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Biomedical subjects

S K Jones

Publications and source records attributed to S K Jones.

At least 19 recordsLinked to original sources
PubMed2005

Modelling heating of liver tumours with heterogeneous magnetic microsphere deposition.

Ferromagnetic embolization hyperthermia (FEH) is a novel treatment for liver cancer. Magnetic microspheres are injected into the hepatic artery and cluster in the periphery of tumours and are heated with externally applied magnetic fields. In order to more accurately simulate FEH, we modelled a three-dimensional heterogeneous distribution of heat sources. We constructed a fractal model of the vasculature in the periphery of a tumour. We used this model to compute the spatial distribution of the microspheres that lodge in capillaries. We used the distribution model as input to a finite-element heat transfer model of the FEH treatment. The overall appearance of the vascular tree is subjectively similar to that of the disorganized vascular network which encapsulates tumours. The microspheres are distributed in the tumour periphery in similar patterns to experimental observations. We expect the vasculature and microsphere deposition models to also be of interest to researchers of any targeted cancer therapies such as localized intra-arterial chemotherapy and selective internal radiotherapy. Our results show that heterogeneous microsphere distributions give significantly different results to those for a homogeneous model and thus are preferable when accurate results are required.

Embolization, Therapeutic↗
PubMed2005

Mathematical models for the early detection and treatment of colorectal cancer.

Colorectal cancer is a major cause of death for men and women in the Western world. When the cancer is detected through an awareness of the symptoms by a patient, typically it is at an advanced stage. It is possible to detect cancer at an early stage through screening and the marked differences in survival for early and late stages provide the incentive for the primary prevention or early detection of colorectal cancer. This paper considers mathematical models for colorectal cancer screening together with models for the treatment of patients. Illustrative results demonstrate that detailed attention to the processes involved in diseases, interventions and treatment enable us to combine data and expert knowledge from various sources. Thus a detailed operational model is a very useful tool in helping to make decisions about screening at national and local levels.

Colorectal Neoplasms↗
PubMed2003

A magnetic resonance imaging based method for measurement of tissue iron concentration in liver arterially embolized with ferrimagnetic particles designed for magnetic hyperthermia treatment of tumors.

Rabbit liver was loaded with ferrimagnetic particles of gamma -Fe2 O3 (designed for magnetic hyperthermia treatment of liver tumors) by injecting various doses of a suspension of the particles into the hepatic artery in vivo. Proton transverse relaxation rate (R(2)) images of the livers in vivo, excised, and dissected were generated from a series of single spin-echo images. Mean R(2) values for samples of ferrimagnetic-particle-loaded liver dissected into approximate 1 cm cubes were found to linearly correlate with tissue iron concentration over the range from approximately 0.1 to at least 2.7 mg Fe/g dry tissue when measured at room temperature. Changing the temperature of ferrimagnetic-particle-loaded samples of liver from 1 degrees C to 37 degrees C had no observable effect on tissue R(2) values. However, a small but significant decrease in R(2) was found for control samples containing no ferrimagnetic material on raising the temperature from 1 degrees C to 37 degrees C. Both chemically measured iron concentrations and mean R(2) values for rabbit livers with implanted tumors tended to be higher than those measured for tumor-free liver. This study indicates that tissue R(2) measurement and imaging by nuclear magnetic resonance may have a useful role in magnetic hyperthermia therapy protocols for the treatment of liver cancer.

Animals↗
PubMed2003

Nonsynchronized segmented heterochromia in black scalp hair.

Nonsynchronized segmented heterochromia in black scalp hair is a rarely reported entity, the only previous report being described in association with iron deficiency anaemia. A 14-year-old girl presented with a 2-year history of nonsynchronized segmented heterochromia. She was otherwise well and her serum iron, copper, zinc and protein levels were all within the normal range. She had no clinical evidence of vitiligo or alopecia areata. This patient is believed to represent the first reported case of nonsynchronized segmented heterochromia in black scalp hair as a presentation of premature greying of the hair.

Adolescent↗
PubMed2003

A randomised clinical trial of nicotine patches for treatment of spit tobacco addiction among adolescents.

BACKGROUND: This study tested the efficacy of nicotine patches in combination with behavioural therapy for the treatment of adolescent spit tobacco addiction. Prior interventions had resulted in mean cessation rates below 15% at one year. METHODS: This study, the PATCH Project, used a three group, placebo controlled, randomised clinical trial design. The control group received a standard 3-5 minute counselling followed by a two week follow up phone call. The two intervention groups received a six week behavioural intervention; in addition, one group received active nicotine patches while the other group received placebo patches. Both groups received quarterly stage based telephone counselling. RESULTS: At one year, the usual care group's spit tobacco cessation rate was 11.4% (exact 95% confidence interval (CI) 6.1% to 19.1%), placebo patch 25.0% (95% CI 16.9% to 34.7%), and the active patch 17.3% (95% CI 10.4% to 26.3%). When both patch groups were combined, the cessation rate was 21.2% (95% CI 15.7% to 27.6%). The cessation rates for active and placebo patch were not significantly different (exact two sided p = 0.22), while the combined patch groups had a significantly greater cessation rate than usual care (exact two sided p = 0.04). CONCLUSIONS: The behavioural intervention proved to be about twice as successful as previous interventions, but the nicotine patch offered no improvement in cessation rates. The behavioural intervention is based on publicly available materials and can be easily adapted for widespread use, particularly in high schools.

Administration, Topical↗
PubMed2001

Status of hyperthermia in the treatment of advanced liver cancer.

The vast majority of patients with malignant liver tumors have inoperable disease. These patients must rely on chemotherapy, radiotherapy, and various locoregional treatments. Although these treatments have demonstrated encouraging response rates, symptom palliation and occasional down staging of tumors, their impact on survival is minor. As a result there has been renewed interest in hyperthermia as a treatment option. This study reviews the current modalities of hyperthermia in terms of clinical results, side effects, limitations, and therapeutic standing.

Carcinoma, Hepatocellular↗
PubMed2001

Targeting liver tumors with hyperthermia: ferromagnetic embolization in a rabbit liver tumor model.

BACKGROUND AND OBJECTIVES: Ferromagnetic embolization hyperthermia (FEH) consists of arterially embolizing liver tumors with ferromagnetic particles, and then applying an external alternating magnetic field to generate hysteretic heating within the embolized particles. The objective of this study was to assess the ability of FEH to selectively target liver tumors with hyperthermia. METHODS: Twenty rabbits containing hepatic VX2 carcinomas were arterially infused with ferromagnetic particles suspended in lipiodol, and then exposed to an external alternating magnetic field. Temperatures in the tumor, normal hepatic parenchyma (NHP), and rectum were recorded. Tumour and NHP were chemically analyzed for iron content, which was then correlated with the observed heating rates. RESULTS: The mean tumor-to-NHP iron concentration ratio was 5.3:1 (P < 0.001, N = 20). The mean tumor heating rates were 3.0-11.5 times greater than those in the NHP (P < 0.001, N = 20). After 5 min of heating, the greatest increase in mean tumor temperature was 11.0 degrees C and the greatest increase in mean NHP temperature was 1.3 degrees C. There was a positive relationship between tumor iron concentration and heating rate (correlation coefficient = 0.82, P < 0.001, N = 20). A tumor iron concentration of 2-3 mg/g resulted in tumor heating rates of 0.5-1.0 degrees C/min. CONCLUSIONS: Hepatic arterial infusion of lipiodol containing ferromagnetic particles can result in excellent targeting of liver tumors with hyperthermia on the subsequent application of an external alternating magnetic field. The promising results of this study warrant further investigation of FEH as a potential treatment for advanced liver cancer.

Animals↗
PubMed2001

Experimental examination of a targeted hyperthermia system using inductively heated ferromagnetic microspheres in rabbit kidney.

It is known that significant heating can be generated by magnetic hysteresis effects in small ferromagnetic particles exposed to a rapidly alternating magnetic field. If such particles can be made to infiltrate the vascular bed surrounding a tumour by intravascular infusion then it may be possible to generate sufficient heating to destroy the tumour by hyperthermia. One of the constraints on such a technique is the limited amount of magnetic material that can be delivered to a tumour via the intravascular route and the consequent heating that can be induced by this material. Here, we report on a series of experiments in which doses of microspheres containing different amounts of ferromagnetic material were infused into rabbit kidneys via the renal artery with the aim of testing whether adequate tissue heating could be achieved using realistic concentrations of the embolised material. Heating rates were measured for each infused quantity under similar conditions with the animal alive and dead to examine the role of blood flow in the heating process. The results show that tissue temperatures above the therapeutic threshold of 42 degrees C can be readily achieved using this method with clinically relevant concentrations of microspheres in living tissue.

Animals↗
PubMed2000

Immunoassays for pentamidine and related compounds: development of a facile inhibitory ELISA suitable for clinical use.

Aromatic dicationic drugs have a broad spectrum of activity against protozoal and fungal pathogens including Pneumocystis carinii, Leishmania mexicana amazonensis, Cryptosporidium parvum and Cryptococcus neoformans. Pentamidine serves as the exemplar for an extensive collection of newly synthesized related compounds, which have reduced toxicity and a wider range of target organisms. Assays of pentamidine and related compounds have depended on HPLC-tandem mass spectrometry (HPLC-TMS) for the quantitation and identification of drug and metabolites. Immunoassays for pentamidine would have many advantages over the HPLC methods including relative simplicity of assay format and required equipment, convenience in sample preparation and reduction in time and cost of assays. In this report we describe a simple ELISA based immunoassay for pentamidine and pentamidine-like drugs with requisite sensitivity and specificity for use as a clinical assay (EC50 value of about 50 nanomolar). Immunogen was synthesized by coupling the hapten aminopentamidine to ovalbumin (chemically modified to provide an optimal number of -SH groups) using sulfo-MBS. Maleic-anhydride activated ELISA plates were covalently sensitized using the aminopentamidine hapten and used in an inhibitory ELISA assay format whereby the ability of analyte to suppress antibody binding to sensitized plate was measured. The assay detects primarily the phenolic amidine of pentamidine when in a para position and hence can also detect structurally related derivatives of pentamidine of potential interest as new therapeutic agents.

Animals↗
PubMed1999

Ocular toxicity and hydroxychloroquine: guidelines for screening.

Chloroquine and hydroxychloroquine (4-aminoquinolones) are used by dermatologists for the treatment of a wide range of disorders. It is widely recognized that their use may lead to ocular complications, but policies for ophthalmological screening and follow-up vary widely. In this article, the current literature on the ocular complications of antimalarials is reviewed, together with the results of a recent survey of dermatological practice on screening. New recommendations for ophthalmological screening recently produced by the Royal College of Ophthalmologists, the British Association of Dermatologists and the British Association of Rheumatologists are presented. It is recommended that baseline screening should include an assessment of renal and liver function, an enquiry about visual impairment and the recording of near visual acuity. Follow-up should comprise an enquiry about visual problems at each clinic visit and assessment of visual acuity once yearly. The multidisciplinary nature of the committee producing the new guidelines will hopefully mean that they will be acceptable to and usable by all those who routinely prescribe antimalarial drugs.

Antimalarials↗
PubMed1998

In vitro antifungal activities of a series of dication-substituted carbazoles, furans, and benzimidazoles.

Aromatic dicationic compounds possess antimicrobial activity against a wide range of eucaryotic pathogens, and in the present study an examination of the structures-functions of a series of compounds against fungi was performed. Sixty-seven dicationic molecules were screened for their inhibitory and fungicidal activities against Candida albicans and Cryptococcus neoformans. The MICs of a large number of compounds were comparable to those of the standard antifungal drugs amphotericin B and fluconazole. Unlike fluconazole, potent inhibitory compounds in this series were found to have excellent fungicidal activities. The MIC of one of the most potent compounds against C. albicans was 0.39 microg/ml, and it was the most potent compound against C. neoformans (MIC, </=0.09 microg/ml). Selected compounds were also found to be active against Aspergillus fumigatus, Fusarium solani, Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. Since some of these compounds have been safely given to animals, these classes of molecules have the potential to be developed as antifungal agents.

Antifungal Agents↗
PubMed1998

Anti-Pneumocystis activities of aromatic diamidoxime prodrugs.

Aromatic dicationic compounds, such as pentamidine, have potent antimicrobial activities. Clinical use of these compounds has been restricted, however, by their toxicity and limited oral activity. A novel approach, using amidoxime derivatives as prodrugs, has recently been proposed to overcome these limitations. Although results were presented for amidoxime derivatives of only one diamidine, pentamidine, the authors in the original proposal claimed that amidoxime derivatives would work as effective prodrugs for all pharmacologically active diamidines. Nine novel amidoxime derivatives were synthesized and tested in the present study for activity against Pneumocystis carinii in corticosteroid-suppressed rats. Only three of the nine compounds had significant oral anti-Pneumocystis activity. The bisbenzamidoxime derivatives of three direct pentamidine analogs had excellent oral and intravenous activities and reduced acute host toxicity. These compounds are not likely candidates for future drug development, however, because they have chronic toxic effects and the active amidine compounds have multiple sites susceptible to oxidative metabolism, which complicates their pharmacology and toxicology. Novel diamidoximes from three other structural classes, containing different groups linking the cationic moieties, lacked significant oral or intravenous anti-Pneumocystis activity, even though the corresponding diamidines were very active intravenously. Both active and inactive amidoximes were readily metabolized to the corresponding amidines by cell-free liver homogenates. Thus, the amidoxime prodrug approach may provide a strategy to exploit the potent antimicrobial and other pharmacological activities of selected, but certainly not all, aromatic diamidines.

Adrenal Cortex Hormones↗
PubMed1996

Complexes formed between calmodulin and the antagonists J-8 and TFP in solution.

The binding of the antagonists N-(8-aminooctyl)-5-iodonaphthalene-1-sulfonamide (J-8) and trifluoperazine (TFP) to intact calcium-saturated bovine calmodulin (CaM) and also of J-8 to the C-terminal domain (tr2c) has been investigated. Using a combination of NMR methods, including NOESY data, mobility measurements, and chemical shift and line-shape analysis, we show that the primary interaction between J-8 and tr2c is between the naphthalene ring of the antagonist and the hydrophobic pocket of the protein, similar to the binding of the hydrophobic side-chain residues of calmodulin target peptides. Comparison of the mobility of the drug, the intensity and pattern of intermolecular NOESY cross-peaks, and chemical shift changes shows that there is no significant change in the binding mode in J-8. CaM compared to J-8.tr2c, with one molecule binding to each domain. In particular, we find that the mobility of the aliphatic amino "tail" of J-8 remains highly mobile in both systems. This contrasts with the notion that the tail may bridge between the two domains to give a "globular" form of CaM. We also show that TFP induces very similar shift changes to J-8 and that the stoichiometry of the major binding event in all three cases is one drug molecule per domain. It also appears that secondary binding sites for the drug molecules are present in all three systems.

Animals↗
PubMed1995

Dicationic diarylfurans as anti-Pneumocystis carinii agents.

Seven dicationic 2,5-diarylfurans have been synthesized, and their interactions with poly(dA-dT) and the duplex oligomer d(CGCCAATTCGCG)2 were evaluated by Tm measurements. The inhibition of topoisomerase II isolated from Giardia lamblia, the inhibition of growth of G. lamblia in cell culture by these furans, and the effectiveness of these compounds against Pneumocystis carinii in the immunosuppressed rat model have been assessed. Strong binding affinities to poly(dA-dT) and to the oligomer were observed for the dicationic furans, and the interaction strength is directly correlated to the biological activity of the compounds. An X-ray structure for the complex of the dicationic amidine derivative, 2,5-bis(4-guanylphenyl)furan (1), with the oligomer demonstrates the snug fit of these compounds with the AATT minor-groove binding site and hydrogen bonds to AT base pairs at the floor of the minor groove. The stronger DNA binding molecules are the most effective inhibitors of topoisomerase II and G. lamblia in cell culture, and there is a correlation for both DNA interaction and topoisomerase II inhibition with the biological activity of these compounds against G. lamblia. Compound 1 is the most effective against P. carinii, it is more active and less toxic than pentamidine on intravenous administration and it is also effective by oral dosage. The results presented here suggest a model for the biological action of these compounds in which the dication first binds in the minor groove of DNA and forms a complex that results in the inhibition of the microbial topoisomerase II enzyme.

Animals↗
PubMed1994

Pentamidine congeners. 2. 2-butene-bridged aromatic diamidines and diimidazolines as potential anti-Pneumocystis carinii pneumonia agents.

We have synthesized cis and trans geometric isomers 1-8 as semirigid congeners of pentamidine. Compounds 1-4 were more potent than pentamidine in treating Pneumocystis carinii pneumonia in immunosuppressed rats. These compounds also demonstrated no clinical toxicity or histopathologic abnormalities. Introduction of methoxy substituents meta to the amidine or imidazoline groups of the phenyl rings as in compounds 5-8 generally resulted in compounds with decreased anti-P. carinii activity and increased toxicity to the host. Compounds 1-4 were evaluated as DNA binders. These compounds showed greater affinity for poly(dA).poly(dT) than for calf thymus DNA. The cis isomers, 1 and 2, demonstrated greater affinity for DNA than their trans counterparts 3 and 4. This difference in DNA binding affinity, however, did not reflect in a corresponding difference in the anti-P. carinii activity of these compounds.

Animals↗