Dezinamide for partial seizures: results of an n-of-1 design trial.

BACKGROUND: Dezinamide (DZM, ADD 94057) is a potential antiepileptic drug that binds to the voltage-sensitive sodium channel and showed preliminary evidence of efficacy and safety in an open-label study. METHODS: Our double-blind, placebo-controlled trial at two sites used an n-of-1 (single-patient) design. All 15 patients had medically intractable partial-onset seizures and were comedicated with phenytoin (PHT) only. Treatment was for six 5-week periods (three active paired with three placebo in random sequence). Assuming nonlinear kinetics, we used an initial pharmacokinetic profile to estimate dosages for reaching target plasma concentrations of DZM. RESULTS: Statistically significant seizure reduction was found by both a randomization test (p = 0.0025) and a signed rank test (p = 0.048). Median seizure frequency decreased 37.9%, and 40% of patients had > 50% seizure reduction, both compared with placebo. Pharmacokinetic predictions were not accurate; mean plasma concentrations fell well below target values. Plasma PHT concentrations increased (mean = 17.1%) during DZM treatment. The most common adverse experiences were fatigue, light-headedness, and abnormal gait; five patients required DZM dosage reductions. CONCLUSIONS: DZM showed minimal clinical toxicity and significant efficacy despite lower plasma concentrations than predicted by pharmacokinetics. This trial establishes the suitability of the n-of-1 design to investigational antiepileptic drug trials.

Experimental isovolemic haemodilution-induced augmentation of carotid blood flow and oxygen transport through graded carotid stenoses.

The effect of haemodilution without volume expansion (isovolemic haemodilution) was assessed with respect to blood flow and oxygen transport across stenotic lesions of progressive severity in the dog carotid artery. As the mean haematocrit (Hct) was reduced from 40 +/- 1% (+/- SEM) to 32 +/- 0% (p less than 0.001), reductions in vascular resistance were significant across the 90% (p less than 0.001) and 95% (p less than 0.0003) relative carotid stenoses. Isovolemic haemodilution reduced fresh blood viscosity significantly by 27 +/- 3% (p less than 0.001) and 42 +/- 4% (p less than 0.001) at the low shear rates of 10 sec-1 and 1 sec-1 which are typical of low-flow states. Following a 20% reduction in Hct 30 to 35% increase (p less 0.001) in carotid blood flow occurred at non-critical degrees of stenosis while a mean 83% increase (p less than 0.001) occurred at the highly critical 95% relative stenosis. Oxygen transport after a 22% decrease in blood haemoglobin was significantly increased by 28% (p less than 0.01) at the 95% relative stenosis level. These data provide a physiologic rationale for the beneficial effects of haemodilution in acute cerebral ischaemia, cerebral vasospasm and cerebral revascularization or carotid endarterectomy.

LC determination of the diastereomers of 1-(beta-D-glucopyranosyl)phenobarbital in human urine.

The "product enantioselectivity" associated with the urinary excretion of the phenobarbital N-glucoside conjugates has not been determined previously. A liquid chromatography method using gradient elution was developed for quantifying both phenobarbital N-glucoside conjugates, phenobarbital, and p-hydroxyphenobarbital. Following a single oral dose of phenobarbital to male Caucasian and Oriental subjects, both phenobarbital N-glucoside conjugates were observed in the urine. In seven subjects, 3.3-10.6% of the phenobarbital dose was detected as a single phenobarbital N-glucoside (S configuration at the C-5 position of the barbiturate ring). The other phenobarbital N-glucoside diastereomer accounted for less than 1.5% of the phenobarbital dose. The urinary excretion of the major phenobarbital N-glucoside diastereomer paralleled the urinary excretion of phenobarbital and was comparable in both Caucasian and Oriental subjects. These results indicate a pronounced selectivity for the formation and/or urinary excretion of the phenobarbital N-glucosides.

High-performance liquid chromatographic method for the determination of salicylic acid and its metabolites in urine by direct injection.

A direct injection method has been developed for the determination of salicylic acid and its metabolites in urine. Urine samples are treated with hydroxylamine to convert salicyl acyl glucuronide to salicylhydroxamic acid, which can be accurately quantitated by direct injection into a high-performance liquid chromatographic system along with salicylic acid, gentisic acid and salicyluric acid. Salicyl phenolic glucuronide is quantitated by difference after hydrochloric acid hydrolysis at 65 degrees C with no loss of salicylic acid by sublimation or hydrolytic loss of salicyluric acid. This method has been applied to urine samples from human subjects and the results are discussed.

Pathophysiology of cerebrospinal fluid in head injury: Part 2. Biochemical markers for central nervous system trauma.

Many substances are released into the cerebrospinal fluid after head injury. The study of these substances and their relationship to the severity and outcome of head trauma has lead to the search for biochemical markers to aid in the quantification of the severity of the lesion and serve as a prognostic guide. The authors review the potential usefulness of biochemical markers, qualities of an ideal marker, and several potential enzymes that may be utilized as markers in central nervous system trauma.

Pathophysiology of cerebrospinal fluid in head injury: Part 1. Pathological changes in cerebrospinal fluid solute composition after traumatic injury.

After head injury, many complex neurochemical events occur locally, at the site of initial injury, and globally, as a result of secondary phenomena. Neurochemical alterations in the cerebrospinal fluid after injury can be utilized to reflect these events. The authors review the role of the cerebrospinal fluid in the treatment of head injury as it relates to the diagnosis, prognosis, and further elucidation of the pathophysiological manifestations of head injury at the cellular and biochemical level.

Management of spasmodic torticollis.

Based on a review of the literature, the management of spasmodic torticollis may begin with the conservative measures of pharmacotherapy, sensory feedback, or percutaneous dorsal column stimulation. Approximately 50% of patients will benefit from an adequate trial of these modalities. With particularly resistant and disabling torticollis, the ablative procedures of microsurgical cervical rhizotomy or stereotaxic thalamotomy have offered significant relief in about 74% and 56%, respectively, of properly selected cases. Nevertheless, the variability in the duration of response to all forms of therapy has made the treatment of spasmodic torticollis a difficult and often frustrating undertaking.

Physiological neuroendocrinology of peptides, steroids and other hormones in cerebrospinal fluid.

Cerebrospinal fluid acts as a conduit in neuroendocrine regulation. Valid assessment of normal cerebrospinal fluid levels of peptides, steroids and other hormones requires clarification of reference concentrations in control patients and normal volunteers. Awareness of factors which may alter neuronal activity and, in turn, the relative composition of cerebrospinal fluid constituents is essential to the accurate sampling and hormonal analysis of cerebrospinal fluid.

Primary lymphoma of the central nervous system diagnosed by computed tomographic scan-directed needle biopsy with a frozen section immunoperoxidase technique.

Primary lymphoma of the central nervous system is an uncommon neoplasm that requires definitive diagnosis because it is potentially treatable. We report a case in which the diagnosis of lymphoma was unsuspected and was made by needle biopsy with computed tomographic scan direction. A frozen section immunoperoxidase technique demonstrated monoclonality. When combined with a compatible morphological appearance, this confirmed the diagnosis of lymphoma. This case demonstrates the importance of this immunochemical method in the rapid diagnosis of central nervous system lymphomas.

The effect of ranitidine and cimetidine on single-dose diltiazem pharmacokinetics.

The effects of two histamine 2-receptor antagonists, cimetidine and ranitidine, on the single-dose pharmacokinetics of diltiazem were studied in 6 healthy subjects. A single 60-mg oral dose of diltiazem was administered alone, after ranitidine 150 mg twice daily for 7 days, and after cimetidine 300 mg 4 times a day for 7 days. Plasma samples were obtained over a 10-hour period and analyzed for the parent drug and one of its metabolites, deacetyldiltiazem (DAD). Concurrent cimetidine produced a significant (p less than 0.05) increase in diltiazem levels at most time points, in peak concentration and area under the concentration-time curve. These variables were also increased during concurrent ranitidine administration but did not reach statistical significance. The DAD plasma concentration was below measurable levels during the control phase but increased during concurrent cimetidine and ranitidine administration. Caution should be exercised when diltiazem is administered concurrently with cimetidine and possibly, ranitidine.

Augmentation of cerebral blood flow induced by hemodilution in stroke patients after superficial temporal-middle cerebral arterial bypass operation.

Experimental hemodilutional therapy has been shown to raise collateral perfusion to acutely ischemic brain regions distal to occluded internal carotid (ICA) and middle cerebral (MCA) arteries and to reduce infarct size. Superficial temporal (STA)-MCA anastomosis surgically establishes additional regional collateralization, and this bypass angiographically enlarges over time. Despite bypass patency verification by Doppler recording made at the edge of the craniectomy, the microsurgical STA-MCA anastomosis in 11 stroke patients did not produce early changes in cerebral perfusion parameters in the MCA territory of either hemisphere as determined by 133xenon inhalation. Therefore, hemodilution was initiated in an effort to increase cerebral perfusion during this marginal period when the STA was beginning to dilate progressively. Incremental venesections with equal intravenous volume replacement with 5% human serum albumin caused a significant lowering of the hematocrit from 40 +/- 1 to 33 +/- 1%. This isovolemic hemodilutional therapy resulted in significant mean regional cerebral blood flow (rCBF) elevations of 23 +/- 5% (SE) in the bypassed MCA territory and of 25 +/- 6% in the opposite MCA region. The mean gray flow (F1) in the involved and homologous MCA regions significantly increased 27 +/- 8% and 30 +/- 11%, respectively. Similarly, the initial slope index (ISI2) significantly rose by 17 +/- 5% in the bypassed MCA territory and by 18 +/- 6% in the homologous region. These data objectively support the premise that reductions in hematocrit without intravascular volume expansion augment cerebral blood flow, probably by reducing blood viscosity.(ABSTRACT TRUNCATED AT 250 WORDS)

Rheology of the cerebral circulation.

Current concepts of brain perfusion focus on the importance of rheological factors in the determination of cerebral blood flow. Blood viscosity, a primary determinant of blood flow, increases as the shear rate (velocity gradient) decreases, thereby impeding cerebral perfusion. Hematocrit, erythrocyte aggregation, erythrocyte flexibility, platelet aggregation, and plasma viscosity differentially influence blood flow through the conductance vessels and microcirculation of the brain. In addition, the microcirculation is also affected by the Fahraeus effect, the inversion phenomenon, and the screening effect. Knowledge of these factors affecting blood flow provides a rationale for experimental and clinical rheological therapies in the treatment or prevention of acute focal cerebral ischemia.