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E A Gale

Publications and source records attributed to E A Gale.

At least 19 recordsLinked to original sources
PubMed2001

Lessons from the glitazones: a story of drug development.

Troglitazone, the first in the thiazolidinedione class of oral hypoglycaemic agents, was launched in the USA in March, 1997. It reached Europe later that year, only to be withdrawn within weeks on the grounds of liver toxicity. Meanwhile it went on to generate sales of over $2 billion in the USA, and caused at least 90 cases of liver failure (70 resulting in death or transplantation) before it was withdrawn in March, 2000. Rosiglitazone and pioglitazone reached the US market in 1999 as first-line agents to be used alone or in combination with other drugs, but in Europe the same dossiers were used one year later to apply for a limited licence as second-line agents restricted to oral combination therapy. How should we use the glitazones? And how did they achieve blockbuster status without any clear evidence of advantage over existing therapy?

Adverse Drug Reaction Reporting Systems↗
PubMed2001

Diabetes and gender.

It is often assumed that there is little or no sex bias within either Type I (insulin-dependent) or Type II (non-insulin-dependent) diabetes mellitus. This review considers evidence that sex effects of interest and importance are present in both forms of the disease. Type I diabetes is the only major organ-specific autoimmune disorder not to show a strong female bias. The overall sex ratio is roughly equal in children diagnosed under the age of 15 but while populations with the highest incidence all show male excess, the lowest risk populations studied, mostly of non-European origin, characteristically show a female bias. In contrast, male excess is a consistent finding in populations of European origin aged 15-40 years, with an approximate 3:2 male:female ratio. This ratio has remained constant in young adults over two or three generations in some populations. Further, fathers with Type I diabetes are more likely than affected mothers to transmit the condition to their offspring. Women of childbearing age are therefore less likely to develop Type I diabetes, and--should this occur--are less likely to transmit it to their offspring. Type II diabetes showed a pronounced female excess in the first half of the last century but is now equally prevalent among men and women in most populations, with some evidence of male preponderance in early middle age. Men seem more susceptible than women to the consequences of indolence and obesity, possibly due to differences in insulin sensitivity and regional fat deposition. Women are, however, more likely to transmit Type II diabetes to their offspring. Understanding these experiments of nature might suggest ways of influencing the early course of both forms of the disease.

Adolescent↗
PubMed2001

A comparison of the prevalence of islet autoantibodies in children from two countries with differing incidence of diabetes.

AIMS/HYPOTHESIS: To examine the prevalence of sub-: clinical islet autoimmunity in children from two countries with a twofold to threefold difference in incidence of childhood Type I (insulin-dependent) diabetes mellitus. METHODS: Sera were collected from 2,860 English and 3,053 Lithuanian non-diabetic schoolchildren according to the same protocol. Occult diabetes was excluded by blood glucose measurement. Antibodies to GAD and the protein tyrosine phosphatase IA-2 were measured with standardised radiobinding assays in a single laboratory. Islet cell antibodies and insulin autoantibodies were additionally measured in all samples with GAD and/or IA-2 antibody levels above the 97.5th centile of the English schoolchildren. RESULTS: Of Lithuanian schoolchildren 2.7 % had GAD antibodies above the 97.5th centile of the English schoolchildren but only 0.2 % had antibodies to IA-2 above this threshold (p < 0.001). Islet cell and/ or insulin autoantibodies above the 97.5th centile were found in 22 Lithuanian and 16 English schoolchildren and the overall prevalence of two or more antibodies on or above the 97.5th centile was similar [0.7 % (0.5-1.1) vs 0.6 % (0.4-1.0)] in the two cohorts. CONCLUSION/INTERPRETATION: The prevalence of multiple antibody markers was similar in the cohorts from the two populations, despite the two to three-fold difference in incidence of diabetes. The unexpectedly high prevalence of subclinical islet autoimmunity suggests that the incidence of diabetes in Lithuania is likely to increase in the near future.

Adolescent↗
PubMed2001

Does partial preservation of residual beta-cell function justify immune intervention in recent onset Type I diabetes?

Immune intervention seems to offer the prospect of preventing or reversing the hyperglycaemic phase of Type I (insulin-dependent) diabetes mellitus. A number of prevention trials have been undertaken before disease onset but the logistics of such trials are prohibitive. More rapid and less expensive means of testing new therapies are needed and the current emphasis is therefore on intervention after diagnosis to salvage residual beta-cell function. At present, because restoration of normal metabolism seems unattainable, such interventions are tested against their ability to maintain C-peptide production over the first months or years of diabetes.

C-Peptide↗
PubMed2001

The discovery of type 1 diabetes.

The etiological heterogeneity of idiopathic diabetes has been recognized for 25 years, and subdivision into type 1 and type 2 diabetes is fundamental to the way we think about the disease. Review of the literature suggests that the concept of type 1 diabetes as an immunemediated disease emerged rapidly over the period from 1974 to 1976 and showed many of the features of a classic paradigm shift. A few key observations triggered recognition and acceptance of the new paradigm, but the necessary context was provided by scientific developments in areas mainly unrelated to diabetes. The disease paradigm established by 1976 is still widely accepted, and its essential features have been modified only in detail by the revolution in molecular biology that has occurred over the intervening period. Notwithstanding, some of the underlying assumptions remain imprecise, unchallenged, or unconfirmed. Appreciation of the historical origin and subsequent evolution of these fundamental concepts could stimulate critical analysis and help prepare the way for a new paradigm.

Animals↗
PubMed2001

The high prevalence of autoantibodies to tissue transglutaminase in first-degree relatives of patients with type 1 diabetes is not associated with islet autoimmunity.

OBJECTIVE: To determine the extent of celiac autoimmunity in type 1 diabetic patients and the overlap between islet and celiac autoimmunity in their nondiabetic relatives. RESEARCH DESIGN AND METHODS: IgA antibodies to tissue transglutaminase were determined in serum taken from 433 type 1 diabetic patients and 1,442 nondiabetic first-degree relatives. Samples with transglutaminase antibodies above the 97.5th percentile of 347 schoolchildren were also assayed for IgA anti-endomysial antibodies (EMAs). Markers of islet autoimmunity (islet cell antibodies and autoantibodies to insulin, glutamate decarboxylase. and protein tyrosine phosphatase IA-2) had previously been measured in all relatives. RESULTS: In the absence of known celiac disease, the prevalence of transglutaminase antibody levels above the 97.5th percentile of the schoolchildren was 13.4% in diabetic patients and 7.0% in nondiabetic relatives. ENMAs were found in addition to transglutaminase antibodies in 2.6% of probands and in 1.9% of first-degree relatives, but none of the schoolchildren. Transglutaminase antibodies were found to persist in 10 of 30 patients and in 30 of 59 relatives with follow-up samples taken at least 2 years after the initial sample. Of 186 nondiabetic relatives with islet autoantibodies, only 10 also had transglutaminase antibodies. CONCLUSIONS: We found a high prevalence of celiac autoimmunity in patients and first-degree relatives of children with type 1 diabetes, but we found limited overlap between islet and celiac autoimmunity in nondiabetic relatives. The high prevalence of celiac autoimmunity may be explained by shared genetic susceptibility and identifies a population within which screening for the disease may be justified.

Adolescent↗
PubMed2000

Influence of maternal age at delivery and birth order on risk of type 1 diabetes in childhood: prospective population based family study. Bart's-Oxford Family Study Group.

OBJECTIVES: To examine the influence of parental age at delivery and birth order on subsequent risk of childhood diabetes. DESIGN: Prospective population based family study. SETTING: Area formerly administered by the Oxford Regional Health Authority. PARTICIPANTS: 1375 families in which one child or more had diabetes. Of 3221 offspring, 1431 had diabetes (median age at diagnosis 10.5 years, range 0.4-28.5) and 1790 remained non-diabetic at a median age of 16. 1 years. MAIN OUTCOME MEASURES: Disease free survival and hazard ratios for the development of type 1 diabetes in all offspring, assessed by Cox proportional hazard regression. RESULTS: Maternal age at delivery was strongly related to risk of type 1 diabetes in the offspring; risk increased by 25% (95% confidence interval 17% to 34%) for each five year band of maternal age, so that maternal age at delivery of 45 years or more was associated with a relative risk of 3.11 (2.07 to 4.66) compared with a maternal age of less than 20 years. Paternal age was also associated with a 9% (3% to 16%) increase for each five year increase in paternal age. The relative risk of diabetes, adjusted for parental age at delivery and sex of offspring, decreased with increasing birth order; the overall effect was a 15% risk reduction (10% to 21%) per child born. CONCLUSIONS: A strong association was found between increasing maternal age at delivery and risk of diabetes in the child. Risk was highest in firstborn children and decreased progressively with higher birth order. The fetal environment seems to have a strong influence on risk of type 1 diabetes in the child. The increase in maternal age at delivery in the United Kingdom over the past two decades could partly account for the increase in incidence of childhood diabetes over this period.

Adult↗
PubMed2000

Measurement of N-methyl-2-pyridone-5-carboxamide in urine by high performance liquid chromatography.

We have previously described a simple and reproducible method for the measurement of nicotinamide and its major metabolite N-methyl-2-pyridone-5-carboxamide (2-pyr) in human plasma. We now describe a low-cost high-throughput method for measurement of urinary 2-pyr, and demonstrate that Isolute C18 bulk can replace use of the column to clean up the samples prior to injection into the HPLC apparatus. Using a standard curve together with an internal standard for each sample, with mean recovery of 2-pyr greater than 95%, the assay has proved reproducible, with considerable savings in cost and time. The principal advantages of this method are the rapid column clean up of samples prior to injection and the simple but effective methodology.

Chromatography, High Pressure Liquid↗
PubMed2000

Safety of high-dose nicotinamide: a review.

Nicotinamide, the amide derivative of nicotinic acid, has over the past forty years been given at high doses for a variety of therapeutic applications. It is currently in trial as a potential means of preventing the onset of Type I (insulin-dependent) diabetes mellitus in high-risk, first-degree relatives. Nicotinamide is for regulatory purposes classed as a food additive rather than a drug and has not therefore required the formal safety evaluation normally expected of a new therapy. Because the safety of treatment with megadoses of vitamins cannot be assumed, a full literature review has been undertaken. The therapeutic index of nicotinamide is wide but at very high doses reversible hepatotoxicity has been reported in animals and humans. Minor abnormalities of liver enzymes can infrequently occur at the doses used for diabetes prevention. There is no evidence of teratogenicity from animal studies and nicotinamide is not in itself oncogenic; at very high doses it does however potentiate islet tumour formation in rats treated with streptozotocin or alloxan. There is no evidence of oncogenicity in man. Growth inhibition can occur in rats but growth in children is unaffected. Studies of its effects on glucose kinetics and insulin sensitivity are inconsistent but minor degrees of insulin resistance have been reported. The drug is well tolerated, especially in recent studies which have used relatively pure preparations of the vitamin. Experience to date therefore suggests that the ratio of risk to benefit of long-term nicotinamide treatment would be highly favourable, should the drug prove efficacious in diabetes prevention. High-dose nicotinamide should still, however, be considered as a drug with toxic potential at adult doses in excess of 3 gm/day and unsupervised use should be discouraged.

Abnormalities, Drug-Induced↗
PubMed2000

HLA class II typing of whole genome amplified mouth swab DNA.

Postal collection of mouth swabs provides a cheap and convenient means of DNA sampling but hitherto has not provided sufficient genetic material for HLA typing by polymerase chain reaction using sequence-specific primers (PCR-SSP). This study examined the feasibility of collecting mouth swabs from a test population by post, amplifying the DNA by whole genome amplification and genotyping for selected HLA class II alleles. We optimised a strategy for whole genome amplification or primer extension preamplification using a random 15 base pair primer which resulted in a 1,000-fold increase in DNA template. The amplified DNA was of sufficient quality for analysis of selected HLA Class II alleles by PCR-SSP and PCR using sequence-specific oligonucleotide probes. To test the reliability of our data, blood DNA from 30 individuals in 10 families, previously tested for all DRB1 alleles in a routine diagnostic laboratory, was then tested in our laboratory for DRB1 *03 and *04 following whole genome amplification. Further whole genome amplified product from another 10 families was tested for DRB1 *03, *04 in our laboratory and then tested for all DRB1 alleles in a routine diagnostic laboratory. One repeat typing was required to achieve 100% concordance between laboratories. Amplification of whole genome amplified DNA by PCR-SSP was then extended successfully to low-resolution HLA DRB1, DQA1, DQB1 and DPB1 typing. Mouth swab collection by post, followed by whole genome amplification of DNA provides an effective strategy for genetic analysis of large cohorts. We have optimised conditions for HLA class II typing on whole genome amplified DNA collected by mouth swab, but this method could potentially be applied to low concentrations of DNA from other sources.

Adult↗
PubMed2000

A randomized, controlled trial comparing insulin lispro with human soluble insulin in patients with Type 1 diabetes on intensified insulin therapy. The UK Trial Group.

AIMS: Despite considerable experience with insulin lispro, few blinded comparisons with soluble insulin are available. This study compared insulin lispro with human soluble insulin in patients with Type 1 diabetes mellitus on multiple injection therapy who inject shortly before meals. METHODS: Glucose control, frequency of hypoglycaemia and patient preference were examined in the course of a prospective, randomized, double-blind, crossover comparison, with a 6-week run-in period and 12 weeks on each therapy. Ninety-three patients took part, all on multiple daily doses of insulin, with soluble insulin before meals and NPH (isophane) insulin at night. The main outcome measures were self-monitored blood glucose profiles, glycated haemoglobin, frequency of hypoglycaemic episodes, patient satisfaction and well-being and patient preference. RESULTS: Blood glucose levels were significantly lower after breakfast and lunch, but higher before breakfast, lunch and supper, in patients taking insulin lispro. Levels of HbA(1c) were 7.4 +/- 1.1% on Humulin S and 7.5 +/- 1.1% on insulin lispro (P = 0.807). The overall frequency of symptomatic hypoglycaemia did not differ, but patients on insulin lispro were less likely to experience hypoglycaemia between midnight and 6 a.m., and more likely to experience episodes from 6 a.m. to midday. Questionnaires completed by 84/87 patients at the end of the study showed that 43 (51%) were able to identify each insulin correctly, nine (11%) were incorrect, and 32 (38%) were unable to tell the insulins apart. No significant preference emerged: 35 (42%) opted for insulin lispro, 24 (29%) opted for Humulin S, while the remainder had no clear preference. CONCLUSIONS: Substitution of insulin lispro for soluble insulin in a multiple injection regimen improved post-prandial glucose control at the expense of an increase in fasting and pre-prandial glucose levels. Patients who already injected shortly before meals expressed no clear preference for the fast-acting analogue, and did not improve their overall control as a result of using it. Nocturnal hypoglycaemia was however, less frequent on insulin lispro, and may emerge as a robust indication for its use.

Adolescent↗
PubMed1999

Evaluation of a high-throughput second antibody radiobinding assay for measuring IgA antibodies to human tissue transglutaminase.

We describe a novel high-throughput radiobinding assay for IgA antibodies to tissue transglutaminase (TG) which uses second antibody precipitation to isolate immune complexes. Using this assay, 24 of 25 patients with untreated coeliac disease (96%) and nine of 526 healthy blood donors (2%) had TG antibody levels above a threshold defined by the 97.5th centile of 347 schoolchildren. All patients and five of the nine blood donors with transglutaminase antibodies above this threshold were endomysial antibody (EMA) positive. Using this threshold, 410/445 (92%) routine clinical samples were concordant for TG antibodies and EMA, including 72 of 75 with EMA. TG antibodies above the 97.5th centile were found in 32 of 370 EMA negative samples, 15 of whom had anti-gliadin antibodies (AGA), histologically proven coeliac disease or partial villous atrophy. We conclude that this assay achieves a sensitivity and a specificity at least equivalent to those of EMA. It is technically simple and suitable for coeliac disease screening.

Adolescent↗