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Biomedical subjects

M Hurst

Publications and source records attributed to M Hurst.

At least 19 recordsLinked to original sources

Oestrogens and oestrogenic activity in raw and treated water in Severn Trent Water.

Sewage effluent discharged to surface water has been shown to contain human hormones, particularly oestrogens, and synthetic chemicals which may be able to disrupt the endocrine system. Since many surface waters which receive sewage effluent are subsequently used as drinking water sources, it is important to demonstrate that treated drinking water is not contaminated. Oestrogenic activity in rivers and drinking water in the region of Severn Trent Water was studied using a combination of bioassay, to integrate exposure over time, and advanced chemical analysis. There was little or no evidence of substances that were oestrogenic, even in waters receiving significant amounts of sewage effluent. Oestrogenic activity, as measured in the rainbow trout vitellogenin assay, was seen at the Tame/Trent confluence but this activity was relatively weak. There was no activity detected at raw water intakes and no hormones or substances that are oestrogenic were detected in the final drinking water.

Animals↗

Magnetic resonance imaging as the primary imaging modality in children presenting with acute non-traumatic hip pain.

The role of magnetic resonance imaging (MRI) in children presenting with acute non-traumatic hip pain was evaluated prospectively. Hip MRI was performed in addition to standard investigations (arthrosonography +/- hip radiographs) in 50 children presenting to the accident and emergency department of a paediatric hospital. MRI was performed on an open 0.23T system and comprised gradient echo T1 weighted coronal, fast spin echo T2 weighted coronal and inversion recovery spin echo (IRSE) axial sequences. Diagnostic quality MRI examinations were obtained in 94% of children. The IRSE sequence was the most reliable at determining underlying disorder (p<0.002). Interobserver agreement on the MRI examinations was very good with unweighted kappa value of 0.89, 95% confidence intervals 0.79, 0.99. Sensitivity of MRI was 0.79 (0.68, 0.90, specificity 1.00 (0.89, 1.00), accuracy 0.81 (0.70, 0.92), PPV 1.00 (0.89, 1), NPV 0.36 (0.25, 0.47). Sensitivity of standard imaging was 0.70 (0.54-0.86), specificity 0.57 (0.41, 0.73), accuracy 0.72 (0.56, 0.88), PPV 0.91 (0.75, 1.00), NPV 0.24 (0.08, 0.40). MRI correctly identified all seven children with serious underlying disorder whereas conventional imaging correctly diagnosed only two. Pelvic musculoskeletal infection was associated with the combination of marked alteration in signal in tissues adjacent to a symptomatic hip and an erythrocyte sedimentation rate of >20 mm 1st h (p<0.0001). In conclusion, MRI is a practical, well accepted and accurate non-invasive imaging technique in children presenting with acute non-traumatic hip pain. Combined with inflammatory markers MRI can be used to determine those children who require aggressive management. Where it is available, MRI is the imaging modality of choice in this condition.

Adolescent↗

Perindopril: an updated review of its use in hypertension.

UNLABELLED: Perindopril erbumine (perindopril) is a prodrug ester of perindoprilat, an angiotensin converting enzyme (ACE) inhibitor. Perindopril 4 to 8 mg once daily significantly reduces supine systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline values in hypertensive patients. These reductions are maintained for at least 24 hours, as evidenced by trough/peak ratios of >50%. Vascular abnormalities associated with hypertension were improved or normalised during perindopril treatment. Perindopril 4 to 8 mg once daily significantly decreased carotid-femoral aortic pulse wave velocity (PWV), improved arterial compliance, reduced left ventricular mass index and, in patients with recent cerebral ischaemia and/or stroke, preserved cerebral blood flow despite significantly reducing SBP and DBP. Further research is needed to establish the significance of promising results showing that reductions in aortic PWV were associated with reduced mortality in patients with end-stage renal failure, a third of whom received perindopril. Response rates (numbers of patients with supine DBP < or = 90 mm Hg) were significantly higher with perindopril 4 to 8 mg once daily (67 to 80%) than with captopril 25 to 50 mg twice daily (44 to 57%) in 3 randomised double-blind trials. In other clinical trials, the antihypertensive effects of perindopril were similar to those of other ACE inhibitors (including enalapril) and calcium-channel antagonists. Combination treatment with perindopril and an antihypertensive agent from another treatment class provided additional benefits, either as first-line treatment or in patients failing to respond to monotherapy. Perindopril monotherapy was also effective in the elderly and in patients with hypertension and concomitant disease. Perindopril has a similar adverse event profile to that of other ACE inhibitors; cough is the most common event reported during treatment, and is also the most common adverse event responsible for treatment withdrawal. CONCLUSIONS: Perindopril is a well tolerated ACE inhibitor that is significantly better than captopril (in terms of response rates) in the treatment of hypertension, and as effective as other ACE inhibitors. Perindopril appears to reverse some of the vascular abnormalities associated with hypertension, including arterial stiffness and left ventricular hypertrophy, although further research is needed to confirm promising results regarding its ability to decrease associated cardiovascular morbidity and mortality. Results from ongoing studies will help confirm the place of perindopril in the treatment of hypertension; currently, it is an effective and well tolerated treatment for patients with mild to moderate essential hypertension.

Angiotensin-Converting Enzyme Inhibitors↗

Paclitaxel: a pharmacoeconomic review of its use in non-small cell lung cancer.

UNLABELLED: A number of first-line chemotherapy options for patients with advanced non-small cell lung cancer (NSCLC) are advocated in treatment guidelines and/or by various clinical investigators. Platinum-based chemotherapy has clearly demonstrated efficacy in patients with advanced NSCLC and is generally recommended as first-line therapy, although there is increasing interest in the use of non-platinum chemotherapy regimens. Among the platinum-based combinations currently used in clinical practice are regimens such as cisplatin or carboplatin combined with paclitaxel, vinorelbine, gemcitabine, docetaxel or irinotecan. The particular combinations employed may vary between institutions and geographical regions. Several pharmacoeconomic analyses have been conducted on paclitaxel in NSCLC and most have focused on its use in combination with cisplatin. In terms of clinical efficacy, paclitaxel-cisplatin combinations achieved significantly higher response rates than teniposide plus cisplatin or etoposide plus cisplatin (previously thought to be among the more effective regimens available) in two large randomised trials. One of these studies showed a survival advantage for paclitaxel plus cisplatin [with or without a granulocyte colony-stimulating factor (G-CSF)] compared with etoposide plus cisplatin. A Canadian cost-effectiveness analysis incorporated data from one of the large randomised comparative trials and showed that the incremental cost per life-year saved for outpatient administration of paclitaxel plus cisplatin versus etoposide plus cisplatin was $US 22181 (30619 Canadian dollars; $Can) [1997 costs]. A European analysis incorporated data from the other large randomised study and showed slightly higher costs per responder for paclitaxel plus cisplatin than for teniposide plus cisplatin in The Netherlands ($US 30769 vs $US 29592) and Spain ($US 19 923 vs $US 19724) but lower costs per responder in Belgium ($US 22852 vs $US 25000) and France ($US28 080 vs $US 34747) [1995/96 costs]. In other cost-effectiveness analyses, paclitaxel plus cisplatin was associated with a cost per life-year saved relative to best supportive care of approximately $US 10000 in a US study (year of costing not reported) or $US 11200 in a Canadian analysis ($Can 15400; 1995 costs). Results were less favourable when combining paclitaxel with carboplatin instead of cisplatin and particularly when G-CSF was added to paclitaxel plus cisplatin. The Canadian study incorporated the concept of extended dominance in a threshold analysis and ranked paclitaxel plus cisplatin first among several comparator regimens (including vinorelbine plus cisplatin) when the threshold level was $Can 75000 ($US 54526) per life-year saved or per quality-adjusted life-year gained (1995 values). CONCLUSION: Current treatment guidelines for advanced NSCLC recognise paclitaxel-platinum combinations as one of the first-line chemotherapy treatment options. In two large head-to-head comparative clinical trials, paclitaxel plus cisplatin was associated with significantly greater response rates than cisplatin in combination with either teniposide or etoposide, and a survival advantage was shown for paclitaxel plus cisplatin (with or without G-CSF) over etoposide plus cisplatin. There are limitations to the currently available pharmacoeconomic data and further economic analyses of paclitaxel-carboplatin regimens are warranted, as this combination is widely used in NSCLC and appears to have some clinical advantages over paclitaxel plus cisplatin in terms of ease of administration and tolerability profile. Nevertheless, results of various cost-effectiveness studies support the use of paclitaxel-platinum combinations, particularly paclitaxel plus cisplatin, as a first-line chemotherapy treatment option in patients with advanced NSCLC.

Antineoplastic Agents, Phytogenic↗

Meropenem: a review of its use in patients in intensive care.

UNLABELLED: Meropenem is a carbapenem antibacterial agent that has antimicrobial activity against gram-negative, gram-positive and anaerobic micro-organisms. In vitro studies involving isolates from patients in intensive care units (ICUs) indicate that meropenem is more active against most gram-negative pathogens than other comparators (including imipenem), although, compared with imipenem, meropenem is less active against most gram-positive organisms. Resistance to meropenem is uncommon in most bacteria. Treatment with meropenem as initial empirical monotherapy was effective in a range of serious infections in adult and paediatric ICU patients. Meropenem monotherapy was as effective as imipenem/cilastatin in 4 comparative trials in terms of satisfactory clinical and bacteriological responses. Meropenem monotherapy was significantly more effective than ceftazidime-based combination treatments in 2 trials in patients with nosocomial lower respiratory tract infections (LRTIs) in terms of both clinical and bacteriological responses. Meropenem was also more active than ceftazidime-based treatments against both gram-positive and gram-negative organisms. However, 2 studies in patients with a range of serious infections found no significant differences between meropenem and cephalosporin-based treatments in terms of clinical or bacteriological response. Meropenem was also as effective as cephalosporin-based treatments in comparative trials in children with serious infections. Meropenem is well tolerated as either a bolus or an infusion, and clinical trials have shown similar incidences of adverse events to those observed with cephalosporin-based treatments. It is well tolerated by the CNS, with seizures reported infrequently, and can therefore be used at high doses and in patients with meningitis. The incidence of drug-related nausea and vomiting is low and, in contrast to imipenem/cilastatin, does not increase with dose or speed of administration. CONCLUSIONS: Meropenem is a well tolerated broad spectrum antibacterial agent that, when used as initial empirical monotherapy, is as effective as imipenem/cilastatin in the treatment of a range of serious infections (including nosocomial) in adults and children in ICUs. Compared with cephalosporin-based combination treatments, meropenem monotherapy may be more effective in the treatment of nosocomial LRTIs and can be used as monotherapy. Meropenem has an important role in the empirical treatment of serious infections in adults and children in ICUs.

Adult↗

Ebastine: an update of its use in allergic disorders.

UNLABELLED: Ebastine is a second-generation antihistamine which undergoes transformation to its active metabolite, carebastine. Its antihistaminic and antiallergic effects have been demonstrated in in vitro and in vivo studies, in addition to data obtained from clinical trials. Patients with allergic rhinitis or chronic idiopathic urticaria experienced significant improvement in their symptoms with ebastine 10 or 20 mg once daily. Some studies in patients with seasonal allergic rhinitis (SAR) have indicated trends towards greater efficacy with the 20 mg than the 10 mg dose, although only 1 study has shown statistically significant benefits. In comparative trials in patients with SAR, ebastine 10 mg was as effective as most other second-generation antihistamines, including astemizole, azelastine, cetirizine, loratadine and terfenadine. Ebastine 20 mg/day was significantly superior to loratadine 10 mg/day in patients with SAR according to effects on secondary efficacy variables in comparative studies; 1 study found significantly greater changes from baseline in mean total symptom score with ebastine 20 mg (-43 vs -36% with loratadine, p = 0.045). In patients with perennial allergic rhinitis, ebastine 10 or 20 mg daily was significantly more effective than loratadine in reducing total symptom scores from baseline 1 comparative study. There have been no reports of serious adverse cardiac effects during ebastine therapy. Increases in corrected QT interval have been observed during clinical trials; however, these have not been considered clinically significant and were generally of similar magnitude to those seen with loratadine. The normal diurnal variation in QTc interval and the problems associated in correcting for changes in heart rate also complicate assessment of this issue. The incidence of adverse events during ebastine treatment is not significantly greater than that observed with placebo or other second-generation antihistamines. CONCLUSIONS: Ebastine 10 mg daily is a well tolerated and effective treatment for allergic rhinitis and chronic idiopathic urticaria. At this dosage, it is as effective as the other second-generation antihistamines against which it has been compared. Ebastine 20 mg has similar tolerability to the 10 mg dose, and trends towards greater efficacy with the higher dose have been shown in some studies. Ebastine does not appear to be associated with any significant cardiac adverse events. Ebastine is a useful treatment option for patients with allergic rhinitis or chronic idiopathic urticaria.

Animals↗

Lopinavir.

Lopinavir is a protease inhibitor with high specificity for HIV-1 protease. Ritonavir strongly inhibits lopinavir metabolism; coadministration of lopinavir and ritonavir in healthy volunteers increased the area under the lopinavir plasma concentration-time curve >100-fold. Trough plasma concentration: antiviral 50% effective concentration ratio for lopinavir was >75 for wild-type HIV at the dose used in clinical trials, compared to values of < or = 4 for other commonly used protease inhibitors. Coformulated lopinavir and ritonavir (lopinavir/ ritonavir) 400/100mg twice daily for 48 weeks suppressed HIV replication in significantly more antiretroviral-naive patients than nelfinavir 750mg 3 times daily (all patients also received stavudine and lamivudine). Suppression of viral replication was observed in most protease inhibitor-experienced patients with lopinavir/ ritonavir (400/100, 400/200 or 533/133mg twice daily for 48 or 96 weeks) in combination with > or = 2 nucleoside reverse transcriptase inhibitors (NRTIs) and either efavirenz or nevirapine. 48 weeks of treatment with twice daily lopinavir/ ritonavir (230/57.5 or 300/75 mg/m2 for the first 12 weeks and then 300/75 mg/m2) in combination with 1 or2 NRTIs, with or without nevirapine, suppressed viral replication in the majority of antiretroviral-naive and -experienced paediatric patients (aged 6 months to 12 years). Diarrhoea, nausea and asthenia were the most frequently reported adverse effects in patients receiving lopinavir/ritonavir-based regimens. Elevated total cholesterol, triglyceride and hepatic enzyme levels were also reported.

Adult↗

Clodronate: a review of its use in breast cancer.

UNLABELLED: Like other members of its class, the bisphosphonate clodronate (clodronic acid) inhibits bone resorption. The efficacy of oral clodronate 1600 mg/day in reducing the incidence of skeletal complications and metastasis development has been assessed in several clinical trials in patients with breast cancer. Long term use of oral clodronate significantly reduced the total cumulative incidence of skeletal events (including fractures, hypercalcaemia, and the need for radiotherapy for bone pain) compared with that in placebo recipients in 2 randomised double-blind placebo-controlled studies, each involving >100 patients. Significant differences in favour of clodronate were also seen in the frequency of some individual skeletal events in 1 trial. A nonblind trial in 302 patients considered to be at high risk of developing metastases found that, at a 3-year follow-up, significantly fewer patients who received clodronate for 2 years developed skeletal metastases than those in a control group. Clodronate recipients were also significantly less likely than controls to develop visceral metastases, and had significantly higher survival rates. A smaller double-blind placebo-controlled study in women with recurrent breast cancer found that clodronate significantly decreased the total number of new skeletal metastases, but not the number of patients who developed them. In a nonblind trial in 299 patients with node-positive breast cancer, however, the incidence of skeletal metastases did not differ significantly between patients who received clodronate for 3 years and those in a control group. In addition, clodronate recipients had a significantly greater incidence of nonskeletal metastases (local and visceral), and significantly lower survival rates. Intravenous or oral clodronate has been well tolerated in clinical trials. The most common adverse effects reported were mild gastrointestinal disturbances such as nausea, vomiting and diarrhoea. All these events were transient, and usually resolved without stopping treatment. CONCLUSIONS: Clodronate is a well tolerated bisphosphonate, available in both oral and intravenous forms, that significantly reduces the incidence of skeletal complications associated with breast cancer. Further research is needed to establish more clearly its efficacy in reducing metastasis development, to assess its efficacy compared with other bisphosphonates, and to determine which patients will benefit most from treatment. Currently, clodronate is probably most effective in the treatment and prevention of general skeletal complications in patients with breast cancer.

Bone Resorption↗

Stavudine: an update of its use in the treatment of HIV infection.

UNLABELLED: Stavudine is a thymidine nucleoside analogue which is phosphorylated intracellularly to an active metabolite, stavudine 5'-triphosphate. This metabolite inhibits HIV replication, either by competing with thymidine 5'-triphosphate for incorporation into viral DNA by reverse transcriptase or by causing premature termination of the viral chain after incorporation. Resistance to stavudine, either alone or as part of resistance to multiple nucleoside reverse transcriptase inhibitors, has been reported; however, high-level resistance is uncommon even after long periods of treatment. Initial treatment with stavudine-containing triple therapies reduced HIV RNA levels to below the limit of detection (LOD; 500 copies/ml) in 68 to 100% of antiretroviral-naive patients after at least 20 weeks of treatment. Effects on clinical outcomes have not yet been established, although earlier trials showed significant improvements with stavudine (alone or with 1 other drug) in patients who had previously received zidovudine. Results from 2 randomised nonblind clinical trials indicated that the efficacy of stavudine-containing triple therapy was similar to that of zidovudine-containing triple therapy (when used in combination with the same drugs), although there were no statistical comparisons. Improvements in surrogate end-points have also been seen in trials in antiretroviral-experienced patients receiving stavudine and 2 or 3 other antiretroviral agents. Stavudine-containing combination therapies have also been effective in reducing viral load and increasing CD4+ lymphocyte count in children, although data are limited. Like other nucleoside analogues, stavudine treatment can cause mitochondrial toxicity. The major adverse effect from this observed with stavudine therapy is peripheral neuropathy, which is both dosage- and treatment duration-dependent. Most cases respond to short term cessation of treatment and reintroduction of stavudine at half the previous dosage. CONCLUSION: Stavudine-containing triple therapies are effective in the treatment of antiretroviral-naive adults with HIV infection as assessed by surrogate end-points; earlier trials involving 1 or 2-drug therapy showed that stavudine can significantly improve clinical end-points. Stavudine has also been beneficial as part of combination regimens in antiretroviral-experienced patients and children with HIV infection, although data are limited and more studies are needed. High-level resistance to stavudine is uncommon. The major adverse event associated with treatment is peripheral neuropathy, which may limit its use in some patients. Currently, stavudine has a valuable role as part of initial triple therapy in antiretroviral-naive adults with HIV/AIDS.

Anti-HIV Agents↗

Schistosoma japonicum in the pig: the host-parasite relationship as influenced by the intensity and duration of experimental infection.

Parasitologic, clinicopathologic, and pathologic aspects of Schistosoma japonicum infections of varying durations and intensities were studied in growing pigs injected intramuscularly with a dose of either 0, 100, 500, or 2,000 cercariae and killed at 4, 11, 17, or 24 weeks postinfection (PI). The number of viable worm pairs decreased significantly in the high dose group after 11 weeks PI but not in the lower dose groups; however, a stable population of immature worms persisted throughout the study in all dose groups. Liver egg counts also tended to decrease in the high dose group after 11 weeks but not in the other groups. Fecal egg excretion began at six weeks PI, was highest at eight weeks PI with a pronounced peak occurring only in the high dose group, and then decreased to low levels by 14 weeks PI in all groups. Egg counts from the feces as well as the liver correlated strongly with worm pair numbers during the acute phase of infection. The only clinicopathologic abnormality observed was an increase in circulating eosinophils corresponding to cercarial dose in all infected pigs by week six with peak counts occurring between six and eight weeks PI. The pigs exhibited no clinical signs of disease aside from diarrhea at the onset of patency. However, lesions were present throughout the large intestine of all infected pigs from 11 weeks PI, gradually decreasing with time. Severe liver fibrosis occurred in the 500 and 2,000 dose groups mainly at 11 weeks PI and then decreased in severity. In the liver, but not in the intestine, the severity of lesions at all time points was proportional to the cercarial dose given. The results indicate that after several weeks of patency, pigs with high intensities of S. japonicum infection are able to effectively eliminate the majority of adult worms while maintaining a stable population of immature schistosomes.

Animals↗

Optimal temporal frequencies in oscillatory movement hyperacuity measurements of visual function in cataract patients.

Hyperacuity tasks have been suggested for the assessment of potential visual function in the presence of cataracts. To test this suggestion, hyperacuity thresholds for an oscillating bar were measured in 30 subjects with idiopathic cataract and in 24 age-matched normals over a range of oscillation frequencies. Each subject's cataract was categorized using the Oxford Clinical Cataract Classification and Grading System. Cataract was found to have a significant effect on thresholds, although a differential morphological effect on thresholds was equivocal. Thresholds at higher temporal frequencies were significantly raised when compared to the normal group. The main conclusion to be drawn from this study is that motion hyperacuity thresholds appear unaffected by cataract at low oscillation frequencies and should be used in preference to higher frequencies in the assessment of such patients.

Aged↗

Immunohistochemical localization of platelet-derived growth factor receptors in the porcine uterus during the oestrous cycle and pregnancy.

The distribution of alpha- and beta-type receptors for PDGF was studied immunohistochemically in the uterus of cycling and pregnant pigs with well-documented hormonal status in order to determine a possible steroid hormone-dependence of its expression. Peroxidase-antiperoxidase (PAP) labelling at light microscopical level was done with rabbit polyclonal antisera recognizing either both alpha- and beta-type receptors (PDGFR-1), or selectively beta-type (PDGFR-3). Immunoreactivity to the PDGF-receptors of alpha- and beta-type (PDGFR-1) was present in all endometrial samples examined, being located principally on subepithelial stromal and endothelial cells, the wall of endometrial blood vessels and in the fetal placenta (trophoblast and adjoining blood capillaries). In the myometrium, the major reactive cells were the non-vascular smooth muscle cells, and to some extent, also those of the tunica media of major uterine vessels. No dramatic variations in the intensity of the reaction were noticed during the oestrous cycle. A very intense immunoreactivity was present at early pregnancy and at term, i.e. under major oestrogenic influence. The immunoreactivity to the PDGF-receptor antiserum R-3 (against beta-type) was similarly localized as that showed for R-1 antiserum, while of a weaker intensity. The results indicate the presence of PDGF receptors (alpha- and beta-type) in the endo- and myometrium of cycling and pregnant pigs, and that their expression seems to be accentuated under oestrogenic influence.

Animals↗

Embryonic development of the porcine indifferent gonad and testis.

The early gonadal development in the pig from day 18 to day 36 post conception, when distinct testes were present in male embryos, has been studied. The development of the porcine gonad followed the general mammalian pattern. During testicular differentiation, the germ cells and the relevant somatic cells, the Sertoli cells, became enclosed in testicular cords, thus creating an intracordal germ cell compartment and an extracordal compartment. The development of conspicuous cell junctions and the production of a basal lamina were evident in the Sertoli cells during the early testis development. Their origin in this species remains unclear.

Animals↗

Localization of carbonic anhydrase activity in the developing boar testis.

Embryonic and fetal pig gonads were obtained immediately after the sow's slaughter at 18, 21, 25, 28, 30, 36, 55, 63, 80 or 108 days of pregnancy. Semithin plastic sections were incubated for localization of carbonic anhydrase (CA) activity using a cobalt precipitation technique. In the embryonic gonad, CA activity was only present in the coelomic epithelium and in the endothelium of scattered blood capillaries. In the early testes (30-36 days) the CA activity was also localized in the cytoplasm of the sustentacular cells. Both spermatogonia and the developing interstitial cells were negative. At later stages, the testes presented a clear CA cytoplasmic activity in the Sertoli cells and a membrane-bound activity in the peritubular capillaries, resembling the enzymatic localization in the adult. The epithelium of the rete testis had a clear membrane-bound CA activity. CA histochemistry is useful as a marker for topographical studies of Sertoli cells during the prenatal development in the pig.

Animals↗

The subjective assessment of cataract.

The medical treatment of cataract now appears to be a distinct possibility. A number of anti-cataract formulations are being clinically tested, and more clinical trials are being planned. To obtain a true assessment of a drug's efficacy, a battery of tests are needed which can accurately assess cataract progress. A clinical trial of the proposed anti-cataract drug Bendalina is being conducted. The six subjective methods used to assess cataract progression in the trial are presented. These are refractive error, LogMAR visual acuity, contrast sensitivity, glare sensitivity, retinal visual acuity and displacement threshold hyperacuity. The reasons for using each technique and their method of measurement is explained.

Aged↗