-methylcytosine (5mC) and technological advancements in next-generation sequencing have permitted the examination of other cytosine modifications, namely 5-hydroxymethylcytosine (5hmC), in these myeloid malignancies on a genome-wide scale. Due to the prominence of mutations in epigenetic modifiers that can influence cytosine modifications in these disorders, including IDH1/2, TET2, and DNMT3A, many recent studies have evaluated the relative levels, distribution, and functional consequences of cytosine modifications in leukemic cells. Furthermore, several therapies are being used to treat AML and MDS that target various proteins within the cytosine modification pathway in an effort to revert the abnormal epigenetic patterns that contribute to the diseases. In this review, we provide an overview of cytosine modifications and selected technologies currently used to distinguish and analyze these epigenetic marks in the genome. Then, we discuss the role of mutant enzymes, including DNMT3A, TET2, IDH1/2, and the transcription factor, WT1, in disrupting normal patterns of 5mC and 5hmC in AML and MDS. Finally, we describe several therapies, both standard, front-line treatments and new drugs in clinical trials, aimed at inhibiting the proteins that ultimately lead to aberrant cytosine modifications in these diseases.

Development of the algorithm of adverse events/reactions assessment when conducting clinical trials of drugs

The most important role of the assessment of undesirable events of drugs takes a special significance in clinical trials when it is important to specify, identify and comprehensively assess the indirect influence of drugs because such information will be the basis for the further stages of clinical trials, as well as future directions of pharmacovigilance. According to the Ukrainian rules of conducting the clinical trial (order #690 from 23 Sept., 2009) adverse reactions (ARs) are considered as those that at least have a causal relationship between medicinal product administrations. At the same time determination of adverse event (AE) is not so definite because sometimes there may be abnormalities, which may appear without drug administration. The analysis of documentation of 17 clinical trials has been performed in order to determine the definitions of AE/AR regarding assessment, registration and control of undesirable manifestations while conducting the clinical trial of new drugs and bioequivalence studies of drugs. As a result of this analysis the discrepancies in the synchronization of information concerning the understanding and assessment of AE/AR among all participants of clinical trials and bioequivalence studies have been found. The corresponding algorithms of the abnormality assessment have been developed by the study investigator with the purpose of the accurate data entry into the case report forms and source documents. These algorithms help to conduct the comprehensive analysis of AE/AR, minimize the number of mistakes during data entry and make the standards of the data entry process, data capture and AE/AR assessment in accordance with international requirements. The implementation of such algorithms in the system of work of the site unit will improve the work of the monitor, as well as the investigator who is responsible for data capture, monitoring and data entry while conducting the clinical trial.

Antibody slows Alzheimer's mental decline

At last, a ray of hope for people with Alzheimer's disease. In a field where almost all clinical trials of new drugs fail, a drug called aducanumab appears to be bucking the trend. In a small trial, the drug slowed the progression of the disease and reduced deposits of amyloid plaques, the substances blamed for damaging the brains of people with Alzheimer's. This is the first time a drug has a statistically significant effect on both cognition and amyloid in people with mild disease, says Alfred Sandrock at Bioqen, the firm that developed aducanumab, based in Cambridge MA.

Good Clinical Practice (GCP) Compliance of Clinical Trials of New Drugs Approved Between Fiscal Year (FY) 2010 and FY2012 in Japan

Good Clinical Practice (GCP) Compliance of Clinical Trials of New Drugs Approved Between Fiscal Year (FY) 2010 and FY2012 in Japan

Supervised prediction of drug-induced nephrotoxicity based on interleukin-6 and -8 expression levels.

BackgroundDrug-induced nephrotoxicity causes acute kidney injury and chronic kidney diseases, and is a major reason for late-stage failures in the clinical trials of new drugs. Therefore, early, pre-clinical prediction of nephrotoxicity could help to prioritize drug candidates for further evaluations, and increase the success rates of clinical trials. Recently, an in vitro model for predicting renal-proximal-tubular-cell (PTC) toxicity based on the expression levels of two inflammatory markers, interleukin (IL)-6 and -8, has been described. However, this and other existing models usually use linear and manually determined thresholds to predict nephrotoxicity. Automated machine learning algorithms may improve these models, and produce more accurate and unbiased predictions.ResultsHere, we report a systematic comparison of the performances of four supervised classifiers, namely random forest, support vector machine, k-nearest-neighbor and naive Bayes classifiers, in predicting PTC toxicity based on IL-6 and -8 expression levels. Using a dataset of human primary PTCs treated with 41 well-characterized compounds that are toxic or not toxic to PTC, we found that random forest classifiers have the highest cross-validated classification performance (mean balanced accuracy = 87.8%, sensitivity = 89.4%, and specificity = 85.9%). Furthermore, we also found that IL-8 is more predictive than IL-6, but a combination of both markers gives higher classification accuracy. Finally, we also show that random forest classifiers trained automatically on the whole dataset have higher mean balanced accuracy than a previous threshold-based classifier constructed for the same dataset (99.3% vs. 80.7%).ConclusionsOur results suggest that a random forest classifier can be used to automatically predict drug-induced PTC toxicity based on the expression levels of IL-6 and -8.

Monkey-based research on human disease: the implications of genetic differences.

Assertions that the use of monkeys to investigate human diseases is valid scientifically are frequently based on a reported 90-93% genetic similarity between the species. Critical analyses of the relevance of monkey studies to human biology, however, indicate that this genetic similarity does not result in sufficient physiological similarity for monkeys to constitute good models for research, and that monkey data do not translate well to progress in clinical practice for humans. Salient examples include the failure of new drugs in clinical trials, the highly different infectivity and pathology of SIV/HIV, and poor extrapolation of research on Alzheimer's disease, Parkinson's disease and stroke. The major molecular differences underlying these inter-species phenotypic disparities have been revealed by comparative genomics and molecular biology - there are key differences in all aspects of gene expression and protein function, from chromosome and chromatin structure to post-translational modification. The collective effects of these differences are striking, extensive and widespread, and they show that the superficial similarity between human and monkey genetic sequences is of little benefit for biomedical research. The extrapolation of biomedical data from monkeys to humans is therefore highly unreliable, and the use of monkeys must be considered of questionable value, particularly given the breadth and potential of alternative methods of enquiry that are currently available to scientists.

On the relationship between the causal-inference and meta-analytic paradigms for the validation of surrogate endpoints.

The increasing cost of drug development has raised the demand for surrogate endpoints when evaluating new drugs in clinical trials. However, over the years, it has become clear that surrogate endpoints need to be statistically evaluated and deemed valid, before they can be used as substitutes of "true" endpoints in clinical studies. Nowadays, two paradigms, based on causal-inference and meta-analysis, dominate the scene. Nonetheless, although the literature emanating from these paradigms is wide, till now the relationship between them has largely been left unexplored. In the present work, we discuss the conceptual framework underlying both approaches and study the relationship between them using theoretical elements and the analysis of a real case study. Furthermore, we show that the meta-analytic approach can be embedded within a causal-inference framework on the one hand and that it can be heuristically justified why surrogate endpoints successfully evaluated using this approach will often be appealing from a causal-inference perspective as well, on the other. A newly developed and user friendly R package Surrogate is provided to carry out the evaluation exercise.

Progress on clinical trials of new drugs for lymphoma in the 55th annual meeting of American Society of Hematology

Progress on clinical trials of new drugs for lymphoma in the 55th annual meeting of American Society of Hematology

Off-label use and designation of age groupspecific contraindications for pharmacotherapy in children in Korea

Children should be treated with medicines that have been tested for efficacy and safety in the given age groups. In reality the majority of drugs being used in children lack such information, inevitably leading to the “off-label use.” Over decades there have been concerns regarding risk of adverse effects with such off-label uses. However, in most countries rational application of off-label uses have not been prohibited, since it may be the only available and perhaps the best possible treatment option. In contrast, in an effort to minimize such use and per se ‘protect’ children from possible harm associated with it, Korea has launched “Drug Utilization Review” system, which included age group-specific contraindications, based on the labeling information approved by Ministry of Food and Drug Safety. The problem lies in the definition and scope of ‘contraindication.’ Lack of evidence for safety and concern for risk of serious adverse drug reactions are the basis for contraindication. This leads to branding of off-label uses as contraindications in certain age groups. This policy is restricting the already scarce treatment options and suffocating the initiative for developing better pharmacotherapy for children. We should learn from other countries that have travailed more to provide better medicines to children. Clinical trials of new drugs as well as existing drugs in pediatric populations are strongly encouraged. Simple prohibition of off-label use is not the answer, but rather systematized management of off-label use as well as conduct of clinical trials in pediatric age groups must be encouraged and supported. Received 31 Oct 2014 Revised 21 Nov 2014 Accepted 24 Nov 2014

Chapter Eight - Tracking Cellular and Immune Therapies in Cancer

The field of tumor immunology has seen an explosion of renewed interest over the last decade. With the FDA approval of new immunotherapies for prostate cancer and melanoma, as well as several exciting new drugs in clinical trials, tumor immunology is becoming an increasingly important topic in preclinical studies and patient care. However, the current methods for assessing the immune status of a patient and tumor are limited, which has led to the development of novel molecular imaging methods for assessing tumor immunology. From cell tracking for cellular therapeutics to assessing the tumor immune microenvironment, these imaging methods have the potential to further preclinical understanding of immunotherapies and potentially translate into clinically useful tests to predict and assess therapeutic response of these exciting new agents. In this review, we first discuss the recent advances in cancer immunotherapy, followed by a detailed review of the current state of molecular imaging for tumor immunology. Finally, we discuss opportunities for further development and innovation in this rapidly growing field.

PET/SPECT imaging agents for neurodegenerative diseases.

Single photon emission computed tomography (SPECT) or positron emission computed tomography (PET) imaging agents for neurodegenerative diseases have a significant impact on clinical diagnosis and patient care. The examples of Parkinson's Disease (PD) and Alzheimer's Disease (AD) imaging agents described in this paper provide a general view on how imaging agents, i.e. radioactive drugs, are selected, chemically prepared and applied in humans. Imaging the living human brain can provide unique information on the pathology and progression of neurodegenerative diseases, such as AD and PD. The imaging method will also facilitate preclinical and clinical trials of new drugs offering specific information related to drug binding sites in the brain. In the future, chemists will continue to play important roles in identifying specific targets, synthesizing target-specific probes for screening and ultimately testing them by in vitro and in vivo assays.

Primary Myelofibrosis Brazilian Patient Journey: From Initial Symptoms To Treatment

Rationale for StudyPrimary Myelofibrosis (PMF) mainly affects individuals in their sixth decade of life or older. It is the most difficult myeloproliferative neoplasm to be defined, as the phenotype mimics a variety of hematological and non-hematological diseases. No symptom or sign is specific for PMF. Many patients are asymptomatic at presentation and the disease is usually detected by the discovery of a splenomegaly or abnormal blood counts during a routine examination. The only treatment with curative potential for PMF is allogeneic stem cell transplantation. This should be reserved only for high-risk patients, after careful consideration, taking into account the option for participation in clinical trials of new drugs. It is therefore extremely important the early identification of poor prognosis patients, to offer the best therapy. In Brazil, we do not have sufficient data to assess a patient's journey between the first symptoms and diagnosis of PMF. Moreover, the real incidence/ prevalence of this disease is unknown and a sub-diagnosis rate is speculated in our country. ObjectivesUnderstand and identify the journey of patients with PMF (clinical characteristics, diagnosis process and therapeutics interventions) and the problems between the first symptoms and initiation of treatment. MethodsGiven the observational nature of the study and the lack of a specific hypothesis to be tested, the statistical analysis is descriptive. This partial analysis includes descriptive results of contents of the database. Categorical data are presented as frequencies and percentages. For continuous data, mean, standard deviation, median, minimum, and maximum values are presented. Results103 patient disposition (2008-2012); all of them met WHO criteria 2008: median age: 69; 58% male and 13.6% had died. Based on medical history, professional or environmental exposure was related in 4%, but this information was lack in 25% of the medical charts. In almost 42% of the medical records, the family history was not available. Two patients had a positive family history (brother of one and sister from another one with the same disease). Most frequent reason (63,1%) for medical evaluation seeking was symptoms and fatigue happened in 67% of them. Time from symptoms onset date until the confirmed diagnosis took a median of 9.7 months. General physician was the most frequent specialist to do the first evaluation of the patient until confirmed or suspected diagnosis. Bone marrow aspiration and bone marrow biopsy were performed in all patients; mutation status for JAK V617F in 82.5%, PCR for BCR-ABL in 71.8% and bone marrow cytogenetics in 64.1%. According to IPSS (78 patients), 8.5 % were low risk, 63.4% intermediate-1 63.4%, intermediate-2 28.1% and none high risk. Anemia was the most frequent laboratorial finding (67%) and most of the patients were treated with hydroxiurea (75.7%). ConclusionsAlthough most of the patients have apparently the diagnosis of PMF, it took almost 10 months to be done. An expressive number of medical reports do not show a complete history, while 20-30% of them don't have all the laboratory tools for a precise diagnosis. It is important to know Brazilian needs to improve diagnostic and provide a better treatment, since we are facing new drugs for PMF. Disclosures:No relevant conflicts of interest to declare.

Acute osteomyelitis due to Staphylococcus aureus in children: What is the status of treatment today?

Osteomyelitis is an inflammatory process caused by microorganisms and usually accompanied by bone destruction. The process may be limited to one portion of the bone or spread to several areas such as the bone marrow, periosteum or cortex. 1 It is an infection that can occur at all ages. In children, the average age of onset is 6 years. Today, many of these risks factors are poorly understood or inadequately addressed in healthcare. If improperly treated, the infection can progress to chronicity , with possible recurrence several years after the acute episode. Staphylococcus aureus is the most frequently isolated pathogen. The treatment of acute osteomyelitis should be started at the earliest stage and initiated in hospital with intravenous antibiotics. The antibiotic molecules used must have good penetration in the bone and be bactericidal. The choice of the molecule for empirical treatment must take into account the local epidemiological features and results of bacteriological cultures. According to epidemiological data, the prevalence of Methicillin-resistant Staphylococcus aureus (MRSA) varies greatly from one country to another and from one continent to another. Overcrowding and low social-economic background are factors favouring the spread of MRSA in the community. Apart from ensuring early referral, the medical community also needs to do research on the main challenges facing us in the control of acute osteomyelitis, a disease that is especially serious in children, such as improved diagnosis, detection of drug resistance, shortened treatment regimens and clinical trials of new drugs.

SP0153 How to obtain consent from children and their families

Implementation of clinical trial, observational studies or in general research projects that aim to collect data collection of the health status of patients requires the primary need to obtain a...

Recent developments in anti-herpesvirus drugs

Background Herpesviruses notably establish lifelong infections, with latency and reactivation. Many of the known human herpesviruses infect large proportions of the population worldwide. Treatment or prevention of herpes infections and recurrent disease still pose a challenge in the 21st century. Sources of data Original papers and review articles, meeting abstracts, a book (Clinical Virology; DD Richman, RJ Whitley & FG Hayden eds) and company web sites. Areas of agreement For herpes simplex types 1 and 2 and for varicella zoster, acyclovir (ACV; now increasingly replaced by its prodrug valacyclovir, VACV) and famciclovir (FCV) have greatly reduced the burden of disease and have established a remarkable safety record. Drug-resistance, in the otherwise healthy population, has remained below 0.5% after more that 20 years of antiviral use. In immunocompromised patients, drug resistance is more common and alternative drugs with good safety profiles are desirable. For human cytomegalovirus disease, which occurs in immunocompromised patients, ganciclovir and increasingly its prodrug valganciclovir are the drugs of choice. However, alternative drugs, with better safety, are much needed. Areas of controversy Various questions are highlighted. Should the new 1-day therapies for recurrent herpes labialis and genital herpes replace the current standard multi-day therapies? The marked differences between VACV and FCV (e.g. triphosphate stability, effect on latency) may not yet be fully exploited? Do current antivirals reduce post-herpetic neuralgia (PHN)? For immunocompromised patients with varicella zoster virus (VZV) disease, should the first-line treatment be FCV, not ACV or VACV? Should there be more support to explore new avenues for current antivirals, for example in possibly reducing herpes latency or Alzheimer's disease (AD)? Should primary Epstein-Barr virus (EBV) disease in adolescents be treated with antivirals? How can new compounds be progressed when the perceived market need is small but the medical need is great. FCV was reclassified from prescription-only to pharmacist-controlled for herpes labialis in New Zealand in 2010; should this be repeated more widely? This article reviews new drugs in clinical trials and highlights some of the problems hindering their progress.

Metformin: myths, misunderstandings and lessons from history

Clinical trials of new drugs may overstate efficacy and not identify adverse effects. It is therefore unusual for the passage of time to reveal that a drug is less toxic, has greater efficacy and a wider range of uses than first claimed. For decades metformin was misunderstood, vilified and banned in many countries, but it is now one of the most prescribed drugs in the world. In 2010 there were more than 100 million prescriptions worldwide for metformin, alone and in combination tablets. Metformin was developed from a herb, Galega officinalis*, which was used for centuries to treat many ailments including polyuria. It is a rich source of the toxic substance guanidine. A less toxic alkaloid, galegine, was identified in France just before World War I. Its pharmacology and toxicology were studied in Paris and its structure was identified in Edinburgh. In 1922 metformin (dimethyl biguanide) was synthesised in Dublin and shown to lower blood glucose with fewer gastrointestinal adverse effects than its predecessors. However, in the same year insulin was used for the first time, distracting interest from other glucose-lowering drugs. In Paris in 1957 metformin, by then called glucophage (‘glucose eater’), was studied in trials and shown to lower blood glucose in patients with type 2 diabetes, but not in people without diabetes. Unlike sulfonylureas, metformin did not stimulate insulin release, but increased its peripheral uptake and also reduced the release of glucose from the liver. Metformin had gastrointestinal adverse effects which could be minimised by a ‘start low, go slow’ approach to dosing.