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Biomedical subjects

R W Middleton

Publications and source records attributed to R W Middleton.

At least 19 recordsLinked to original sources
PubMed2002

Effect of kava and valerian on human physiological and psychological responses to mental stress assessed under laboratory conditions.

This study investigated whether kava or valerian could moderate the effects of psychological stress induced under laboratory conditions in a group of healthy volunteers. Fifty-four participants performed a standardized colour/word mental stress task on two occasions 1 week apart. Blood pressure (BP), heart rate (HR) and subjective ratings of pressure were assessed at rest and during the mental stress task. Following the first session (time 1 = T1), individuals took a standard dose of kava (n = 18), or valerian (n = 18) for 7 days, while the remainder acted as controls (n = 18). Differences in BP and HR from resting levels were calculated as reactions to the stress task at both time points. At the second session (time 2 = T2) there was a significant decrease in systolic BP responsivity in both the kava and valerian groups relative to T1, but there were no significant reductions in diastolic BP. Between T1 and T2, the HR reaction to mental stress was found to decline in the valerian group but not in the kava group. Individuals taking kava or valerian reported less pressure during the task at T2 relative to T1. There were no significant differences in BP, HR or subjective reports of pressure between T1 and T2 in the controls. Behavioural performance on the colour/word task did not change between the groups over the two time points. The results suggest that kava and valerian may be beneficial to health by reducing physiological reactivity during stressful situations.

Adolescent↗
PubMed2002

Bromelain reduces mild acute knee pain and improves well-being in a dose-dependent fashion in an open study of otherwise healthy adults.

There is preliminary clinical evidence to support the contention that the anti-inflammatory and analgesic properties of bromelain help to reduce symptoms of osteo- and rheumatoid arthritis. However, there have been no controlled studies of its effects on joint health in healthy subjects who lack such diagnosis. The current study investigated the effects of bromelain on mild acute knee pain of less than 3 months duration in otherwise healthy adults. The study was an open, dose-ranging postal study in volunteers who had been recruited through newspaper and magazine articles. Two validated questionnaires (WOMAC knee health Index and the Psychological Well-Being Index) were completed at baseline and after one month's intervention with bromelain, randomly allocated to volunteers as either 200 mg or 400 mg per day. Seventy seven subjects completed the study. In both treatment groups, all WOMAC symptom dimension scores were significantly reduced compared with baseline, with reductions in the final battery (total symptom score) of 41 and 59% (P = 0.0001 and <0.0001) in the low and high dose groups respectively. In addition, improvements in total symptom score (P = 0.036) and the stiffness (P = 0.026) and physical function (P = 0.021) dimensions were significantly greater in the high-dose (400 mg per day) compared with the low-dose group. Compared to baseline, overall psychological well-being was significantly improved in both groups after treatment (P = 0.015 and P = 0.0003 in the low and high dose groups respectively), and again, a significant dose-response relationship was observed. We conclude that bromelain may be effective in ameliorating physical symptoms and improving general well-being in otherwise healthy adults suffering from mild knee pain in a dose-dependant manner. Double blind, placebo-controlled studies are now warranted to confirm these results.

Acute Disease↗
PubMed2002

Artichoke leaf extract reduces mild dyspepsia in an open study.

A recent post-marketing study indicated that high doses of standardised artichoke leaf extract (ALE) may reduce symptoms of dyspepsia. To substantial these findings, this study investigated the efficacy of a low-dose ALE on amelioration of dyspeptic symptoms and improvement of quality of life. The study was an open, dose-ranging postal study. Healthy patients with self-reported dyspepsia were recruited through the media. The Nepean Dyspepsia Index and the State-Trait Anxiety Inventory were completed at baseline and after 2 months of treatment with ALE, which was randomly allocated to volunteers as 320 or 640 mg daily. Of the 516 participants, 454 completed the study. In both dosage groups, compared with baseline, there was a significant reduction of all dyspeptic symptoms, with an average reduction of 40% in global dyspepsia score. However, there were no differences in the primary outcome measures between the two groups, although relief of state anxiety, a secondary outcome, was greater with the higher dosage (P = 0.03). Health-related quality of life was significantly improved in both groups compared with baseline. We conclude that ALE shows promise to ameliorate upper gastro-intestinal symptoms and improve quality of life in otherwise healthy subjects suffering from dyspepsia.

Cholagogues and Choleretics↗
PubMed2001

Artichoke leaf extract reduces symptoms of irritable bowel syndrome in a post-marketing surveillance study.

Irritable bowel syndrome (IBS) is a problem reported to affect 22% of the general population. It is characterized by abdominal pain and altered bowel habit, but has so far defied elucidation of its pathogenesis and proved difficult to treat. There is a growing body of evidence which indicates therapeutic properties for artichoke leaf extract (ALE). Dyspepsia is the condition for which the herb is specifically indicated, but the symptom overlap between dyspeptic syndrome and IBS has given rise to the notion that ALE may have potential for treating IBS as well. A sub-group of patients with IBS symptoms was therefore identified from a sample of individuals with dyspeptic syndrome who were being monitored in a post-marketing surveillance study of ALE for 6 weeks. Analysis of the data from the IBS sub-group revealed significant reductions in the severity of symptoms and favourable evaluations of overall effectiveness by both physicians and patients. Furthermore, 96% of patients rated ALE as better than or at least equal to previous therapies administered for their symptoms, and the tolerability of ALE was very good. These results provide support for the notion that ALE has potential value in relieving IBS symptoms and suggest that a controlled trial is justified.

Asteraceae↗
PubMed1992

Bioreductive fluorescent markers for hypoxic cells: a study of 2-nitroimidazoles with 1-substituents containing fluorescent, bridgehead-nitrogen, bicyclic systems.

The oxygen-sensitive bioreductive binding of 2-nitroimidazoles labeled with fluorescent side chains has been used to stain hypoxic mammalian cells selectively. Several novel compounds were synthesized with a 1-substituent containing a fluorescent, bicyclic system having a bridgehead-nitrogen atom. Additional amine and secondary alcohol substituents were also included in the link between the fluorophor and the nitroimidazole to improve water solubility. Their ability to discriminate between hypoxic and oxic cells was compared by flow cytometric analysis. A wide range of cellular fluorescence and hypoxic-oxic differentials in fluorescence was observed when compounds with indolizine fluorophors were incubated with cells, and one such compound was considered suitable for further evaluation in vivo. Two compounds with bimane fluorophors gave very little cellular fluorescence when incubated with hypoxic cells.

Animals↗
PubMed1991

Fluorescent markers for hypoxic cells. A study of novel heterocyclic compounds that undergo bio-reductive binding.

The bioreductive metabolism and binding of nitroaromatic compounds has been suggested as a method for the identification of hypoxic tumour cells. Bound metabolites of suitable nitroaryl compounds (and some other reducible aromatic compounds) may fluoresce, offering an alternative to radiolabelling or NMR etc. as a diagnostic method. In this paper, the synthesis of some heteroaromatic nitro-compounds is given together with the results obtained from testing of these and other mainly nitroaromatic compounds in vitro as potential bioreductive fluorescent probes for hypoxic cells in tumours. Compounds were incubated with oxygenated or hypoxic mammalian cell suspensions for various times before evaluation of the cellular fluorescence from bioreductive metabolites by fluorescence microscopy and flow cytometry. Among those compounds yielding fluorescent metabolites in cells, considerable variation in hypoxic:oxic differential fluorescence was observed. The in vitro mammalian cell test system showed several of the compounds to be sufficiently promising to merit further investigation in vivo.

Animals↗
PubMed1991

Fluorescent markers for hypoxic cells: a study of nitroaromatic compounds, with fluorescent heterocyclic side chains, that undergo bioreductive binding.

Several novel compounds having both a 2-nitroimidazole nucleus and a fluorescent ring system in their molecular structure were prepared and evaluated as potential fluorescent probes for hypoxia. Bioreduction of nitroimidazoles, which is inhibited by oxygen, is known to lead to binding of bioreductive metabolites to cellular macromolecules and this provides a mechanism for binding the fluorescent moiety to hypoxic cells. These compounds can incorporate a wide range of fluorophors and can therefore be designed to suit the laser-line wavelengths available for excitation of fluorescence in the flow cytometer. Several nitroimidazoles with naphthalimide side chains were rapidly taken up into cells and became concentrated in the cells, thus reducing their concentration in the extracellular medium. This suggests a potential microscopic bioavailability problem with probes of this type when used in vivo as they would become progressively depleted in the extracellular fluid as they diffused from blood vessels, through layers of packed cells in tumors, to the hypoxic cells where they could undergo hypoxia-specific metabolism. Synthesis of nitroimidazoles with coumarin fluorophors led to several potentially useful probes for hypoxia; substituents on the coumarin fluorophor had a marked effect on the cellular fluorescence of these compounds.

Animals↗
PubMed1987

Toxicity of 3-nitronaphthalimides to V79 379A Chinese hamster cells.

The cellular uptake and toxicity of a number of substituted 3-nitronaphthalimides was investigated. Uptake of these compounds into cells was initially rapid and reached a plateau after several hours, where in some cases intracellular concentrations were much greater than the corresponding extracellular concentrations. Little uptake was obtained, however, with a compound carrying an acidic substituent. Toxicity studies divided the compounds into two main groups; those where survival curves were convex and those where survival curves were concave. The shapes of survival curves of the latter group did not appear to reflect depletion of extracellular drug. Uptake and toxicity of different drugs were not well correlated and bioreductive metabolism of the nitro-substituent did not appear to be a major contributor to toxicity. There was no consistent differential toxicity of these drugs in aerobic and hypoxic conditions. It was concluded that the nature of the ring substituent had more effect on toxicity than the absolute concentration of the naphthalimide ring or bioreductive metabolism of the nitro-group.

Aerobiosis↗
PubMed1987

Percutaneous intramedullary rod interchange in osteogenesis imperfecta.

This paper describes the design, development and early surgical experience with a stereotactic device to allow closed retrieval and interchange of intramedullary rods in children with osteogenesis imperfecta. This relatively atraumatic procedure may allow more frequent rod interchange than with other techniques, lessening the likelihood of deformity and fracture in the unsupported skeleton when the bone has outgrown the intramedullary rod. The procedure was developed by design studies in vitro followed by intramedullary rodding of tibiae of New Zealand white rabbits. It has been used in children 12 times, in six tibiae and six femora: 11 rods have been successfully retrieved, with rod interchange in eight of these cases.

Animals↗
PubMed1985

Effects of glutathione depletion using buthionine sulphoximine on the cytotoxicity of nitroaromatic compounds in mammalian cells in vitro.

The inhibitor of glutathione biosynthesis, buthionine sulphoximine (BSO) has been used to deplete endogenous thiols in mammalian cells in vitro. The effect of such depletion on the toxicity of nitroaromatic compounds has been investigated. Substantial enhancement of both aerobic and hypoxic toxicity of the 2-nitroimidazole, misonidazole is observed in thiol-depleted cells; the hypoxic toxicities of metronidazole, nitrofurantoin and nimorazole are also increased by thiol depletion. These data of significance for the potential combined use of BSO with nitroaromatic radiosensitizers to increase their radiosensitizing efficiency in radiotherapy, and as a potential method for enhancing the efficiency of anti-protozoal nitroaromatic drugs.

Animals↗
PubMed1985

Fluorescent markers of hypoxic cells: a comparison of two compounds on three cell lines.

Two compounds, nitroakridin 3582 (NA) and a 3-nitro-naphthalimide (DM113), have been tested as potential fluorescent markers for hypoxic cells. Cellular fluorescence in three cell lines (V79-379A, WHF1B, EMT6) was measured by flow cytometry and high-performance liquid chromatography (HPLC) after incubating the cells with the drugs for various times in air or hypoxia. In all three cell lines, both drugs showed greater fluorescence in hypoxic than in oxic cells. There were, however, differences between the cell lines in respect of the magnitudes of hypoxic and oxic cell fluorescence and in the ratio of hypoxic to oxic fluorescence. Differences in hypoxic cell fluorescence were due to differences in the rate and extent of nitroreduction. Drug uptake and DNA content per cell were relatively unimportant factors in determining the magnitude of fluorescence. There was not a good correlation between cytotoxicity of the drugs and hypoxic fluorescence. Nitroakridin was more toxic to hypoxic than to aerated cells but the reverse was true for DM113. The dependence of fluorescence and radiosensitivity on oxygen concentration were compared for the three cell lines and only small differences between the "K"-curves for the two end-points were found. Two problems with the present compounds which should be addressed in designing future fluorogenic compounds as hypoxic markers were oxic cell fluorescence and leakage of fluorescent products from hypoxic cells.

Aminacrine↗
PubMed1984

Nitroaryl compounds as potential fluorescent probes for hypoxia. I. Chemical criteria and constraints.

Cellular reduction of nitroaryl compounds is efficiently inhibited by oxygen, and detection of products characteristic of reduction could form the basis for diagnostic tests for the presence of hypoxic cells in tumors. The criteria for suitable compounds include a high sensitivity and selectivity of detection response between oxic and hypoxic cells, which can be provided using fluorescence detection and suitable nitroaryl compounds which have very low fluorescence until reduced. Examples described include a nitroacridine and nitronaphthalimides. Although the intercalating ability of these ring systems lead to high sensitivity for detection of reduced metabolites in vitro by flow cytometry, poor bioavailability is an unwanted consequence of intercalation. The application of several model reducing systems for reduction of potential fluorescent probes for hypoxia is described, and the absorption and fluorescence spectral characteristics of other examples of structures which could form the basis for useful probes are outlined.

Aminacrine↗
PubMed1984

Nitroaryl compounds as potential fluorescent probes for hypoxia. II. Identification and properties of reductive metabolites.

Nitroakridin 3582 (NA) and a nitronaphthalimide (DM113), which fluoresce only upon reduction, have been studied by HPLC. V79-379A cells incubated with NA under 20% or 2% O2 and N2 gave increasing amounts of the fluorescent amine with an hypoxic:oxic differential of 160. Measurement of the uptake of NA showed that it was concentrated within the cell by over 1000-fold. Studies in 3 different cell lines of reduction under hypoxia showed a 7-fold range in amine production. DM113 yields more than one fluorescent product, which show different absorption and fluorescence spectra. Chemical reduction of NA or DM113 using a variety of methods gave, depending on conditions, amine and/or (what was presumed to be) hydroxylamine; the latter was non-fluorescent. In vivo, NA is toxic at greater than 0.19 mumol g-1. At this dose much of the drug is found in the liver and kidneys. Plasma levels at 30 minutes are only 2 microM while tumor concentrations are 10 microM compared to 600 microM in the liver. However, the half life is greater than 1 hr and amine was detectable in these tumors.

Aminacrine↗
PubMed1984

Enhancement of misonidazole radiosensitization by buthionine sulphoximine.

The influence of glutathione (GSH) depletion on the radiation response and on the radiosensitizing efficiency of misonidazole (miso) has been studied in two types of mouse tumour and in mouse skin. Buthionine sulphoximine (BSO) has been administered in a variety of regimes, leading to a maximal depletion of GSH to 37% of control values in one tumour (CA MT) and 61% in the other (SA FA). Pretreatment with BSO did not alter the radiosensitivity of either tumour when treated with X-rays. It had a slight effect on the sensitizing efficiency of miso, corresponding to a factor less than three, which was detectable only at the highest X-ray doses used. No enhancement of miso efficiency was seen with 5 daily fractions. Prolonged administration of BSO resulted in a slight radiosensitization of mouse skin. When combined with miso the effect was very small and was only detectable at high X-ray doses. BSO however produced a marked enhancement of the acute toxicity of miso, as judged by lethality after large single doses.

Animals↗
PubMed1984

Supracondylar osteotomy of the humerus for correction of cubitus varus.

Cubitus varus is the most common complication of supracondylar fracture of the humerus in children. Although function of the elbow is not greatly impaired, the deformity is unsightly. It usually results from malunion, since growth disturbance of the humerus after this fracture is uncommon. The normal carrying angle can be restored by supracondylar osteotomy. This operation was done in 32 patients over a ten-year period, 16 of them using the technique described by French (1959). The results in 27 patients are reviewed in the light of previous reports. French's method proved safe and satisfactory.

Child↗
PubMed1984

Closed intramedullary rodding for osteogenesis imperfecta.

Three cases of severe osteogenesis imperfecta are reported. Each was treated by closed intramedullary rodding, combined with osteoclasis to correct deformity. Operation was performed within a few months of birth. Both tibiae and both femora were stabilised in one operation, using x-ray image intensification to monitor placement of the rods. The technique used to insert the rods is described. The procedure appeared to be entirely satisfactory in reducing the incidence of fractures and it allowed the affected infants to be handled much more easily.

Femur↗