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Biomedical subjects

R J Maxwell

Publications and source records attributed to R J Maxwell.

At least 37 records · Page 2Linked to original sources
PubMed1998

Supercritical fluid extraction of clenbuterol from bovine liver tissue.

The development of a supercritical fluid extraction procedure for the extraction of clenbuterol from bovine liver tissue is described. The procedure involves a combination of supercritical fluid extraction with enzyme immunoassay for the determination of clenbuterol residues at the low ppb level. Method validation incorporating inter- and intra-assays was carried out on fortified liver tissue and showed good recoveries and low variations (RSD < 15%) for levels of clenbuterol of 0.5, 2 and 5 ppb. The developed procedure was shown to be successful for the determination of clenbuterol in incurred liver tissue. The effects of organic modifiers and of inherent sample moisture on analyte extractability are also presented.

Adrenergic beta-Agonists↗
PubMed1997

Preclinical evaluation of the fluorinated 2-nitroimidazole N-(2-hydroxy-3,3,3-trifluoropropyl)-2-(2-nitro-1-imidazolyl) acetamide (SR-4554) as a probe for the measurement of tumor hypoxia.

A novel probe, N-(2-hydroxy-3,3,3,-trifluoropropyl)-2-(2-nitro-1-imidazolyl) acetamide (SR-4554), has been used to detect tumor hypoxia noninvasively by 19F magnetic resonance spectroscopy (19F MRS). The compound was designed to undergo a hypoxia-dependent, one-electron reduction to metabolites that are selectively retained in tumors and has attractive pharmacokinetic, toxicological, and detection sensitivity properties. As a prelude to clinical studies, we report here for the first time on the ability to detect a MR signal following SR-4554 administration in various transplantable tumors and describe validation studies, consisting of a correlation between signal retention and radiobiological hypoxic fraction, and the effects of modulating the degree of hypoxia by hydralazine and carbogen breathing. SR-4554 was absorbed and then eliminated from EMT6 tumors with a half-life of 51 min following an injection of 180 mg/kg i.p. of SR-4554. Using a quantitative 19F MRS technique, the 19F retention index (19FRI; 19F signal level at 6 h/45 min) was determined for four commonly used murine tumors (EMT6, SCCVII, KHT, and RIF-1). The retention of high tumor concentrations of fluorinated probe at 6 h, despite the much lower (20-fold) concentration of parent SR-4554 detected by high-performance liquid chromatography, was consistent with the involvement of one or more nitroreduced metabolites and suggested that 19F MRS might give a quantitative measure of tumor hypoxia. In these murine tumors, 19FRI correlated with the reported radiobiological hypoxic fraction of the tumors (r = 0.988; P = 0.01). In addition, changes in tumor microenvironment were detected by 19F MRS. An increase in hypoxia induced by hydralazine treatment of RIF-1 tumor-bearing mice was associated with a 2.4-fold increase in 19FRI compared to untreated controls. In contrast, carbogen breathing by C3H mammary tumor-bearing mice produced a 6-fold decrease in the 19FRI compared to air-breathing mice. The data presented support the preclinical and clinical development of SR-4554 as a noninvasive probe for tumor hypoxia.

Animals↗
PubMed1997

Varied prevalence of age-associated mitochondrial DNA deletions in different species and tissues: a comparison between human and rat.

The prevalence in tissues of mtDNA deletions was compared by PCR between humans and rats of similar "biological ages". Pairs of species-specific primers were used which spanned similar portions of the human and rat mtDNA genomes. There were much fewer PCR products amplified from rat mtDNA than from human mtDNA in each of the three tissues initially analysed: heart, liver and skeletal muscle. By contrast, many more PCR products were amplified from rat kidney than from human kidney. Therefore, while there were far more deletions in heart, liver and skeletal muscle of humans than in corresponding rat tissues, the prevalence of mtDNA deletions was markedly less in human kidney than in rat kidney. The data also indicate that human kidney contains less mtDNA deletions than heart, liver and skeletal muscle in humans; whereas in rat kidney there are more mtDNA deletions than in those three tissues of rat. It is further suggested that, when utilising rodents as experimental models for human ageing, the appropriate tissues should be considered, since not all tissues of rats accumulate mtDNA mutations in the same manner as those of humans.

Adolescent↗
PubMed1997

In vivo detection of ifosfamide by 31P-MRS in rat tumours: increased uptake and cytotoxicity induced by carbogen breathing in GH3 prolactinomas.

The direct detection and monitoring of anti-cancer drugs in vivo by magnetic resonance spectroscopy (MRS) may lead to improved anti-cancer strategies. 31P-MRS has been used to detect and quantify ifosfamide (IF) in vivo in GH3 prolactinomas and N-methyl-N-nitrosourea (MNU)-induced mammary tumours in rats. The average concentration of IF in the GH3 prolactinoma over the first 2 h following a dose of 250 mg kg-1 i.v. was calculated to be 0.42 micromol g-1 wet weight, with a half-life of elimination (t1/2) of 2-4 h. Carbogen (95% oxygen/5% carbon dioxide) breathing increased the amount of IF taken up by the GH3 prolactinoma by 50% (P<0.01) to 0.68 micromol g-1 wet weight, although t1/2 elimination rates were unchanged. IF was also detected in the liver in vivo, with a t1/2 of about 1 h. Carbogen breathing did not affect the maximum peak area (Cmax) or the t1/2 in the liver. Most importantly, the carbogen-induced increase in IF uptake by the tumour caused significant growth delay at all time points in the GH3 tumour growth between day 5 and day 12 (P< 0.01) compared with IF alone. These findings show that carbogen breathing has potential for increasing the efficacy of anti-cancer drugs. Isolated GH3 cells were sensitive to the parent drug (IF) in vitro (IC50 = 1.3 +/- 0.2 mM) suggesting that the GH3 cells may be either expressing P450 enzymes or are sensitive to the parent drug per se.

Animals↗
PubMed1997

The effect of hypoxia and hyperoxia on nucleoside triphosphate/inorganic phosphate, pO2 and radiation response in an experimental tumour model.

This study has evaluated the effect of breathing 100% oxygen, carbogen and carbon monoxide (at 660 p.p.m.) on the bioenergetic and oxygenation status and the radiation response of 200-mm3 C3H mammary carcinomas grown in the feet of CDF mice. Bioenergetic status was assessed by 31P magnetic resonance spectroscopy (MRS) using a 7-tesla spectrometer with both short (2 s) and long (6 s) pulse repetition times. Tumour partial pressure of oxygen (PO2) was measured with an Eppendorf polarographic electrode; the oxygenation parameters were the median pO2 and fraction of pO2 values < or = 2.5 mmHg. The radiation response was estimated using a tumour growth delay assay (time to grow three times treatment volume). Carbon monoxide breathing decreased tumour pO2 and compromised the radiation response, but the beta-nucleoside triphosphate (NTP)/Pi ratio was unchanged. Both carbogen and oxygen (100%) increased tumour pO2 and beta-NTP/Pi and enhanced the radiation response, the effects being similar under the two gassing conditions and dependent on the gas breathing time. Thus, in this tumour model, 31P-MRS can detect hyperoxic changes, but because cells can remain metabolically active even at low oxygen tensions the beta-NTP/Pi did not correlate with low tissue oxygenation. An analysis of variance showed that gas breathing time induced a significant systematic effect on beta-NTP/Pi, the MRS pulse repetition time had a significant effect on beta-NTP/Pi change under hypoxic but not under hyperoxic conditions and the type of gas that was inhaled had a significant effect on beta-NTP/Pi.

Administration, Inhalation↗
PubMed1996

Determination of melengestrol acetate in supercritical fluid-solid phase extracts of bovine fat tissue by HPLC-UV and GC-MS.

A method is developed for the determination of melengestrol acetate in bovine fat tissue at or less than the established tolerance level of 25 ppb. The procedure uses a combination of supercritical fluid extraction (SFE) and solid-phase extraction (SPE) techniques to produce an extract suitable for analysis with either high-performance liquid chromatography with ultraviolet detection or gas chromatography-mass spectrometry. Overall recovery of the analyte from bovine fat tissue is 99.4% with a coefficient of variation of 4.14%. The SFE-SPE procedure uses a total of 12 mL of organic solvent per fat tissue sample versus more than 1.7 L consumed in current extraction procedures.

Adipose Tissue↗
PubMed1996

Colitis complicating chronic granulomatous disease. A clinicopathological case report.

BACKGROUND: This report concerns a female patient now aged 24 years, diagnosed at the age of 7 years as suffering from chronic granulomatous disease. At age 20 she developed diarrhoea accompanied by rectal bleeding. Endoscopy showed extensive colitis. She failed to respond to medical treatment and underwent total colectomy two years later. AIMS: To discuss the histological changes in the colon in chronic granulomatous disease. RESULTS: There was extensive mucosal inflammation throughout colon and rectum resembling ulcerative colitis. In addition characteristic large pigmented macrophages were distributed in the basal mucosa and superficial submucosa. Similar cells accompanied by granulomata were present in mesenteric lymph nodes. CONCLUSIONS: Colitis is an unusual clinical manifestation of chronic granulomatous disease but the presence and characteristic distribution of such pigmented macrophages in colonic biopsy in children and young adults may suggest the diagnosis.

Adult↗
PubMed1996

Effect of hydralazine in spontaneous tumours assessed by oxygen electrodes and 31P-magnetic resonance spectroscopy.

Hydralazine can substantially decrease the blood flow, oxygen status and energy metabolism of transplanted tumours. In spontaneous tumours, two recent studies reported no effects of hydralazine on energy metabolism measured by 31P-magnetic resonance spectroscopy (31P-MRS), although another study saw changes in oxygen partial pressure (pO2) distributions measured with electrodes. We have now performed 31P-MRS and pO2 measurements in the same T138 spontaneous tumours, before and after intravenously (i.v.) injecting anaesthetised mice with 5 mg kg-1 hydralazine. Tumour pO2 was measured with an Eppendorf oxygen electrode and 31P-MRS spectra obtained with a 7-tesla SISCO magnet. Of 12 tumours all showed an increase in the percentage of pO2 values < or = 5 mmHg after hydralazine treatment and 10/12 showed a decrease in median pO2. The average (+/-1 s.e.) values for the percentage < or = 5 mmHg went from 45% (+/-9) to 79% (+/-5) and the median from 9 mmHg (+/-2) to 2 mmHg (+/-1). With the 31P-MRS 8/12 tumours showed an increase in the ratio of the peaks of inorganic phosphate to beta-nucleoside triphosphate with the average (+/-1 s.e.) values going from 1.1 (+/-0.2) to 2.4 (+/-0.9). Thus spontaneous tumours can respond to hydralazine and do so in a way consistent with that reported for transplanted tumours.

Animals↗
PubMed1995

Proton NMR observation of the antineoplastic agent Iproplatin in vivo by selective multiple quantum coherence transfer (Sel-MQC).

We have noninvasively detected the proton signal of an antineoplastic agent Iproplatin in vivo by selective multiple quantum coherence transfer (Sel-MQC). Without isotopic labeling or chemical modification, the Sel-MQC method labels Iproplatin by its intrinsic proton multiple quantum coherences and, hence, differentiates the Iproplatin signal from the intensive overlapping resonances of lipid and lactate. This proton NMR method should also be applicable to study other drugs with appropriate spin coupling patterns.

Animals↗
PubMed1995

Pharmacokinetics of the 13C labeled anticancer agent temozolomide detected in vivo by selective cross-polarization transfer.

The anticancer agent temozolomide labeled with 13C (8-Carbamoyl-3-13C-methylimidazo-[5,1-d]-1,2,3,5-tetrazin-4-(3H)-o ne), was noninvasively detected in subcutaneous RIF-1 tumors by a selective cross polarization 13C NMR method, at a field strength of 9.4T. Pharmacokinetics of the drug, at a dose of 150 mg/kg, were determined for intravenous and intraperitoneal models of administration (three animals per mode). The half-life of the drug in the tumors was approximately 60 min. The uptake and clearance of the drug, however, varied significantly between individual hosts, for both modes of administration. These results demonstrate the feasibility of obtaining pharmacokinetics of anticancer agents for individual tumors without the need for a label that might modify drug activity (e.g., fluorine). The variability of the in vivo measurements, even within the same tumor model, demonstrates the necessity of directly monitoring the tumor to evaluate drug pharmacokinetics.

Animals↗
PubMed1995

Why rationing is on the agenda.

The National Health Service Act of 1946 set out to provide a comprehensive health service, free at the point of use, to the whole population of the UK. The purpose-as Nye Bevan, then Minister of Health, put it-was to ensure that nobody should be denied, on the grounds of lack of means, 'the best that medical skill can provide'. Among the many fears about the Act voiced at the time, the idea that the State would not be able to afford it was not one. Indeed, that wise man William Beveridge had even mistakenly assumed, in the wartime White Paper on Social Security, that good health care would ultimately save money for the State, once an initial backlog of neglect had been made good, and that the cost of health insurance would then fall.

Child↗
PubMed1995

Can we do better?

In the introductory chapter, I claimed that rationing is a fact of life in the NHS, and that the rationing dilemma is worsening over time, primarily because what medicine can offer becomes vastly more sophisticated and in aggregate more expensive. What is implied in Nye Bevan's intent that every citizen should receive 'the best that medical skill can provide' is very different now from what it was in 1946 when the NHS Act was passed. And the going will be ever harder in the years ahead, since medical possibilities, offering genuine benefit for some, will continue to increase faster than national wealth.

Decision Making↗
PubMed1995

Significance of systemic endotoxaemia in inflammatory bowel disease.

Quantitative and qualitative disturbances in faecal flora suggest a role for enteric bacteria and their products in the pathogenesis of inflammatory bowel disease (IBD). This study investigated the hypothesis that systemically circulating endotoxins are of pathogenic significance in IBD by measuring antibody, cytokine, and acute phase protein responses. Systemic endotoxaemia was found in 88% patients with ulcerative colitis (n = 25) and 94% with Crohn's disease (n = 31) during clinical relapse. Systemic endotoxaemia correlated positively with anatomic extent and clinical activity of ulcerative colitis. Circulating tumour necrosis factor (TNF) was detected in 40% of patients with ulcerative colitis and 45% with Crohn's disease. Plasma TNF concentrations correlated with clinical and laboratory measures of disease activity and were associated with a surgical outcome to the disease episode. Plasma soluble TNF receptor p55 concentration correlated positively with disease activity and endotoxin core antibody concentrations. Plasma IgG endotoxin core antibody concentrations were significantly increased in patients with Crohn's disease and correlated with systemic endotoxaemia. The presence of systemic endotoxaemia, its correlation with disease activity, disease extent, and endotoxin core antibody concentration and the detection of circulating TNF and soluble TNF receptors all support a pathogenic role for endotoxins in IBD.

Adolescent↗