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Biomedical subjects

P Lilly

Publications and source records attributed to P Lilly.

12 recordsLinked to original sources
PubMed2000

Concordance of the toxicity of pharmaceuticals in humans and in animals.

This report summarizes the results of a multinational pharmaceutical company survey and the outcome of an International Life Sciences Institute (ILSI) Workshop (April 1999), which served to better understand concordance of the toxicity of pharmaceuticals observed in humans with that observed in experimental animals. The Workshop included representatives from academia, the multinational pharmaceutical industry, and international regulatory scientists. The main aim of this project was to examine the strengths and weaknesses of animal studies to predict human toxicity (HT). The database was developed from a survey which covered only those compounds where HTs were identified during clinical development of new pharmaceuticals, determining whether animal toxicity studies identified concordant target organ toxicities in humans. Data collected included codified compounds, therapeutic category, the HT organ system affected, and the species and duration of studies in which the corresponding HT was either first identified or not observed. This survey includes input from 12 pharmaceutical companies with data compiled from 150 compounds with 221 HT events reported. Multiple HTs were reported in 47 cases. The results showed the true positive HT concordance rate of 71% for rodent and nonrodent species, with nonrodents alone being predictive for 63% of HTs and rodents alone for 43%. The highest incidence of overall concordance was seen in hematological, gastrointestinal, and cardiovascular HTs, and the least was seen in cutaneous HT. Where animal models, in one or more species, identified concordant HT, 94% were first observed in studies of 1 month or less in duration. These survey results support the value of in vivo toxicology studies to predict for many significant HTs associated with pharmaceuticals and have helped to identify HT categories that may benefit from improved methods.

Animals↗
PubMed2000

A human class II MHC-derived peptide antagonizes phosphatidylinositol 3-kinase to block IL-2 signaling.

MHC molecules bind antigenic peptides and present them to T cells. There is a growing body of evidence that MHC molecules also serve other functions. We and others have described synthetic peptides derived from regions of MHC molecules that inhibit T-cell proliferation or cytotoxicity in an allele-nonspecific manner that is independent of interaction with the T-cell receptor. In this report, we describe the mechanism of action of a synthetic MHC class II-derived peptide that blocks T-cell activation induced by IL-2. Both this peptide, corresponding to residues 65-79 of DQA*03011 (DQ 65-79), and rapamycin inhibit p70 S6 kinase activity, but only DQ 65-79 blocks Akt kinase activity, placing the effects of DQ 65-79 upstream of mTOR, a PI kinase family member. DQ 65-79, but not rapamycin, inhibits phosphatidylinositol 3-kinase (PI 3-kinase) activity in vitro. The peptide is taken up by cells, as demonstrated by confocal microscopy. These findings indicate that DQ 65-79 acts as an antagonist with PI 3-kinase, repressing downstream signaling events and inhibiting proliferation. Understanding the mechanism of action of immunomodulatory peptides may provide new insights into T-cell activation and allow the development of novel immunosuppressive agents.

Amino Acid Sequence↗
PubMed1997

A pharmacokinetic model describing pulsatile uptake of orally-administered carbon tetrachloride.

Many rodent bioassays have been conducted using oral gavage for delivery of test chemicals. Highly lipophilic compounds are generally administered to rodents dissolved in corn oil, a dosing vehicle shown to influence xenobiotic toxicity, carcinogenicity and pharmacokinetics by altering chemical absorption processes. In this paper, we present a multi-compartmental description of the gastrointestinal (GI) tract linked to a physiologically based pharmacokinetic (PB-PK) model to describe the complex oral uptake of carbon tetrachloride (CCl4) administered in corn oil and 0.25% Emulphor. The GI submodel was described using a series of subcompartments, each subcompartment described with an absorption constant (Ka, 1/h), a bioavailability term (A, unitless), and a compartment emptying time (T, h). The model was parameterized by fitting multi-peak blood and exhaled breath chamber concentration-time profiles following oral gavage of CCl4 in corn oil and aqueous vehicles to male Fischer 344 rats. Successful fitting of experimental data was accomplished by varying values of Ka, A, and T until adequate fits were obtained. Values of Ka and A required to fit data from aqueous gavage were greater than corn oil. Utilization of the multi-compartmental GI tract submodel provided increased precision in fitting complex oral uptake profiles compared to previously used one- and two-compartment oral uptake models. This model provides estimates of absorption rate constants and bioavailabilities as well as providing a framework for generation of more complete, physiologically-realistic descriptions of oral absorption.

Administration, Oral↗
PubMed1993

A G-protein beta-subunit is essential for Dictyostelium development.

Recent studies have demonstrated that G-protein-linked signal transduction pathways play a significant role in the developmental program of the simple eukaryotic organism Dictyostelium. We have reported previously the isolation of a G-protein beta-subunit and present here a more complete analysis of this gene. Low-stringency Southern blots and RFLP mapping studies suggest that the beta-subunit is a unique gene found on linkage group II. Its deduced amino acid sequence of 347 residues is approximately 60% identical to those of the human, Drosophila, and Caenorhabditis elegans beta-subunits. The carboxy-terminal 300 residues are about 70% identical; the amino-terminal 50 residues are quite divergent, containing only 10 identities. At all stages of growth and development, a single 1.9-kb beta-subunit mRNA is present at a high level, and a specific antibody detects a single 37-kD protein. We propose that G-protein heterotrimers are formed when this beta-subunit couples with each of the eight distinct G-protein alpha-subunits that are transiently expressed during development. Targeted disruption of the beta-subunit gene had no effect on the viability of haploid cells, but resulted in the inability of cells to aggregate.

Amino Acid Sequence↗
PubMed1992

The clinical use of ITI transmucosal implants.

The ITI implant system has a background of research and development of over 15 years. It is distinctive in that the implant fixtures are transmucosal from the time of placement, requiring only a single stage in surgical treatment. In a relatively simplified approach to prosthetic management, standard overdenture components and conventional fixed partial denture techniques are used. In this report the assessment, surgical treatment and post-operative management of patients using ITI Bonefit implants are described and early results from 168 consecutive fixtures placed over a period of 3 years indicated.

Adult↗
PubMed1992

Bar-retained overdentures for implants--technical aspects.

The principles of the laboratory procedures for making overdentures retained by bar abutments on ITI implant fixtures are described, and details of producing the master casts, making a soldered bar, and processing a prosthesis incorporating a cobalt-chromium alloy strengthener are given.

Chromium Alloys↗
PubMed1989

G-protein-linked signal transduction systems control development in Dictyostelium.

G-protein-linked cAMP receptors play an essential role in Dictyostelium development. The cAMP receptors are proposed to have seven transmembrane domains and a cytoplasmic C-terminal region. Overexpression of the receptor in cells, when the endogenous receptor is not present, results in a 10- to 50-fold increase in cAMP-binding sites. Antisense cell lines, which lack cAMP receptors, do not enter the developmental program. Ligand-induced phosphorylation is proposed to occur on serine and threonine residues in the receptor C-terminus. The kinetics of receptor phosphorylation and dephosphorylation correlate closely with the shift of receptor mobility and the adaptation of several cAMP-induced responses. Two alpha-subunits, G-alpha-1 and G-alpha-2, have been cloned and specific antisera developed against each. Both subunits are expressed as multiple RNAs with different developmental time courses. The mutant Frigid A has a functional defect in G-alpha-2 which prevents it from entering development. We propose that G-protein-linked receptor systems will be a major component in the development of many organisms.

Amino Acid Sequence↗
PubMed1981

Hyperphenylalaninaemia of various types among three-quarters of a million neonates tested in a screening programme.

A total of 795 382 infants born in north London was screened for phenylketonuria using the Guthrie test between October 1969 and December 1978. During this period it became recognised that phenylketonuria is not a single disease entity but one that encompasses a number of disorders of differing clinical and biochemical severity. The overall incidence of persistent hyperphenylalaninaemia was of the order of 7 per 100 000 births (or 1 in 15 000) and all the early treated patients made normal developmental progress. During the study there was an appreciable fall in the incidence of uncomplicated transient hyperphenylalaninaemia with or without tyrosinaemia. This reduction coincided with the change in infant feeding practice in the UK which led to lower intakes of protein and phenylalanine. It was concluded that any infant found to have a persistent blood phenylalanine concentration of 240 mumol/1 (4 mg/100 ml) or greater should be followed closely.

Amino Acids↗
PubMed1980

Population screening for congenital hypothyroidism.

A pilot screening programme for congenital hypothyroidism covering most of North London, Essex, Bedfordshire, and Hertfordshire entailed carrying out an assay of thyroid-stimulating hormone on single Guthrie dried blood spots. During one year 87 444 babies were screened and 26 cases of primary congenital hypothyroidism detected, giving an incidence of 1:3363. Only two cases (7.7%) had already been diagnosed on clinical grounds before the results of screening became available. In two other babies the diagnosis was delayed. The programme thus resulted in the early treatment of 22 babies, eight of whom already had pronounced features of hypothyroidism that had not been detected on routine clinical examinations. Although definitive evidence will not be available for some years, the results suggest that the prognosis for most of these babies is likely to be improved by early diagnosis; thus the introduction of national screening should be delayed no longer.

Congenital Hypothyroidism↗
PubMed1979

Changing incidence of neonatal hypermethioninaemia: implications for the detection of homocystinuria.

The Guthrie test was used to measure blood methionine concentrations in 670 764 neonates during the period from May 1970 to December 1977. Raised values (greater than 4 mg/100 ml; 268 mumol/l) were found in 147 babies (6--14 days old) and 55 of these still had raised values when retested 2--6 weeks later. 48 infants had transient hypermethioninaemia of at least 3 weeks' duration, one had a more persistent form associated with abnormal liver function tests, 3 had different forms of homocystinuria, and one infant, who was asymptomatic at the time of detection, had hypermethioninaemia associated with a rapidly fatal form of tyrosinamiea (tyrosinosis). Two infants could not be followed up. Transient hypermethioninaemia has not been detected in this laboratory since 1975. There was a greatly reduced incidence of transient hypermethioninaemia in girls after 1972 and in boys after 1975; this may have been due to recent changes in infant practices in the UK. Homocystinuria was last detected in this laboratory in 1972; the apparent change in incidence is significant (P less than 0.05) and suggests that the diagnostic value of this screening procedure should be reassessed.

Amino Acid Metabolism, Inborn Errors↗