Aims Zolmitriptan (311C90), a novel, selective, centrally and peripherally acting 5‐HT1D‐receptor agonist is under development as an acute treatment for migraine. The tolerability, pharmacokinetics ...and effects on blood pressure and heart rate of multiple doses of 5 or 10 mg (5 doses administered over 24 h) were compared, in healthy adult volunteers, with those after placebo and single doses of zolmitriptan.
Methods Twelve subjects participated in a randomized, balanced, crossover comparison. Plasma and urine concentrations of zolmitriptan and its metabolites, pulse rate and blood pressure were measured at intervals after drug. Ten volunteers completed the study.
Results Zolmitriptan was well tolerated after single and multiple doses throughout the study. There was no evidence of significant changes in the pharmacokinetic parameters of zomitriptan or its metabolites after the last dose compared to the first, except for an expected rise in peak concentrations and a small, apparent increase in the amount of drug excreted in urine and hence in CLR. After the last 10 mg dose, mean dosing interval zolmitriptan AUC was 80.3 ng ml−1 h compared with 86.5 ng ml−1 h after the single 10 mg dose (95% CI for ratio 0.76–1.13). There was no evidence of changes in the pharmacokinetic parameters of zolmitriptan and its metabolites after 10 mg compared with 5 mg, except a small increase in zolmitriptan CLR. There were no statistically significant increases in peak systolic or diastolic blood pressure after the last doses of zolmitriptan compared to placebo or in peak blood pressure after the last dose compared to the first. There were no significant differences between blood pressure immediately before the first and last doses of each multiple dose regimen. Peak erect systolic blood pressure after the last 10 mg dose (137 mmHg) was significantly lower than that after placebo (147 mmHg, 95% CI for difference −18, −2) and that after the last 5 mg dose (148 mmHg, 95% CI −19, −3).
Conclusions Repeated doses of 5 or 10 mg zolmitriptan are well tolerated despite higher plasma concentrations than expected from single doses.
Objectives For years, the reference standard in the evaluation of living donor vascular anatomy has been selective renal angiography (SRA). Because of the potential morbidity associated with SRA, we ...prospectively evaluated magnetic resonance angiography (MRA) in the assessment of renal donors. Methods All patients had SRA and 53 renal units were prospectively evaluated by MRA. We used SRA supplemented by findings at donor nephrectomy (DN) as our standard. We defined a positive test as the detection of any abnormality in the number of renal arteries. Results Selective renal angiography yielded a sensitivity of 86%, specificity of 95%, positive predictive value (PPV) of 75%, and negative predictive value (NPV) of 97% compared with findings at DN. MRA had a sensitivity of 64%, 88% specificity, 58% PPV, and 90% NPV. MRA correctly identified only 7 of 11 renal units with accessory arteries. MRA also incorrectly identified 5 accessory arteries not present on SRA or DN. Two patients diagnosed with fibromuscular dysplasia by SRA were missed using MRA. Conclusions We have shown that MRA is not capable of replacing SRA as the reference standard in renal donor imaging.
Previous studies have shown the value of MR imaging for the identification of cardiac masses. The distinction of intramural tumors from normal myocardium may be equivocal because of the similarity of ...signal intensity between tumor and normal myocardium on ECG-gated SE images. The purpose of this study was to assess the role of Gd-DTPA for improving the contrast between cardiac tumors and myocardium. Four patients with established or suspected cardiac tumors were imaged with a 1.5 T imager. The T1-weighted images (TR = RR interval, TE = 20-30 ms) were obtained before and immediately after the intravenous injection of Gd-DTPA, at a dosage of 0.1 mmol/kg. Tumors were identified in three patients. All tumors were isointense to the myocardium in precontrast images but demonstrated differential enhancement relative to myocardium after the administration of Gd-DTPA. Two tumors were hyperintense relative to myocardium, and the third was mostly hypointense, surrounded by a hyperintense rim. In the remaining case, no tumor was found and the myocardium was homogeneously enhanced on postgadolinium images. Gadolinium DTPA can produce differential enhancement of tumor from normal myocardium and therefore demonstrate intramural masses.
Human cytochrome P450 (CYP)3A is a major P450 enzyme found in the liver and gastrointestinal tract. It plays an important role in the metabolism of a wide variety of drugs, some endogenous steroids ...and harmful environmental contaminants. It has been shown that CYP3A alleles encoding enzymes with little or no activity are largely created by single nucleotide polymorphisms (SNPs) in the sequences of these genes. The most prevalent of these SNPs are often of low allelic frequency, and many are specific to certain ethnic groups. Therefore, an accurate determination of their frequency in any given ethnic population requires investigations involving large sample sizes. A genotyping chip with enzyme-colorimetric detection was developed and used for simultaneous analysis of 22 known CYP3A SNPs in 451 Han Chinese subjects. Following multiplex polymerase chain reaction and allele-specific primer extension labeling, an enzymatic colorimetry detection system was employed to visualize genotype patterns on a nylon membrane. With this robust system, accurate discrimination ratios were obtained, and approximately 9,922 genotypes were determined. We found that the major CYP3A SNPs in the Chinese subjects were CYP3A4*4 (allele frequency 2.4%), CYP3A4*5 (0.7%), CYP3A4*18A (2.7%) and CYP3A5*3C (70.2%). Most of the major CYP3A4 SNPs found in other ethnicities were not found in this study. Using these SNPs, 11 haplotypes were identified. Comparison between present and previous studies shows that CYP3A4*4 and CYP3A4*5 alleles were Chinese-specific. The genotyping chip developed in this study is an efficient, economic and accurate system for screening multiple SNPs in a large population. Application of such technology is expected to be less labor intensive and easier to adapt to specific searches when compared with other methodologies.
ABSTRACT
Pulsed-field gel electrophoresis, ribotyping, and fingerprinting analysis of 22 invasive isolates of multidrug-resistant (MDR) pneumococci from Korea showed that 59 to 82% were genetically ...related. DNA sequencing of the PBP 2B gene showed relatively uniform alterations in nucleotides (5.4 to 7.8%) and amino acids (3.0 to 4.3%), while Asn-276→Lys, Arg-285→Cys and Ser-305→Phe substitutions were unique to Korean MDR strains, suggesting the spread of a few epidemic clones of resistant pneumococci within Korea.
This study aimed to gain mechanistic insights into the nature of the pore pathway of fully hydrated human stratum corneum from lag time data obtained using a model polar permeant, urea. Lag times ...were deduced from transport experiments with human epidermal membranes and with human epidermal membranes after ethanol or chloroform–methanol treatment. A tortuous pore pathway transport model and a `bottleneck' transport model were employed for data analysis, and their appropriateness for the observed data was examined. Important outcomes from the present study with intact and with delipidized stratum corneum were as follows. Long lag times (around 60–800 min) for the transport of urea in human epidermal membranes were generally observed. These results were consistent with an extremely tortuous pore pathway as would be expected if it is associated with the polar/aqueous region of the stratum corneum intercellular lipids (i.e. the bilayers in the intercellular region). The permeability of the stratum corneum increased after ethanol treatment, and, at the same time, the tortuosity decreased but remained relatively high. Chloroform–methanol treatment further increased the permeability and further decreased the tortuosity. Since delipidization by ethanol and chloroform–methanol treatments decreased the tortuosity of the pore pathway, these results suggest that the effectively highly tortuous pathway for polar permeants in stratum corneum may be associated with the polar regions of the intercellular lipids. Untreated skin samples that had high electrical resistance were observed to have longer lag times than those with low resistance; this is consistent with the hypothesis that skin samples of high resistance have less appendage routes or less damage and transport polar permeants predominantly via the tortuous pathways involving the intercellular lipid regions of the stratum corneum. Neither the tortuous pathway transport model alone nor the `bottleneck' transport model alone seems to perfectly represent the experimental data, and a modified model (a hybrid of the two models) has been proposed to be more consistent with the lag time data and the morphology of fully hydrated stratum corneum. The present study has demonstrated the usefulness of lag times obtained with a polar permeant in better understanding the transport mechanisms involved with the pore pathway.
The MACRO underground detector at Grarl Sasso has recorded about 30 million muon events in the period 1989–1995. We have analyzed these data to look for time variations and to study the pointing ...capabilities of the apparatus in the search for astrophysical point sources. We have observed a 3% seasonal variation of the high energy muon rate, due to atmospheric temperature variations, in agreement with theoretical predictions. We report also the detection of the moon shadowing effect with a statistical significance of 3.7 σ. The results obtained straighten the possibility that a “muon astronomy” using underground experiments is possible.
Multi-voxel MR spectroscopic imaging (MRSI) provides chemical metabolite information that can supplement conventional MR imaging in the study of intracranial neoplasia. Our purpose was to use a ...robust semi-automated spectroscopic analysis to distinguish intracranial tumours from non-neoplastic disease.
Twenty intracranial tumours and 15 patients with non-neoplastic disease confirmed on histological examination or serial neuroimaging were studied with 2-dimensional MRSI using point-resolved spectroscopic (PRESS) imaging localisation. Using semi-automated post-processing software, spectra were analysed for peak heights of choline (Cho), creatine (Cr), N-acetyl aspartate (NAA), lactate (Lac) and lipid (Lip). Normalised Cho (nCho) ratios, computed by dividing maximum Cho in the lesion by the normal-appearing brain, were compared between intracranial tumours and non-neoplastic disease.
Meningiomas displayed homogeneously elevated Cho. Malignant tumours, especially large glioblastoma multiforme, displayed inhomogeneity of metabolites within the tumour. All tumours had elevation of nCho >1 (mean 1.91 +/- 0.65), and non-neoplastic diseases had tumour nCho <1 (mean 0.91 +/- 0.46), which was significantly lower (P <0.05). Two patients with non-neoplastic lesions, one with subacute cerebral infarction and the other with cryptococcoma, had elevated Cho compared to normal tissue (false positive rate 13%).
Using semi-automated MRSI method, a simplified normalised Cho algorithm provides a method to distinguish intracranial tumours from non-neoplastic disease.
The adsorption and reaction of acetylene on Pt(111) and the p(2times2) and (radical3timesradical3)R30degreesSn/Pt(111) surface alloys were investigated with low energy electron diffraction (LEED), ...temperature programmed desorption (TPD), and Auger electron spectroscopy (AES). The presence of Sn atoms at the surface of the p(2times2) and (radical3timesradical3)R30degreesSn/Pt(111) surface alloys strongly suppressed the decomposition of acetylene (Csub 2Dsub 2) to deuterium and adsorbed carbon. As a result, a new reaction path is opened on the Sn/Pt(111) surface alloys-benzene formation. Besides benzene desorption, the authors also observed butadiene desorption, which is obviously a Csub 4 product of a stable intermediate in benzene production. The (radical3timesradical3)R30degreesSn/Pt(111) surface shows the highest activity and selectivity for the formation of benzene and butadiene. Following Csub 2Dsub 2 adsorption on the Pt(111) surface at 110 K, LEED shows a faint (2times2) pattern. After saturation dosing of acetylene on the p(2times2)Sn/Pt(111) surface at 110 K they find a large increase in the (2times2) LEED pattern intensity. This implies that an acetylene (2times2) substructure also forms on the p(2times2)Sn/Pt(111) surface. 30 refs., 6 figs.
To describe a surveillance system and summarize data between January 2000 and December 2002 regarding diffuse lamellar keratitis (DLK), a complication of laser in situ keratomileusis (LASIK) surgery.
...Community-based clinics in British Columbia, Canada, in which LASIK surgery is performed.
Monthly, all clinics in which LASIK is performed reported the number of LASIK procedures and nonnominal cases of DLK (by grade and onset date) to the British Columbia Centre for Disease Control. Diffuse lamellar keratitis outbreaks were investigated, and prevention and control measures were recommended.
From 2000 to 2002, approximately 72,000 LASIK procedures were performed, with a mean DLK incidence rate of 0.67% (95% confidence interval, 0.61-0.73). The overall proportion of DLK cases attributed to outbreaks was 64%, decreasing from 72% in 2000 to 40% in 2003.
An effective DLK surveillance program was implemented at all laser refractive clinics in British Columbia. Reported DLK incidence was 0.67 cases per 100 procedures, with 64% occurring in outbreaks.
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