MR spectroscopy findings in early stages of motor neuron disease.

BACKGROUND AND PURPOSE: Upper motor neuron degeneration varies in different phenotypes of MND. We used single-voxel MR spectroscopy of the primary motor cortex to detect corticomotoneuron degeneration and glial hyperactivity in different phenotypes of MND with a relatively short disease duration, contributing to further delineation of the phenotypes. MATERIALS AND METHODS: We prospectively included patients with ALS-B, ALS-L, and PMA and compared their data with those of patients with PLS and healthy controls. Each cohort consisted of 12 individuals. Disease duration was <1 year in ALS and PMA, but longer in PLS by definition. Follow-up examination was at 6 months. We measured ALSFRS-R, finger- and foot-tapping speed, and levels of the following: 1) NAAx, 2) mIns, and 3) Glx in the primary motor cortex. RESULTS: At baseline, we found significantly decreased NAAx levels and increased mIns levels in PLS. Levels of NAAx and mIns in patients with ALS-L and ALS-B were not significantly different from those in controls, but NAAx levels were significantly lower compared with those in PMA. At follow-up, only in PMA was a decrease of NAAx demonstrated. Glx levels varied widely in all groups. Levels of NAAx and mIns correlated well with clinical variables. CONCLUSIONS: Metabolite changes suggest neuronal dysfunction and active glial involvement in PLS. The corticomotoneuron is affected in early ALS-B and ALS-L, but at a later stage also in PMA. MR spectroscopy data are useful to obtain insight into the disease process at the level of the upper motor neuron in various phenotypes of MND.

Clinical identification of dysarthria types among neurologists, residents in neurology and speech therapists.

BACKGROUND: Classification of dysarthria types comprises flaccid, spastic, ataxic, hypo- and hyperkinetic and mixed dysarthria. This study focussed on the ability of neurologists to clinically identify the correct type of dysarthria in neurological patients. METHODS: Eighteen patients with dysarthria and 4 healthy controls were enrolled in the study. The gold standard for dysarthria type was the underlying neurological disease. Recordings of a standard reading passage and free speech were made. Raters were neurologists, residents in neurology and speech therapists, whose scores were compared. RESULTS: Neurologists correctly identified 40% of the recordings, residents 41%, and speech therapists 37%. Interrater agreement was fair among all 3 groups; intrarater agreement was fair to moderate. CONCLUSION: This study suggests that neurologists should be aware of the unreliability of identifying the dysarthria type without the use of additional validated instruments or rating scales in a clinical setting.

Upper motor neuron and extra-motor neuron involvement in amyotrophic lateral sclerosis: a clinical and brain imaging review.

There is an ongoing discussion whether ALS is primarily a disease of upper motor neurons or lower motor neurons. We undertook a review to assess how new insights have contributed to solve this controversy. For this purpose we selected relevant publications from 1995 onwards focussing on (1) primary targets and disease progression in ALS and variants of ALS, (2) brain imaging markers for upper motor neuron lesion, and (3) evidence for ALS being a multisystem disorder. Clinically, upper motor and lower motor neuron symptoms can occur in any order over time. Brain imaging markers show upper motor neuron involvement in early disease. Overlap syndromes of ALS and dementia, and involvement of autonomic and sensory nerves occur frequently. PET/SPECT scans, functional MRI and voxel based morphometry studies clearly show abnormalities in extra-motor areas of the brain. Pathologically, the 43 kDa TAR DNA-binding protein (TDP-43) provides a clue to these overlapping disorders. In conclusion, evidence accumulates that ALS is a multisystem disorder rather than a pure lower and/or upper motor neuron disorder.

Multidisciplinary ALS care improves quality of life in patients with ALS.

OBJECTIVE: To examine the effect of multidisciplinary ALS care on the quality-of-life (QoL) in patients with ALS and their caregivers. METHODS: In a cross-sectional study, 208 patients with ALS and their caregivers were interviewed. QoL was assessed using the 36-item Short Form Health Survey (SF-36) and two visual analogue scales (VAS). Criteria for multidisciplinary ALS care were: an ALS team headed by a consultant in rehabilitation medicine and consisting of at least a physical therapist, occupational therapist, speech pathologist, dietician and a social worker; use of the Dutch ALS consensus guidelines for ALS care; and at least six incident ALS patients per year. RESULTS: Clinical characteristics and functional loss of the 133 patients receiving multidisciplinary ALS care and the 75 patients receiving general ALS care were similar. The percentage of patients with adequate aids and appliances was higher in those with multidisciplinary ALS care (93.1 vs 81.3%, p = 0.008), whereas the number of visits to professional caregivers was similar in both groups. Patients in the multidisciplinary ALS care group had a better mental QoL on the SF-36 Mental Summary Score than those in the general care group (p = 0.01). The difference in QoL was most pronounced in the domains of Social Functioning and Mental Health, and was independent of the presence of aids and appliances. No significant differences were found in the SF-36 Physical Summary Score, VAS, or in QoL of caregivers of patients with ALS. CONCLUSION: High standard of care improves mental quality-of-life in patients with ALS.

Unilateral thalamic infarction and vertical gaze palsy: cause or coincidence?

Although vertical gaze palsy (VGP) is commonly associated with lesions of the rostral mesencephalon, there is some evidence that VGP may also be caused by a unilateral thalamic lesion. The case of a 68-year-old man with persistent upward gaze palsy after a unilateral thalamic infarction, demonstrated on computed tomography and magnetic resonance imaging scans, is presented. Subsequent high-resolution magnetic resonance scanning, however, showed involvement of the rostral mesencephalon as well. The authors suggest that in previous patients with VGP ascribed to a unilateral thalamic infarction, a coexisting mesencephalic involvement may have been missed because of inappropriate imaging techniques. Strong evidence of unilateral thalamic infarction as a cause of VGP is still lacking.

Correlation of apparent intrinsic clearances of simultaneously administered S (+) and d3R (-) hexobarbital in the rat.

Pseudoracemic hexobarbital (HB), consisting of equal molar fractions of S (+) HB and deuterium-labeled R (-) HB, d3 R (-) HB, was administered orally to rats in a dose of 50 mg/kg. Concentrations of both enantiomers in blood were measured by an enantioselective mass fragmentographic assay. Clearance data of S (+) HB and d3 R (-) HB were correlated in untreated rats, and in rats pretreated with 3-methylcholanthrene (MC), carbon tetrachloride (CCl4), and different doses of phenobarbital (PB). Although in the different groups some variation in the clearance ratio of S (+) HB over d3 R (-) HB was found, the clearance of S (+) HB was generally up to a factor of five higher than the clearance of d3 R (-) HB, except for the CCl4-treated rats. From the present data it can be tentatively concluded that S (+) HB and R (-) HB are metabolized by similar (PB-inducible) cytochrome P-450s in control and PB- and MC-pretreated rats and that clearance data obtained with racemic HB following different pretreatments may be employed as a reflection of (PB-inducible) cytochrome P-450 activity.

Correlation between the metabolism of hexobarbital and aminopyrine in vivo in rats.

Two model substrates for oxidative hepatic enzyme activity, namely hexobarbital and aminopyrine, were simultaneously orally administered to rats, and blood concentrations of the substrates measured by g.l.c. The apparent intrinsic clearances of hexobarbital (Cl*int.HB) and of aminopyrine (Cl*int,AM) were correlated in untreated rats, and in rats pretreated with phenobarbital, 3-methylcholanthrene, polychlorinated biphenyls or carbon tetrachloride. Cl*int,HB and Cl*int,AM were both increased by phenobarbital and polychlorinated biphenyl pretreatment. Pretreatment with 3-methylcholanthrene had hardly any effect, and carbon tetrachloride caused a strong diminution of Cl*int.HB and Cl*int.AM. When the dose of aminopyrine was decreased, both Cl*int,HB and Cl*int,AM increased. This indicated that the primary metabolite of aminopyrine, monomethylaminopyrine, inhibits cytochrome P-450. The correlation coefficient for all clearance data was 0.92 (N = 36). It was concluded that both hexobarbital and aminopyrine are metabolized in vivo by the same or closely related cytochrome P-450 isozymes, and both may be used as model substrates in vivo for metabolic conversions primarily mediated by the major phenobarbital-inducible cytochrome P-450 subspecies.

Non-linear pharmacokinetics of sparteine in the rat.

In rats, blood concentrations of sparteine (SP) and relative concentrations of sodium borohydride-reducible metabolite following intra-arterial (i.a.) and portal venous administration of SP-sulphate were estimated up to 200 min. In 24 hr urine, unchanged SP was quantitated. Borohydride-reducible metabolite was measured as the difference in SP concentrations before and after reduction. Administration of SP in a dose of 50 mg/kg SP-sulphate i.a. revealed a blood concentration-time profile which did not allow characterization of the terminal half-life or systemic clearance. Therefore, the dose over the area under the curve up to 120 min after administration, CL0-120app, was defined as an apparent average clearance value over the time interval studied. After a dose of 50 mg/kg the CL0-120app was 34.8 +/- 5.9 ml/min/kg when administered i.a. and 80.4 +/- 7.5 ml/min/kg when administered via the portal vein, thus affording an estimate of 0.64 +/- 0.12 for the hepatic extraction ratio. A possible biliary excretion and enterohepatic circulation was studied in rats with a bile fistula. Although SP levels in blood were lower than in control rats, no SP was excreted in the bile and excretion of SP in urine was even slightly higher, which renders circulation of SP itself unlikely. About 25% of the dose was recovered in 180 min bile as borohydride-reducible metabolite, but the urinary excretion of borohydride-reducible metabolite was not changed. The gradual levelling-off of blood concentration versus time curves may partly be explained by the formation of reactive intermediates in the course of metabolism, which inactivate P-450. In support of this, the intrinsic clearance of orally administered hexobarbital (25 mg/kg) was determined 5 and 50 min after i.a. administered SP-sulphate (50 mg/kg), and decreased from 343 +/- 18 to 220 +/- 36 ml/min/kg (p less than 0.05).

Dose-dependent pharmacokinetics of zoxazolamine in the rat.

Zoxazolamine (ZX) is a model substrate frequently used in studies on (methylcholanthrene-inducible) hepatic cytochrome P-450 activity. The iv pharmacokinetics of ZX were studied in rats at four dose levels: 5 mg X kg-1 (n = 6), 25 mg X kg-1 (n = 6), 50 mg X kg-1 (n = 5), and 60 mg X kg-1 (n = 4). Concentrations of ZX in blood, as well as the urinary excretion of unchanged ZX and chlorzoxazone, were determined. The apparent systemic clearance (CLs,app) decreased with increasing dose from 52.6 +/- 3.9 at 5 mg X kg-1 to 9.3 +/- 0.4 ml X min-1 X kg-1 at 60 mg X kg-1. The apparent elimination half-life, t1/2,app, increased from 16.1 +/- 0.3 min to 141 +/- 28.5 min. There was only slight concentration dependency of plasma protein binding: 86.0 +/- 0.9% at 4.2 +/- 0.2 micrograms X ml-1 (n = 6) vs. 80.4 +/- 0.4% at 27.1 +/- 1.1 micrograms X ml-1 (n = 6). Since from clearance and protein binding data nonrestrictive clearance of ZX could be inferred, this small change in binding was regarded as irrelevant for the interpretation of pharmacokinetic data of ZX. The blood-plasma concentration ratio was larger than unity: 2.11 +/- 0.09 at 5.4 +/- 0.9 micrograms X ml-1, and 1.85 +/- 0.08 at 47.9 +/- 4.9 micrograms X ml-1 (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of orally administered hexobarbital in plasma and saliva of healthy subjects.

Hexobarbital (HB) concentrations were determined in plasma and saliva of 8 healthy subjects, following oral administration of 500 mg HB-Na. Mean plasma half-lives were 3.2 +/- 0.1 h, and salivary half-lives 3.3 +/- 0.2 h. Mean plasma clearance was 22.9 +/- 2.3 1 h-1. There was a linear relationship between HB concentrations in saliva and plasma (r = 0.92). Mean salivary levels were 34 per cent of plasma levels. Salivary pH was constant throughout the experiment, 7.06 +/- 0.09. There was an inconsistent tendency of the saliva over plasma ratios to increase as a function of time. The percentage of protein binding calculated from saliva over plasma ratios was in reasonable agreement with in vitro data of equilibrium dialysis, 64.1 +/- 2.6 per cent and 65.9 +/- 0.8 per cent, respectively. The experiment was repeated in 4 subjects, and considerable intraindividual differences were shown to exist in saliva over plasma ratio, half-lives, and protein binding. It was concluded that HB elimination half-lives can relatively accurately be determined from salivary concentrations. Oral plasma clearance can only be estimated if the individual saliva over plasma ratios are known; this would require the taking of at least one blood sample during the experiment. When employing HB as a model substrate for drug metabolizing enzyme activity in vivo, the determination of its pharmacokinetic parameters, particularly oral plasma clearance as a reflection of cytochrome P-450 activity, cannot be achieved by taking saliva samples only.

Intra-arterial administration of hexobarbital enantiomers to the rat: disposition and estimation of apparent extraction ratio.

The enantiomers of hexobarbital, designated as S(+)-HB and R(-)-HB, were administered intra-arterially to rats in a dose of 25 mg X kg-1. Blood pharmacokinetics of the parent compound and two metabolites as well as urinary excretion of three major metabolites were studied. Using previously obtained data following oral administration of S(+)-HB and R(-)-HB two different methods for calculation of the hepatic extraction ratio (E) were compared. The metabolite profile in the urine after intra-arterial administration was not basically different from corresponding data on oral administration. The clearance of low-dose, intra-arterially administered S(+)-HB is useful as an indicator of hepatic blood flow in the rat.

Disposition of allylic oxidation pathway metabolites of racemic hexobarbital in the rat.

The pharmacokinetics in blood of the major metabolites of hexobarbital (HB), 3'-hydroxyhexobarbital (OH-HB) and 3'-ketohexobarbital (K-HB) were studied in rats. In addition urinary excretion of OH-HB and K-HB and 1,5-dimethylbarbituric acid (DMBA) was determined. Half-lives of OH-HB and K-HB were slightly longer than that of the parent drug. Urinary recovery of OH-HB, K-HB and DMBA following i.a. administration of OH-HB (75%) was more complete than the recovery following i.a. administration of K-HB (52%). Most probably further metabolism of K-HB takes place. Of K-HB, 41% was excreted renally, and 3.4% of K-HB reverted back to OH-HB. Of OH-HB, about 45% was excreted renally, following p.o. or i.a. administration. Since about 10% of both OH-HB and K-HB was converted to DMBA, it seems that the epoxide-diol pathway as proposed for HB also plays a minor role in the metabolism of OH-HB and K-HB. It is further concluded that measuring allylic pathway oxidation metabolites of HB does not improve the usefulness of HB as a model compound in the assessment of the activity of oxidative drug metabolizing activity.

Selected ion monitoring analysis of pseudoracemic hexobarbital and its major metabolites in blood and urine of rats.

A stereospecific synthesis of N1-(2H3)-labelled R(-)-hexobarbital is described. A sensitive and rapid selected ion monitoring assay procedure for pseudoracemic hexobarbital, consisting of equal amounts of S(+)-hexobarbital (1a) and (2H3)-R(-)-hexobarbital (1b) in 100 microliters blood samples of rats was developed. Both the parent enantiomers in blood and three major metabolites excreted in urine were quantified. An application of the method in rats is described, and the results are compared to previously obtained data of separately administered enantiomers.

Route- and dose-dependent pharmacokinetics of hexobarbitone in the rat: a re-evaluation of the use of sleeping times in metabolic studies.

The metabolic clearance (CL) and half-life of racemic hexobarbitone and sleeping time were studied in rats following intra-arterial (i.a.), intraperitoneal (i.p.) and oral (p.o.) administration, at dose levels of 25 and 100 mg kg-1 of its sodium salt. CLp.o. was higher than CLi.a. at both 25 and 100 mg kg-1. CLi.a. and CLi.p. values were much lower, but CLi.p. was higher than CLi.a. at 25 mg kg-1 and lower than CLi.a. at 100 mg kg-1. There was no distinct dependency of the half-lives on route of administration, but a slight increase upon increasing the dose was observed. Hexobarbitone blood concentrations at which the rats awoke were significantly higher after 100 mg kg-1 i.p. than after 100 mg kg-1 i.a., although there was only a small difference in sleeping time. It is postulated that the rate of uptake of the barbiturates into the portal system after i.p. administration is so high that transient saturation of hepatic first-pass metabolism occurs. Therefore neither CLi.p. nor sleeping times can be used as an accurate reflection of drug-metabolizing enzyme activity in the rat; instead CLp.o. should be used.