Showing papers by "Leicester Royal Infirmary published in 1999"

Optimal strategies for measuring diffusion in anisotropic systems by magnetic resonance imaging.

Abstract: The optimization of acquisition parameters for precise measurement of diffusion in anisotropic systems is described. First, an algorithm is presented that minimizes the bias inherent in making measurements with a fixed set of gradient vector directions by spreading out measurements in 3-dimensional gradient vector space. Next, it is shown how the set of b—matrices and echo time can be optimized for estimating the diffusion tensor and its scalar invariants. The standard deviation in the estimate of the tensor trace in a water phantom was reduced by more than 40% and the artefactual anisotropy was reduced by more than 60% when using the optimized scheme compared with a more conventional scheme for the same scan time, and marked improvements are demonstrated in the human brain with the optimized sequences. Use of these optimal schemes results in reduced scan times, increased precision, or improved resolution in diffusion tensor images. Magn Reson Med 42:515‐ 525, 1999. r 1999 Wiley-Liss, Inc.

Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia

Abstract: Familial platelet disorder with predisposition to acute myelogenous leukaemia (FPD/AML, MIM 601399) is an autosomal dominant disorder characterized by qualitative and quantitative platelet defects, and propensity to develop acute myelogenous leukaemia (AML). Informative recombination events in 6 FPD/AML pedigrees with evidence of linkage to markers on chromosome 21q identified an 880-kb interval containing the disease gene. Mutational analysis of regional candidate genes showed nonsense mutations or intragenic deletion of one allele of the haematopoietic transcription factor CBFA2 (formerly AML1) that co-segregated with the disease in four FPD/AML pedigrees. We identified heterozygous CBFA2 missense mutations that co-segregated with the disease in the remaining two FPD/AML pedigrees at phylogenetically conserved amino acids R166 and R201, respectively. Analysis of bone marrow or peripheral blood cells from affected FPD/AML individuals showed a decrement in megakaryocyte colony formation, demonstrating that CBFA2 dosage affects megakaryopoiesis. Our findings support a model for FPD/AML in which haploinsufficiency of CBFA2 causes an autosomal dominant congenital platelet defect and predisposes to the acquisition of additional mutations that cause leukaemia.

Guidelines for management of hypertension: report of the third working party of the British Hypertension Society.

Abstract: Use non-pharmacological measures in all hypertensive and borderline hypertensive people. Initiate antihypertensive drug therapy in people with sustained systolic blood pressures (BP) >/=160 mm Hg or sustained diastolic BP >/=100 mm Hg. Decide on treatment in people with sustained systolic BP between 140 and 159 mm Hg or sustained diastolic BP between 90 and 99 mm Hg according to the presence or absence of target organ damage, cardiovascular disease or a 10-year coronary heart disease (CHD) risk of >/=15% according to the Joint British Societies CHD risk assessment programme/risk chart. In people with diabetes mellitus, initiate antihypertensive drug therapy if systolic BP is sustained >/=140 mm Hg or diastolic BP is sustained >/=90 mm Hg. In non-diabetic hypertensive people, optimal BP treatment targets are: systolic BP /=15% and in whom blood pressure is controlled to the audit standard. In accordance with existing British recommendations, statin therapy is recommended for hypertensive people with a total cholesterol >/=5 mmol/L and established vascular disease, or 10-year CHD risk >/=30% estimated from the Joint British Societies CHD risk chart. Glycaemic control should also be optimised in diabetic subjects. Specific advice is given on the management of hypertension in specific patient groups, ie, the elderly, ethnic subgroups, diabetes mellitus, chronic renal disease and in women (pregnancy, oral contraceptive use and hormone replacement therapy). Suggestions for the implementation and audit of these guidelines in primary care are provided.

Non-invasive assessment of axonal fiber connectivity in the human brain via diffusion tensor MRI.

Abstract: A technique for assessing in vivo fiber connectivity in the human brain is presented. The method utilizes a novel connectivity algorithm that operates in three spatial dimensions and uses estimates of fiber tract orientation and tissue anisotropy, obtained from diffusion tensor magnetic resonance imaging, to establish the pathways of fiber tracts. Sample in vivo connectivity images from healthy human brain are presented that demonstrate connections in the white matter tracts. White matter connectivity information is potentially of interest in the study of a range of neurological, psychiatric, and developmental disorders and shows promise for following the natural history of disease.

Characterization of White Matter Damage in Ischemic Leukoaraiosis with Diffusion Tensor MRI

Abstract: BACKGROUND AND PURPOSE: Information on the neuropathological changes underlying ischemic leukoaraiosis is only available postmortem, and there are limited data on histological appearances early in the disease. Diffusion tensor imaging allows determination of the directionality of diffusion, which is greater in the direction of white matter bundles. Therefore, the technique might be expected to show loss of anisotropy (directional diffusion) in leukoaraiosis. METHODS: Nine patients with ischemic leukoaraiosis (radiological leukoaraiosis and clinical lacunar stroke) and 10 age-matched controls were studied. Diffusion tensor imaging was performed, and maps of diffusion trace and fractional anisotropy were constructed. Mean values of trace and fractional anisotropy were determined in standard regions of the anterior and posterior white matter in both hemispheres. RESULTS: In all patients with ischemic leukoaraiosis, a characteristic abnormal pattern was found, with loss of anisotropy and increased trace in the white matter. For example, in the right anterior white matter mean (SD) trace/3 was 1.12 (0.33) x10(-3) mm2 s-1 in patients and 0.75 (0.11) in controls (P=0.001). In the same region, fractional anisotropy was 0.53 (0.11) in patients and 0.78 (0.09) in controls (P<0.001). Within the white matter regions, there was a strong negative correlation between mean diffusivity and anisotropy (r=-0.92, P<0.0001). CONCLUSIONS: The characteristic pattern found on diffusion tensor imaging in this patient group is consistent with axonal loss and gliosis leading to impairment to and loss of directional diffusion. The "in vivo histological" information obtained may be useful in monitoring disease progression and in investigating the pathogenesis of the cognitive impairment that may be present.

Lamotrigine monotherapy in newly diagnosed untreated epilepsy: a double-blind comparison with phenytoin.

Abstract: Summary: Purpose: Lamotrigine is an effective add-on therapy against a range of epileptic seizure types. Comparative studies with carbamazepine (CBZ) as monotherapy in newly diagnosed epilepsy suggest similar efficacy. In this study, lamotrigine (LTG) and phenytoin (PHT) are compared. Methods: In a double-blind parallel-groups study, 181 patients with newly diagnosed untreated partial seizures or secondarily or primary generalised tonic-clonic seizures were randomised to two treatment groups. One group (n = 86) received LTG titrated over 6 weeks from a starting dose of 100 mg/day. The other (n = 95) received PHT titrated from 200 mg/day. Treatment continued for <48 weeks. Results: The percentages of patients remaining on each treatment and seizure free during the last 24 and 40 weeks of the study, and times to first seizure after the first 6 weeks of treatment (dose-titration period), did not differ significantly between the treatment groups. These were measures of efficacy. Time to discontinuation, a composite index of efficacy and safety, likewise did not distinguish between treatments. Adverse events led to discontinuation of 13 (15%) patients from LTG and 18 (19%) from PHT. The adverse-event profile for LTG was dominated by skin rash [discontinuation of 10 (11.6%) patients compared with five (5.3%) from PHT] rather than central nervous system side effects: asthenia, somnolence, and ataxia were each significantly more frequent in the PHT group. The high rate of rash with LTG was probably due to the high starting dose and may be avoidable. A quality-of-life instrument, the SEALS inventory, favoured LTG. Patients taking PHT showed the biochemical changes expected of an enzyme-inducing drug, whereas those taking LTG did not. Conclusions: LTG and PHT monotherapy were similarly effective against these seizure types in patients with newly diagnosed epilepsy. LTG was better tolerated, more frequently causing rash, but with a lower incidence of central nervous system side effects.

Linear and nonlinear analysis of human dynamic cerebral autoregulation

Abstract: The linear dynamic relationship between systemic arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV) was studied by time- and frequency-domain analysis methods. A nonlinear moving...

Effect of CO2 on dynamic cerebral autoregulation measurement

Abstract: Arterial pCO2 is known to influence cerebral autoregulation but its effect on the dynamic relationship between mean arterial blood pressure (ABP) and mean cerebral blood flow velocity (CBFV), obtained from spontaneous fluctuations in ABP, has not been established. In 16 normal subjects, ABP was measured non-invasively (Finapres), CBFV was estimated with Doppler ultrasound in the middle cerebral artery, and end-tidal CO2 (EtCO2) was measured with an infrared capnograph. Recordings were made before, during and after breathing a mixture of 5% CO2 in air. The coherence function, amplitude and phase frequency responses, and impulse and step responses for the effects of ABP on CBFV were calculated by spectral analysis of beat-to-beat changes in mean ABP and CBFV before (mean CO2 5.55±0.38 kPa), during (6.43±0.31 kPa) and after 5% CO2 (5.43±0.26 kPa). During 5% CO2, the coherence function and the amplitude frequency response were significantly increased for frequencies below 0.05 Hz and the phase was reduced for the frequency range 0.02 - 0.1 Hz. The impulse and step responses indicated that 5% CO2 reduces the efficiency of the autoregulatory mechanism. A 20.7% average increase in CBFV induced by a 14.4% increase in EtCO2 was found to be mediated by a 25.9% reduction in critical closing pressure, while the change in resistance-area product was non-significant.

Vascular surgical society of great britain and ireland: angiogenesis and the atherosclerotic carotid plaque: association between symptomatology and plaque morphology

Abstract: Background: Symptomatic carotid disease due to thromboembolism has been associated with acute plaque instability and intraplaque haemorrhage. These features may be influenced by the fragility and position of plaque neovessels. The purpose of this study was, therefore, to determine whether any association existed between neovessel density, position, morphology and thromboembolic sequelae. Methods: Carotid endarterectomy (CEA) samples were collected from 15 asymptomatic patients with greater than 80 per cent stenosis and from 13 patients with greater than 80 per cent stenosis and symptoms within 30 days of CEA. Groups were matched for sex, age, risk factors and plaque size. Samples were stained with haematoxylin and eosin, and Van Gieson stains. An endothelial-specific antibody to CD31 was used for immunohistochemistry. Plaques were assessed for histological characteristics while neovessels were counted and characterized by size, site and shape. Results: There were more neovessels in plaques (P< 0·00001) and fibrous caps (P< 0·0001) from symptomatic than asymptomatic patients. Symptomatic plaque neovessels were larger in size (P< 0·004) and more irregular in shape. There was a significant increase in plaque necrosis and rupture in symptomatic plaques. Plaque haemorrhage and rupture were associated with more neovessels within the plaque (P< 0·02, P< 0·001) and fibrous cap (P< 0·05, P< 0·004). Patients with preoperative or intraoperative embolization had more plaque and fibrous cap neovessels (P< 0·03, P< 0·001). Conclusion: Symptomatic carotid disease is associated with increased neovascularization within the atherosclerotic plaque and fibrous cap; these vessels appear larger in size, more irregular in shape and may contribute to plaque instability and onset of thromboembolic events. © 1999 British Journal of Surgery Society Ltd

Visual field defects associated with vigabatrin therapy

Abstract: OBJECTIVE—To estimate the prevalence of visual field defects in patients taking the anticonvulsant drug vigabatrin and to characterise the features of visual dysfunction found. METHODS—Thirty three unselected patients attending neurology and epilepsy clinics were identified as taking vigabatrin and asked to attend for neuro-ophthalmic evaluation. A control group of 16patients with epilepsy unexposed to vigabatrin was also evaluated. Visual fields were examined by static perimetry using a Humphrey field analyser. Patients underwent detailed ophthalmic examination, various blood tests, and brain MRI where necessary. Visual evoked responses (VERs), electro-oculograms (EOGs), and electroretinograms (ERGs) were recorded. RESULTS—Of 31 assessable patients treated with vigabatrin, 16 (52%) had definitely abnormal visual fields, nine (29%) had fields that were inconclusive, four (13%) had normal fields, and two (6%) proved unable to cooperate with testing. In four patients some plausible cause was found for the field abnormality leaving 12patients (39%) in whom a definite bilateral field defect was found, possibly caused by vigabatrin treatment. Of 16 control patients none had definitely abnormal fields, 12 (75%) had normal fields, and four (25%) had fields that were inconclusive. The field defects associated with vigabatrin treatment showed a characteristic pattern of concentric peripheral field loss with temporal and macular sparing. The VERs and ERGs were normal. The EOG Arden Index was reduced in patients taking vigabatrin, although this returned towards normal when vigabatrin was stopped, even in the presence of persistent field defects. Multifocal ERGs recorded in two patients were abnormal, showing marked reduction in amplitude of the peripheral focal ERG. CONCLUSIONS—Treatment with vigabatrin was associated with a high prevalence of peripheral visual field defects. This seemed to be the result of a toxic effect of vigabatrin on the retina and seemed to persist if the drug was withdrawn.

Structural characteristics of term human fetal membranes prior to labour: identification of an area of altered morphology overlying the cervix

Abstract: Premature rupture of fetal membranes can have serious clinical implications, especially for the initiation of preterm labour and its consequences. To account for this phenomenon many studies have attempted to identify membrane features that may be uniquely associated with the site of rupture. Our previous work has identified an area of the fetal membrane, following spontaneous term birth which exhibits alterations consistent with structural weakness. The aim of this study was to determine if these changes existed prior to labour. In formalin-fixed paraffin-embedded tissue sections an area of the fetal membrane overlying the cervix, termed the 'cervical membranes', was characterized by an increased thickness of the connective tissue layer (215% increase, P < 0.01) and decreased thickness of both the cytotrophoblast (36% reduction, P < 0.01) and decidual layers (64% reduction, P < 0.01) compared to the rest of the membrane. This resulted in the cervical membranes being significantly thinner (P < 0.05) than the rest of the membrane. Similar changes were also detected in frozen sections of fetal membranes. These regional differences have two important implications in that: (i) the cervical membrane may represent a region of structural weakness susceptible to rupture during labour, and (ii) the paracrine relationships between fetal membranes and the myometrium may be qualitatively affected within different regions of the uterus.

Marimastat (BB2516): current status of development.

Abstract: Marimastat (BB-2516) is the first matrix metalloproteinase inhibitor to have entered clinical trials in the field of oncology. It has excellent bioavailability and has completed phase I and II trials. Phase I studies involved healthy volunteers who received short courses of marimastat; these were well tolerated. Symptoms experienced by many patients with various malignancies included severe joint and muscle pain which were debilitating in >60% of patients at doses >50 mg bid. These symptoms were reversible on discontinuation of the drug, and their incidence has been decreased by using marimastat 10 mg bid, the dose used in current studies. Phase II studies involved the use of serum tumor markers as surrogate indicators of antitumor activity. Six studies in colorectal, ovarian, and prostate cancer have been completed and pooled analysis has demonstrated a dose-dependent biological effect (as defined by the authors); 58% of patients respond at doses >50 mg bid. Effects on tumor markers were associated with increased survival. Small phase II studies have suggested potential activity in pancreatic and gastric cancer and have demonstrated the safety of combining cytotoxic chemotherapeutic agents with marimastat. Ongoing phase III studies are investigating the effects of marimastat in addition to chemotherapy in the treatment of small cell lung cancer and pancreatic and gastric carcinoma.

Epoetin alpha prevents anaemia and reduces transfusion requirements in patients undergoing primarily platinum-based chemotherapy for small cell lung cancer.

Abstract: Anaemia commonly occurs in cancer patients receiving chemotherapy, often necessitating blood transfusion. This multicentre study was designed to evaluate the efficacy and safety of epoetin alpha in preventing the decline in haemoglobin (Hb) level, and to determine whether the transfusion requirement could be reduced, in patients receiving 4-6 cycles of primarily platinum-based combination cyclic chemotherapy for small cell lung cancer (SCLC). A total of 130 non-anaemic SCLC patients were randomized to receive no additional treatment (n = 44), epoetin alpha 150 IU kg(-1) subcutaneously (s.c.) three times a week (n = 42) or 300 IU kg(-1) s.c. three times a week (n = 44). Reductions in epoetin alpha dosage were made during the study if Hb level increased to >15 g dl(-1). The mean weekly dosage was 335 and 612 IU kg(-1), respectively, in the two active treatment groups. Significantly fewer (P < 0.05) epoetin alpha-treated patients experienced anaemia (Hb < 10 g dl(-1)) during the course of chemotherapy (300 IU kg(-1), 39%; 150 IU kg(-1), 48%; untreated, 66%). This was reflected in the significantly lower number of treated patients transfused [300 IU kg(-1), 20% (P< 0.001); 150 IU kg(-1), 45% (P< 0.05); untreated, 59%]. Epoetin alpha was well-tolerated, and there was no evidence of sustained, clinically significant, hypertension. In summary, epoetin alpha is effective and well-tolerated in maintaining Hb level and reducing transfusion requirement in patients undergoing cyclic chemotherapy for SCLC.

Mapping eddy current induced fields for the correction of diffusion-weighted echo planar images.

Abstract: Diffusion-weighted echo-planar magnetic resonance imaging is potentially of great importance as a diagnostic imaging tool; however, the technique currently suffers a number of limitations, including the image distortion caused by the eddy current induced fields when the diffusion-weighting magnetic field gradient pulses are applied. The distortions cause mis-registration between images with different diffusion-weighting, that then results in artifacts in quantitative diffusion images. A method is presented to measure the magnetic fields generated from the eddy currents for each of three orthogonal gradient pulse vectors, and then to use these to ascertain the image distortion that occurs in subsequent diffusion-weighted images with arbitrary gradient pulse vector amplitude and direction, and image plane orientation. The image distortion can then be reversed. Both temporal and spatial dependence of the residual eddy current induced fields are included in the analysis. Image distortion was substantially reduced by the correction scheme, for arbitrary slice position and angulation. This method of correction is unaffected by the changes in image contrast that occur due to diffusion weighting, and does not need any additional scanning time during the patient scan. It is particularly suitable for use with single-shot echo planar imaging.

Molecular Analysis of SALL1 Mutations in Townes-Brocks Syndrome

Abstract: Summary Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited malformation syndrome characterized by anal, renal, limb, and ear anomalies. Recently, we showed that mutations in the putative zinc finger transcription factor gene SALL1 cause TBS. To determine the spectrum of SALL1 mutations and to investigate the genotype-phenotype correlations in TBS, we examined 23 additional families with TBS or similar phenotypes for SALL1 mutations. In 9 of these families mutations were identified. None of the mutations has previously been described. Two of these mutations are nonsense mutations, one of which occurred in three unrelated families. Five of the mutations are short deletions. All of the mutations are located 5′ of the first double zinc finger (DZF) encoding region and are therefore predicted to result in putative prematurely terminated proteins lacking all DZF domains. This suggests that only SALL1 mutations that remove the DZF domains result in TBS. We also present evidence that in rare cases SALL1 mutations can lead to phenotypes similar to Goldenhar syndrome. However, phenotypic differences in TBS do not seem to depend on the site of mutation.

Mapping the prevalence of sickle cell and beta thalassaemia in England: estimating and validating ethnic‐specific rates

Abstract: A range of estimates for sickle cell and beta thalassaemia have been derived for the different ethnic groups living in the U.K., reflecting uncertainty over the true population value in certain countries and the heterogeneity within and between countries of origin comprising the same ethnic group. These were validated against six community screening programmes, with the estimated range correctly predicting the number of affected births observed by the programmes. In England approximately 3000 affected babies (0.47%) carry sickle cell trait and 2800 (0.44%) carry beta thalassaemia trait annually: with approximately 178 (0.28 per 1000 conceptions) affected by sickle cell disease (SCD) and 43 (0.07 per 1000) by beta thalassaemia major/intermedia. Allowing for termination, about 140-175 (0.22-0.28 per 1000) affected infants are born annually with SCD and from 10 to 25 (0.02-0.04 per 1000) with beta thalassaemia major/intermedia. These are the first evidence-based rates for sickle cell and beta thalassaemia for use in the U.K., and should underpin the future planning of services. The long-term solution to monitoring changes in the rates of trait and disease in the population is to introduce a standardized instrument for collecting ethnicity for all community screening programmes.

Increased incidence of apoptosis in non-labour-affected cytotrophoblast cells in term fetal membranes overlying the cervix

Abstract: A regional reduction in the cellularity of the cytotrophoblastic and decidual layers occurs in the fetal membranes overlying the cervix in the lower uterine segment prior to labour. Although the mechanism(s) involved are not known it could result from regionally increased apoptosis, the histological manifestation of programmed cell death, or decreased proliferation. Apoptosis was assessed in regionally sampled fetal membranes from women undergoing elective Caesarean section (n = 14) by the presence of apoptotic bodies by light and electron microscopy. Cell proliferation was assessed by immunocytochemical detection of the protein Ki-67. Apoptotic bodies were identified in all regions of the fetal membrane with the highest incidence found within the cytotrophoblast layer. However, this layer in fetal membranes biopsied over the cervix contained significantly more apoptotic bodies (mean +/- SD 0.085 +/- 0.020%) compared to the layer in fetal membranes obtained from the mid-zone (0.020 +/- 0.008%) apoptotic bodies. Isolated Ki-67 positive cells were detected in the cytotrophoblast layer, but no regional differences in their incidence were seen. Fetal membranes also failed to exhibit significant immunoreactivity for BCL-2 but exhibited strong BAX immunoreactivity within the decidual layer. We conclude that the regionally increased incidence of apoptosis in the cytotrophoblastic layer in the membrane overlying the cervix may account for the reduction in its cellularity but not the relative decrease in the decidual layer. Given the consequence of the loss of local function in degrading uterotonins and stabilizing the fetal membrane, the study of the regulation of apoptosis in these cells may have important implications for fetal membrane rupture and parturition.

Critical closing pressure explains cerebral hemodynamics during the Valsalva maneuver

Abstract: The Valsalva maneuver (VM), a voluntary increase in intrathoracic pressure of ∼40 mmHg, has been used to examine cerebral autoregulation (CA). During phase IV of the VM there are pronounced changes...

Stereoselective Interaction of Ketamine with Recombinant [micro sign], [small kappa, Greek], and [small delta, Greek] Opioid Receptors Expressed in Chinese Hamster Ovary Cells

Abstract: BackgroundThe authors examined the interaction of ketamine with recombinant [micro sign], [small kappa, Greek], and [small delta, Greek] opioid receptors and recombinant orphan opioid receptors expressed in Chinese hamster ovary cells (CHO-[micro sign], CHO-[Greek small letter kappa, CHO-[small delt

Insulin stimulates pancreatic-duodenal homoeobox factor-1 (PDX1) DNA-binding activity and insulin promoter activity in pancreatic beta cells.

Abstract: Pancreatic-duodenal homoeobox factor-1 (PDX1) is a homoeodomain transcription factor that plays an important role in linking glucose metabolism in pancreatic β cells to the regulation of insulin gene transcription. Our previous results indicated that glucose activates PDX1 DNA-binding activity and insulin promoter activity via a stress-activated signalling pathway involving phosphatidylinositol 3-kinase (PtdIns 3-kinase) and stress-activated protein kinase 2 (SAPK2/p38). The present study was undertaken to determine the effects of other metabolizable and non-metabolizable nutrients. The results indicate that non-metabolizable nutrients, with the exception of 2-deoxyglucose, had no effect. Metabolizable nutrients that could stimulate calcium uptake and insulin release were shown to activate both PDX1 and the insulin promoter. The possible role of insulin acting via an autoregulatory loop was therefore examined. Insulin was shown to potently activate PDX1 DNA-binding activity and insulin promoter activity. The effects of insulin were inhibited by the PtdIns 3-kinase inhibitors wortmannin and LY294002 and by the SAPK2 inhibitor SB203580, suggesting that its effects were mediated via activation of PtdIns 3-kinase and SAPK2. Further support for the insulin-mediated activation of SAPK2 came from the observation that both glucose and insulin stimulated the phosphorylation of SAPK2. These results suggest that both glucose and insulin stimulate PDX1 DNA-binding activity and insulin promoter activity via a pathway involving PtdIns 3-kinase and SAPK2.

Bioequivalence of two tablet formulations of capecitabine and exploration of age, gender, body surface area, and creatinine clearance as factors influencing systemic exposure in cancer patients

Abstract: Purpose: The objective of the study was to assess the bioequivalence of two tablet formulations of capecitabine and to explore the effect of age, gender, body surface area and creatinine clearance on the systemic exposure to capecitabine and its metabolites. Methods: The study was designed as an open, randomized two-way crossover trial. A single oral dose of 2000 mg capecitabine was administered on two separate days to 25 patients with solid tumors. On one day, the patients received four 500-mg tablets of formulation B (test formulation) and on the other day, four 500-mg tablets of formulation A (reference formulation). The washout period between the two administrations was between 2 and 8 days. After each administration, serial blood and urine samples were collected for up to 12 and 24 h, respectively. Unchanged capecitabine and its metabolites were determined in plasma using LC/MS-MS and in urine by NMRS. Results: Based on the primary pharmacokinetic parameter, AUC0–∞ of 5′-DFUR, equivalence was concluded for the two formulations, since the 90% confidence interval of the estimate of formulation B relative to formulation A of 97% to 107% was within the acceptance region 80% to 125%. There was no clinically significant difference between the tmax for the two formulations (median 2.1 versus 2.0 h). The estimate for Cmax was 111% for formulation B compared to formulation A and the 90% confidence interval of 95% to 136% was within the reference region 70% to 143%. Overall, these results suggest no relevant difference between the two formulations regarding the extent to which 5′-DFUR reached the systemic circulation and the rate at which 5′-DFUR appeared in the systemic circulation. The overall urinary excretions were 86.0% and 86.5% of the dose, respectively, and the proportion recovered as each metabolite was similar for the two formulations. The majority of the dose was excreted as FBAL (61.5% and 60.3%), all other chemical species making a minor contribution. Univariate and multivariate regression analysis to explore the influence of age, gender, body surface area and creatinine clearance on the log-transformed pharmacokinetic parameters AUC0–∞ and Cmax of capecitabine and its metabolites revealed no clinically significant effects. The only statistically significant results were obtained for AUC0–∞ and Cmax of intact drug and for Cmax of FBAL, which were higher in females than in males. Conclusion: The bioavailability of 5′-DFUR in the systemic circulation was practically identical after administration of the two tablet formulations. Therefore, the two formulations can be regarded as bioequivalent. The variables investigated (age, gender, body surface area, and creatinine clearance) had no clinically significant effect on the pharmacokinetics of capecitabine or its metabolites.

Angiotensin II activates MAPK and stimulates growth of human pulmonary artery smooth muscle via AT1 receptors

Abstract: To determine a potential role for the renin-angiotensin system in the growth of human pulmonary artery (PA) smooth muscle, we studied the localization of angiotensin (ANG) II-receptor subtypes by a...

Comparison of the effects of [Phe1Ψ(CH2-NH)Gly2]Nociceptin (1-13)NH2 in rat brain, rat vas deferens and CHO cells expressing recombinant human nociceptin receptors

Abstract: Nociceptin(NC) is the endogenous ligand for the opioid receptor like-1 receptor (NC-receptor). [Phe1ΨC(CH2-NH)Gly2]Nociceptin(1–13)NH2 ([F/G]NC(1–13)NH2) has been reported to antagonize NC actions in peripheral guinea-pig and mouse tissues. In this study, we investigated the effects of a range of NC C-terminal truncated fragments and [F/G]NC(1–13)NH2 on NC receptor binding, glutamate release from rat cerebrocortical slices (rCX), inhibition of cyclic AMP accumulation in CHO cells expressing the NC receptor (CHONCR) and electrically evoked contractions of the rat vas deferens (rVD). In radioligand binding assays, a range of ligands inhibited [125I]-Tyr14-NC binding in membranes from rCX and CHONCR cells. As the peptide was truncated there was a general decline in pKi. [F/G]NC(1–13)NH2 was as potent as NC(1–13)NH2. The order of potency for NC fragments to inhibit cyclic AMP accumulation in whole CHONCR cells was NCNH2NC=NC(1–13)NH2>NC(1–12)NH2>>NC(1–11)NH2. [F/G]NC(1–13)NH2 was a full agonist with a pEC50 value of 8.65. NCNH2 and [F/G]NC(1–13)NH2 both inhibited K+ evoked glutamate release from rCX with pEC50 and maximum inhibition of 8.16, 48.5±4.9% and 7.39, 58.9±6.8% respectively. In rVD NC inhibited electrically evoked contractions with a pEC50 of 6.63. Although [F/G]NC(1–13)NH2, displayed a small (instrinsic activity α=0.19) but consistent residual agonist activity, it acted as a competitive antagonist (pA2 6.76) in the rVD. The differences between [F/G]NC(1–13)NH2 action on central and peripheral NC signalling could be explained if [F/G]NC(1–13)NH2 was a partial agonist with high strength of coupling in the CNS and low in the periphery. An alternative explanation could be the existence of central and peripheral receptor isoforms. British Journal of Pharmacology (1999) 127, 123–130; doi:10.1038/sj.bjp.0702539

An investigation into the use of polymer gel dosimetry in low dose rate brachytherapy.

Abstract: An investigation has been carried out into the properties of the BANG polymer gel and its use in the dosimetry of low dose rate brachytherapy. It was discovered that the response of the gel was reproducible and linear to 10 Gy. The gel was found to be tissue equivalent with a response independent of energy to within experimental accuracy (standard error of measurement +/- 5%). The slope of the calibration curve was found to increase from 0.28 +/- 0.01 s-1 Gy-1 to 0.50 +/- 0.02 s-1 Gy-1 for an increase in monomer concentration from 6 to 9%. Absorbed dose distributions for a straight applicator containing 36 137Cs sources were measured using the gel and the results compared with measurements made with thermoluminescent dosemeters (TLDs) and calculated values. Good agreement was found for the relative measurements. The root mean square residual percentage errors were 3%, 1% and 4% for the gel and the two groups of TLDs, respectively. There were some significant differences in absolute values of absorbed dose...