Biomedical subjects

John Caldwell

Publications and source records attributed to John Caldwell.

10 recordsLinked to original sources

PubMed2004

Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity.

Diclofenac is a nonsteroidal anti-inflammatory drug that causes rare but serious hepatotoxicity, the mechanism of which is unclear. The purpose of the present study was to explore the potential role played by the immune processes. Antibodies to diclofenac metabolite-modified liver protein adducts were detected in the sera of seven out of seven patients with diclofenac-induced hepatotoxicity, 12 of 20 subjects on diclofenac without hepatotoxicity, and none of four healthy controls. The antibodies recognized adducts expressed in livers from rats treated with multiple doses of diclofenac, but not in those given single doses. In addition, several potential diclofenac adducts were identified in the liver of a patient with diclofenac-induced hepatic failure, but not from a normal human donor liver, by immunoblotting with an adduct-selective rabbit antiserum. To determine whether or not polymorphisms in genes encoding cytokine-related proteins influence susceptibility to hepatotoxicity, genotyping for the polymorphisms -627 in the interleukin (IL)-10 gene, -590 in the IL-4 gene, and codon 551 in the IL-4 receptor (IL-4R) were performed on DNA from 24 patients on diclofenac with hepatotoxicity, 48 subjects on diclofenac without hepatotoxicity, and healthy controls. The frequencies of the variant alleles for IL-10 and IL-4 were higher in patients (OR [odds ratio]: 2.8 for IL-10; 2.6 for IL-4; 5.3 for IL-10 + IL-4) compared with healthy controls and subjects on diclofenac without hepatotoxicity (OR: 2.8 for IL-10; 1.2 for IL-4; 5.0 for IL-10 + IL-4). In conclusion, the observed polymorphisms, resulting in low IL-10 and high IL-4 gene transcription, could favor a T helper (Th)-2 mediated antibody response to neoantigenic stimulation associated with disease susceptibility.

Adult↗

PubMed2004

Pharmacogenetics and individual variation in the range of amino acid adequacy: the biological aspects.

There have been major developments in our understanding of the ways in which genetic variation among individuals in a population can affect responses to drugs, and use of such information can improve the safety and efficacy of medicines. The brief review summarizes the emergence of modern pharmacogenetics, illustrating the importance of the field using the CYP 2D6 polymorphism as a paradigm. These pharmacogenetic polymorphisms are compared and contrasted with the long-established inborn errors of amino acid biochemistry, exemplified by phenylketonuria, suggesting ways in which the approaches of pharmacogenetics might inform the safe and effective use of amino acids as food additives and supplements.

Amino Acid Metabolism, Inborn Errors↗

PubMed2003

A comparison of gene expression changes in response to diethylstilbestrol treatment in wild-type and p53+/- hemizygous knockout mice using focussed arrays.

We have investigated the hepatic response of female C57BL/6J wild-type and p53(+/-) hemizygous mice to genotoxic levels of diethylstilbestrol (DES) using cell cycle and apoptosis-focussed cDNA expression arrays. DES induced the expression of 12 genes (bad, bax, bcl-x, caspase-1, p53, cyclin D3, GADD45, p21, p15, p27, p57 and Skp1) and down-regulated the expression of eight genes (bcl-2, caspase-2, caspase-7, caspase-8, E124, iNOS, mdm2 and NFkappab1) at twofold or greater levels. Taken together, these changes were strongly reflective of the induction of apoptosis in the livers of DES-treated mice. Of those genes showing the greatest changes in response to DES, p53, p21 and p57 were expressed at 2.1, 1.7 and 1.6 times greater (respectively) in wild-type mice as compared with p53(+/-) hemizygous mice. Differences in p53, p21 and bax expression were confirmed by RT-PCR and we conclude that the compromised response of p53(+/-) mice is likely to play a central role in the earlier appearance of tumours in this model, following exposure to genotoxic carcinogens.

Animals↗

PubMed2003

Pretransitional population control and equilibrium.

A persistent theme in much anthropological writing is the concept of the deliberate control of population numbers by hunter-gatherers as a means of achieving moderate family size, adequate nutrition, and constrained adult mortality. An analysis of the mix of theory and field evidence that led to this conclusion finds the case not proven. On the contrary, Malthusian constraints can operate, and probably did operate, to produce a hunter-gatherer society where most adults were reasonably robust and healthy even though child mortality was high and life expectancy short. The absence of population limitation in pre-Neolithic times implies high mortality as well as high fertility, and weakens the argument positing a Neolithic mortality crisis.

Demography↗

PubMed2002

Protein binding of indobufen enantiomers: pharmacokinetics of free fraction-studies after single or multiple doses of rac-indobufen.

The binding of the enantiomers of indobufen (INDB) to human serum proteins was investigated using the racemic mixture or the pure (+)-S-enantiomer in a concentration range of 2.5-100.0 mg/L. In addition, the pharmacokinetics of free (unbound) and total INDB enantiomers were studied 1) following administration of a single 200 mg rac-INDB tablet to healthy volunteers, and 2) in obliterative atherosclerosis patients at steady state. The free fraction of INDB was obtained by ultrafiltration. Using the racemic mixture, the binding parameters of the two enantiomers were different, showing enantioselectivity in protein binding. The (-)-R-enantiomer was bound more strongly to human serum albumin, with association constant K = 11.95 +/- 0.98 x 10(5) M(-1) and n = 0.72 +/- 0.02 binding sites. The comparable data for the (+)-S-enantiomer were K = 4.65 +/- 0.02 x 10(5) M(-1), n = 0.92 +/- 0.01. When the binding of (+)-S-enantiomer was studied alone, the association constant K (2.10 +/- 0.18 x 10(5) M(-1)) was lower and the number of binding sites was increased, to n = 1.87 +/- 0.17. Competition occurred between the enantiomers, with the (-)-R-enantiomer displacing its antipode. The fraction of both enantiomers bound to serum proteins was 99.0%, which increased with decreasing initial concentration of the enantiomers. In healthy volunteers the (+)-S-enantiomer was eliminated faster than its (-)-R antipode, resulting in a lower AUC for the (+)-S-enantiomer. Significant differences were observed in the total INDB enantiomer concentrations. The mean unbound fraction of (-)-R- and (+)-S-INDB was 0.45% and 0.43%, respectively. Levels of the free (+)-S-enantiomer were higher than its (-)-R-antipode at steady state in patients with obliterative atherosclerosis who also took other drugs. The free enantiomer fraction increased to around 1% upon repeated administration. We conclude that the more rapid elimination of the (+)-S enantiomer is associated with its weaker binding to serum proteins.

Adult↗

PubMed2002

Putting chirality to work: the strategy of chiral switches.

Most of the new drugs reaching the market today are single enantiomers, rather than the racemic mixtures that dominated up to ten years ago. Many of the new single-enantiomer drugs were developed as such, but there are also important examples of new single-enantiomer drugs derived from 'chiral switches' of established racemates. Indeed, a well-timed chiral switch can offer enhanced therapy and further profitability as a 'line extension' of a major racemic drug with patents that are expiring.

Animals↗

PubMed2002

Fluconazole mouthrinses for oral candidiasis in postirradiation, transplant, and other patients.

OBJECTIVE: Oral candidiasis is associated with multiple local and systemic factors. Morbidity and deaths, in high-risk patients, may be prevented by recognition and adequate management. Fluconazole is a systemic antifungal medication that demonstrated clinical advantages in rinsing before swallowing. The purpose of the present study was to evaluate the clinical efficacy of fluconazole aqueous mouthrinses to treat oral candidiasis. METHODS: Ten women and 9 men diagnosed with oral candidiasis used fluconazole (2 mg/mL) aqueous solution 3 times per day as a rinse and-spit topical treatment. The outcome was assessed after 1 week of treatment. RESULTS: Complete symptomatic and clinical relief was noted in 94% of the patients, and a mycologic cure was documented in all but 1 patient. No side effects were reported. Oral rinses with fluconazole suspension may be useful to manage patients with dry mouth or those who have difficulties in swallowing caused by oral candidiasis. CONCLUSIONS: Further double-blind studies are needed to establish the optimal treatment regimen and the usefulness of fluconazole mouthrinses in patients with different risk factors for infection.

Adult↗

PubMed2002

Evolutionary computational methods to predict oral bioavailability QSPRs.

This review discusses evolutionary and adaptive methods for predicting oral bioavailability (OB) from chemical structure. Genetic Programming (GP), a specific form of evolutionary computing, is compared with some other advanced computational methods for OB prediction. The results show that classifying drugs into 'high' and 'low' OB classes on the basis of their structure alone is solvable, and initial models are already producing output that would be useful for pharmaceutical research. The results also suggest that quantitative prediction of OB will be tractable. Critical aspects of the solution will involve the use of techniques that can: (i) handle problems with a very large number of variables (high dimensionality); (ii) cope with 'noisy' data; and (iii) implement binary choices to sub-classify molecules with behavior that are qualitatively different. Detailed quantitative predictions will emerge from more refined models that are hybrids derived from mechanistic models of the biology of oral absorption and the power of advanced computing techniques to predict the behavior of the components of those models in silico.

Animals↗

PubMed2001

Stereochemistry: definitions and a note on nomenclature.

The impact of stereochemistry in medicine is increasingly being felt with the realisation of the therapeutic potential offered by single enantiomers. Consequently, a basic comprehension of the terminology and nomenclature used in stereochemistry is becoming a requirement for many researchers and clinicians. The first aim of this article is to familiarise readers with some of the well-established terms used to define key principles in stereochemistry. The issue of nomenclature in stereochemistry can be confusing to the uninitiated. A search through the literature reveals a number of different designation systems, some of which may not be interchangeable or may be obsolete. The second aim of this article is, therefore, to clarify this issue. It is hoped that this article will assist the reader of this supplement, as well as facilitate the interpretation of both new and existing literature concerning enantiomeric drugs. Copyright 2001 John Wiley & Sons, Ltd.

Journal Article↗

PubMed2001

Do single enantiomers have something special to offer?

Single enantiomers have a significant role to play in enhancing drug discovery and development. Researchers are overcoming the technical limitations associated with developing single enantiomers, and the growth in targeted drug development already means that more single enantiomers are developed ab initio. Moreover, as pharmaceutical companies decide whether to progress a single enantiomer, rather than a racemate, early in development, increasingly fewer racemates will reach the market. Developing a single enantiomer as a line extension of a profitable drug is of growing importance and is reflected in the increasing number of speculative patents on chiral switches. The implications are that single enantiomers will eventually touch every area of clinical medicine. As the number of chiral drugs launched onto the market increases, so clinicians need to be aware of the key issues surrounding enantiomers. This review examines some of the issues arising from the growing importance of enantiomers in medicine. Copyright 2001 John Wiley & Sons, Ltd.

Journal Article↗