In vivo effect of clarithromycin on multiple cytochrome P450s.

The in vivo effects of oral clarithromycin administration on the in vivo activity of cytochrome P450 1A2, 2C9, and 2D6 were determined. The cytochrome P450 probes caffeine (CYP1A2), tolbutamide (CYP2C9), and dextromethorphan (CYP2D6) were administered as an oral cocktail prior to and 7 days after oral clarithromycin (500 mg twice daily) administration to 12 healthy male subjects. Blood and urine samples were collected and assayed for each of the compounds and their metabolites using high-performance liquid chromatography. The CYP1A2 indices, oral caffeine clearance (6.2 +/- 3.3 l/h before and 5.7 +/- 4.2 l/h after, p > 0.05) and the 6-h paraxanthine to caffeine serum concentration ratio (0.49 +/- 0.3 before and 0.44 +/- 0.3 after, p > 0.05), were unchanged following clarithromycin dosing. Neither the tolbutamide oral clearance (0.77 +/- 0.28 l/h before and 0.72 +/-0.24 l/h after, p > 0.05) nor the tolbutamide urinary metabolic ratio (779 +/- 294 before and 681 +/- 416 after, p > 0.05) indices of CYP2C9 were altered by clarithromycin administration. In the case of CYP2D6, the dextromethorphan to dextrorphan urinary ratio was not significantly different before (0.021 +/- 0.04) and after (0.024 +/- 0.06) clarithromycin dosing. In conclusion, clarithromycin does not appear to alter the in vivo catalytic activity of CYP1A2, CYP2C9, and CYP2D6 in healthy individuals as assessed by caffeine, tolbutamide, and dextromethorphan, respectively.

The effect of rifampin administration on the disposition of fexofenadine.

OBJECTIVE: Our objective was to assess the effect of rifampin (INN, rifampicin) on the pharmacokinetics of fexofenadine and to assess the influence of advanced age and sex. METHODS: Twelve young volunteers (6 men and 6 women; age range, 22 to 35 years) and twelve elderly volunteers (6 men and 6 women; age range, 65 to 76 years) received a 60-mg oral dose of fexofenadine before and after treatment with 600 mg of oral rifampin for 6 days. Blood and urine were collected for 48 hours and assayed for fexofenadine, azacyclonol, and rifampin by HPLC with either fluorescence or mass spectrometry detection. RESULTS: All of the groups had a significant increase (P <.05) in the oral clearance of fexofenadine after rifampin treatment: young men, 2955 +/- 1516 versus 5524 +/- 3410 mL/min; young women, 2632 +/- 996 versus 7091 +/- 5,379 mL/min; elderly men, 1760 +/- 850 versus 4608 +/- 1159 mL/min; and elderly women, 2210 +/- 554 versus 4845 +/- 1600 mL/min. The peak serum concentration of fexofenadine was also significantly reduced (P <.05) by rifampin treatment: young men, 77 +/- 31 versus 52 +/- 17 ng/mL; young women, 72 +/- 19 versus 36 +/- 14 ng/mL; elderly men, 106 +/- 42 versus 52 +/- 14 ng/mL; elderly women, 76 +/- 23 versus 46 +/- 19 ng/mL. Half-life (150 to 230 minutes), time to maximum concentration (130 to 205 minutes), renal clearance (95 to 153 mL/min), and fraction unbound (2.9% to 3.7%) of fexofenadine showed no significant difference between control and treatment. The amount of azacyclonol, a CYP3A4 mediated metabolite of fexofenadine, eliminated renally increased on average 2-fold after rifampin dosing; however, this pathway accounted for less than 0.5% of the dose. No effect of age or sex on fexofenadine disposition or serum trough rifampin concentration (0.2 microg/mL to 1.8 microg/mL) was observed before or after rifampin treatment. CONCLUSION: This study showed that rifampin effectively increased fexofenadine oral clearance and that this effect was independent of age and sex. We conclude that the cause of the increased oral clearance of fexofenadine is a reduced bioavailability caused by induction of intestinal P-glycoprotein.

Calibration assessment in quantitative electroencephalographic brainmapping and evoked potential studies.

Acquisition of a Cadwell Spectrum 32 resulted in the introduction of quantitative electrophysiological brainmapping techniques in our neurophysiology laboratory. To ascertain the accuracy and consistency of our equipment, we performed the following tests: inputting a calibration signal and measuring the resultant amplitudes for quantitative electroencephalographs (qEEGs) and evoked potentials (EPs) in the mapping and standard montages, inputting a synchronous calibration signal and mapping it at varying times for qEEGs and EPs, as well as re-analysing the same electroencephalographic (EEG) epochs previously selected from 20 control subjects. QEEG amplitudes varied from -5.4% to +5.8% and EPs by 9.5% or less, and after an EP software upgrade, by 5.5% or less. QEEG voltage mapping showed variation of only one color increment across the map, which could, in our example, represent up to 25.2% of the scale used. Re-analysis of previously selected epochs yielded identical results. We have established some of the accuracy and consistency limits of the hard- and software of our system with respect to the quantitative and topographic data. We conclude that such systems need to be calibration-checked in the laboratories in which they are used, with an independent signal generator. Users also need to be aware that scaling of topographic maps could lead to erroneous conclusions, as perceived amplitude changes could affect the interpretation of both initial and serial studies.

Quality assurance in a neurophysiology laboratory.

In order to assess patient satisfaction with the Neurophysiology Services within our department, we undertook a pilot study using a simple questionnaire designed by staff members (MAHB and ABB). Patients were approached after their tests (nerve conduction tests (NCTs), electromyography (EMG) and electroencephalography (EEG)) were completed, by staff not involved in the testing. 31 patients were approached and all completed the questionnaire. None reported being inconvenienced by an undue waiting time. All felt that adequate information about the test had been provided, that their personal comfort and feelings were considered, and that they were adequately informed of the time and place at which the test results would be available. 61% considered their overall treatment excellent, the remainder good. To date, increased departmental awareness has resulted in staff participation in program evaluation, design of an outcomes hierarchy for the department, redesigning the patients' waiting area and, overall, a more active participation in quality assurance. We see this pilot study as a baseline for future more in-depth client and staff evaluations thereby promoting quality performance improvement.

Interoperator variability in quantitative electroencephalography.

The purpose of the study was to determine whether quantitative or discriminant analysis of the electroencephalograph (EEG) would vary significantly when the same EEG was analysed by 3 different operators. EEGs on 10 healthy volunteers were recorded on the Cadwell Spectrum AT 386, using the Electrocap (10-20 system). The EEGs were analysed independently, with each operator selecting the first 48 artifact-free epochs. The results were analysed using the non-parametric Friedman two-way analysis of variance (ANOVA) for the discrimination analysis and a one-way ANOVA for the monopolar and bipolar Absolute Power raw measures. Statistical analysis of the discriminant data showed no significant differences between operators, with 7 of 10 studies yielding the same results. The remaining 3 studies were classified either as borderline or normal when analysed by different operators. Although a series of "t" tests comparing 2 operators showed most variability occurring in Absolute Power as compared with Relative Power, Power Asymmetry and Coherence, ANOVA of the raw mono- and bipolar Absolute Power measures showed no significant differences between the operators at the P = 0.05 level. Thus the differences between the operators were non-significant when comparing quantitative EEG analyses with respect to both the raw measures and the discriminant analyses.

Familial spastic paraplegia: an electrophysiological study of central sensory conduction pathways.

An electrophysiological assessment has been performed studying somatosensory, visual and auditory pathways in clinically affected and unaffected members from 4 pedigrees with the autosomal form of 'pure' familial spastic paraplegia (n = 32). In some members from 2 families, testing of all 3 sensory pathways showed abnormal results, even in those clinically unaffected. In another family, some had abnormal somatosensory and visual pathways, with no involvement of the auditory pathway. In a further family, the somatosensory and brainstem auditory pathways were abnormal, with sparing of the visual pathway. These findings indicate that the neuronal degeneration in familial spastic paraplegia extends beyond the spinal cord and involves the visual and auditory pathways. The differences between families, and the asymptomatic abnormalities in clinically unaffected members, suggest diversity in the expression of the genetic defect.

Physical mapping of a translocation breakpoint in neurofibromatosis.

The gene for von Recklinghausen neurofibromatosis (NF1), one of the most common autosomal-dominant disorders of humans, was recently mapped to chromosome 17 by linkage analysis. The identification of two NF1 patients with balanced translocations that involved chromosome 17q11.2 suggests that the disease can arise by gross rearrangement of the NF1 locus, and that the NF1 gene might be identified by cloning the region around these translocation breakpoints. To further define the region of these translocations, a series of chromosome 17 Not I-linking clones has been mapped to proximal 17q and studied by pulsed-field gel electrophoresis. One clone, 17L1 (D17S133), clearly identifies the breakpoint in an NF1 patient with a t(1;17) translocation. A 2.3-megabase pulsed-field map of this region was constructed and indicates that the NF1 breakpoint is only 10 to 240 kilobases away from 17L1. This finding prepares the way for the cloning of NF1.

Effect of acetate infusion on energy expenditure and substrate oxidation rates in non-diabetic and diabetic subjects.

Sodium acetate was infused intravenously at 2.5 mmoles/min for 60 min into 6 normal subjects and 6 non-insulin dependent diabetic patients. In control experiments the same subjects received equimolar sodium bicarbonate infusions. Plasma non-esterified fatty acid and blood glycerol levels fell during acetate infusion in both groups, suggesting impairment of lipolysis. The respiratory quotient fell on acetate infusion as expected, although total energy expenditure was unaffected. If acetate oxidation was assumed to be 90 per cent of the infusion rate, then it accounted for about 40 per cent of total oxygen consumption; fat oxidation was reduced, whilst carbohydrate oxidation was unchanged. These results suggest that resting energy expenditure is maintained during acetate infusion since acetate replaces fat as an oxidative fuel, without affecting glucose oxidation. The reduction in fat oxidation appears to be due to reduced fat mobilization from adipose tissue. The metabolic effects of acetate infusion are similar in normal and in non-insulin dependent diabetic subjects.

A refined genetic map of the region of chromosome 17 surrounding the von Recklinghausen neurofibromatosis (NF1) gene.

The von Recklinghausen neurofibromatosis (NF1) gene has been mapped to the pericentromeric region of chromosome 17. We conducted linkage analyses of NF1 by using 10 polymorphic DNA markers from this chromosomal region. We ascertained 20 American Caucasian NF1 families (163 individuals, 98 NF1 affected) in Michigan and Ohio and also studied a large family ascertained primarily in North Carolina. The following markers were used in this study: HHH202, TH17.19, D17Z1, ERBA1, EW203, EW206, EW207, EW301, CRI-L581, and CRI-L946. NF1 did not recombine with either TH17.19 or HHH202 in any of the informative meioses surveyed (maximum lod scores of 17.04 and 7.21, respectively, at a recombination fraction of .00), indicating that these markers map very close to the NF1 gene. We also report evidence of three instances of recombination between NF1 and the centromeric marker D17Z1 (maximum lod score of 13.43 at a recombination fraction of .04), as well as two crossovers between pairs of marker loci. We find no evidence of locus heterogeneity, and our results support the localization of the NF1 gene to proximal chromosome 17q.

Evaluation of evoked potentials and cerebrospinal fluid analysis in the differential diagnosis of multiple sclerosis.

During the 6 years to December 1988, 191 patients underwent evoked potential (EP) studies and cerebrospinal fluid (CSF) analysis for oligoclonal bands at the Queen Elizabeth Hospital, for the differential diagnosis of multiple sclerosis (MS). Clinical data at the time of study separated patients into 3 groups, as follows: (i) multiple sclerosis (n = 90) - McDonald and Halliday Classification, 1977, (ii) other neurological disease (n = 82) and (iii) no neurological disease (n = 19). In cases of clinically definite MS, visual evoked potentials (VEPs) were abnormal and oligoclonal bands were detected in 64% and 59% of cases, respectively. However, only 15% of patients with suspected MS had abnormal VEPs, and only 23% had oligoclonal bands. Other studies have shown figures differing from these, though not necessarily significantly. We found a substantial number of EP (20%) but few CSF (4%) abnormalities in disorders other than MS, and no abnormalities in cases without neurological disease. The various figures for abnormal results in cases assessed for the differential diagnosis of MS are influenced not only by laboratory methods, but by the degree of clinical suspicion in relation to the cases selected, as well as by differences in populations from which cases are derived. Long-term prospective studies of diagnostically indeterminate cases are still required to determine the diagnostic weighting that can be applied on the basis of abnormal investigational results. Magnetic resonance imaging will not resolve these questions since it has limitations of its own, particularly with regard to specificity.

The flight of colours test. Its value as an indicator of dysfunction of the visual pathways.

The flight of colours (FOC) test was compared with visual evoked potentials (VEPs) in 135 patients in a 2 year prospective study, to determine whether the FOC test is a sensitive and reliable alternative. We obtained an 80% overall agreement between the tests, confirming the levels of agreement reported by Rolak (87%) and Swart and Millac (92%). Abnormal VEPs, however, were more closely associated with cases of clinically definite multiple sclerosis (MS) while abnormal FOCs were more frequent in cases of non-demyelinating disease and cases without clinically evident optic nerve or other ocular disorder. We cannot explain this result by any demonstrated superiority of the FOC test over VEPs in non-demyelinating visual disturbances, whether clinically evident or not. Thus the study does not confirm the earlier expectation that the FOC test would be a reliable alternative to the study of VEPs in the differential diagnosis of MS.

Linkage analysis of von Recklinghausen neurofibromatosis to DNA markers on chromosome 17.

Several recent studies indicate that the von Recklinghausen neurofibromatosis (NF1) gene is located near the centromere of chromosome 17 in some families. However, variable expressivity and a very high mutation rate suggest that defects at several different loci could result in phenotypes categorized as NF1. In order to assess this possibility and to map the NF1 gene more precisely, we have used two polymorphic DNA markers from chromosome 17 to screen several pedigrees for linkage to NF1. We ascertained a large Caucasian pedigree (33 individuals sampled, 17 NF1 affected) as well as eight smaller pedigrees and nuclear families (50 individuals sampled, 30 NF1 affected). Here, we report strong evidence of linkage of NF1 to the centromeric marker D17Z1 (maximum lod = 4.42) and a weaker suggestion of linkage to the ERBA1 oncogene (maximum lod = 0.57), both at a recombination fraction of zero. Since obligate cross-overs with NF1 were not observed for either marker in any of the informative families tested, the possibility of NF1 locus heterogeneity is not supported.

Leucocyte sodium pump activity after meals or insulin in normal and obese subjects: cause for increased energetic efficiency in obesity?

As cellular sodium pumping is an energy consuming process and differences in the obese may account for their energetic efficiency, leucocyte sodium-22 efflux was studied in obese and normal volunteers both in the fasting state and after a test meal or infusion of glucose and insulin intravenously. The 22Na ouabain sensitive efflux rate constant was significantly higher in obese subjects than normal (mean (1 SD) 2.69 (0.40)/h v 2.35 (0.49)/h). Two hours after a 4.2 MJ (1000 kcal) meal there was an increase in the efflux rate constant from its fasting value in normal weight subjects (2.39 (0.33)/h to 2.71 (0.40)/h) but not in obese subjects (2.65 (0.54)/h to 2.61 (0.58)/h). The rise in ouabain sensitive efflux rates was significantly higher in normal than obese subjects. Both groups showed a rise in intracellular sodium concentrations. The euglycaemic clamp produced similar results. Feeding or infusion of insulin increases sodium pump activity more in normal than obese subjects. This difference may contribute to any defective dietary thermogenesis in obesity, which may lead to energetic efficiency and a tendency to gain weight.

Criterion-referenced measurement in the college classroom.

One format was presented that met the practical parameters of classroom education while improving the clarity and effectiveness of classroom testing, and facilitating the assurance of future practitioner competence. While employing criterion-referenced testing, this format did not adhere strictly to a competency-based model, nor were test questions evaluated for statistical validity or reliability. Criterion-referenced measurement has the potential to be a meaningful tool in professional education, but it is not a panacea for educational demands. Difficult questions confront every educator who considers using criterion-referenced measurement toward a goal of student mastery. Criterion-referenced measurement is practical, and the educators who use it make a statement regarding their beliefs about the education process.

Atypical electrocardiogram in acute pericarditis: characteristics and prevalence.

Stage One ST segment deviations are virtually diagnostic of acute pericarditis when typically distributed among limb and precordial ECG tracings. Atypical ECG responses include absence of ST deviations, which conceals the diagnosis, and restricted distribution of ST deviations, which suggests myocardial injury. Among 44 consecutive patients with acute pericarditis, 19 (43%) had atypical ECGs. Although all 19 had a pericardial rub, eight had no ST deviations in the limb leads and seven developed no ST changes, including three with no ECG abnormalities of any kind. Patients with typical ECGs by ST segment criteria were more likely to progress to T wave inversion. PR segment deviations occurred in 14 patients with typical, and 14 with atypical ECGs. In four of the latter, the PR segment shifts were the only ECG sign. Presence or absence of heart disease and etiology of pericarditis could not be statistically associated with particular electrocardiographic responses.