Neuroprotection for Parkinson's disease.

Although still a disorder of unknown etiology, Parkinson's disease (PD) has provided a number of clues that have led to clinical trials of neuroprotection. For example, defects in mitochondrial metabolism and evidence for oxidative stress in PD have fostered therapeutic interventions aimed at slowing disease progression. More than a dozen compounds already have been tested in PD for disease modification, and others are in planning stages for clinical trials. The challenge is to find a highly effective therapy halting disease progression (beyond the relatively modest clinical effect exemplified by recent findings with coenzyme Q-10 treatment administered at 1200mg/day). Clinical exam-based ratings and disability assessments still serve at providing the primary evidence of efficacy. However, with surrogate biomarkers such as radiotracer neuroimaging of the dopaminergic system, the pace of clinical investigation can be increased. Recent years have seen the utilization of more sensitive study methods in PD neuroprotection research, such as staggered wash-in, 2 x 2 factorial, and "futility" trial designs. The results of several ongoing PD neuroprotection trials are planned for release in the near future.

Insulinopenic diabetes after rodenticide (Vacor) ingestion: a unique model of acquired diabetes in man.

A clinical syndrome, characterized by acute diabetic ketoacidosis associated with a toxic neuropathy, developed in five men who intentionally ingested a recently introduced rodenticide (Vacor) containing N-3-pyridylmethyl-N'-p-nitrophenyl urea (RH-787). A 7-yr-old boy, who accidentally ingested this poison, died within 14 h. Marked insulinopenia, without a reduction in glucagon levels, suggested a specific beta-cytotoxic effect, which was supported after autopsy in three cases by histopathologic evidence of extensive beta cell destruction. Lethal effects in rats prevented investigation of RH-787's diabetogenicity in vivo; however, studies in isolated rat islets confirmed a direct inhibitory effect, which was prevented by concomitant incubation with nicotinamide, suggesting a mechanism of action similar to that of streptozotocin. We detected islet cell-surface antibodies in two of four patients studied. These findings indicate that this nongenetic, acquired form of insulinopenic diabetes, which has persisted in the surviving patients for up to 3 yr, presents a unique opportunity to test in man the concept that hyperglycemia and the accompanying metabolic consequences of insulinopenia can induced diabetic microangiopathy in the absence of genetic predisposition.

Deprenyl's effect at slowing progression of parkinsonian disability: the DATATOP study. The Parkinson Study Group.

Studying a cohort of 800 mildly-affected parkinsonians, the North American DATATOP* project has concluded that progression in disability can be attenuated by the use of deprenyl, 10 mg/day. Interim results of this controlled clinical trial were reported after participants received treatment for an average of 12 months. The study found that deprenyl treatment almost halved the risk of reaching a stage of Parkinsonism at which the start of levodopa treatment becomes imperative for lessening disability. In addition to this study end-point, other ratings supported an improved clinical outcome from the chronic deprenyl (DP) regimen. The 34 investigators conducted clinical evaluations both while subjects received medication and after a 4-week wash-out. Though some subjects experienced mild symptomatic improvements of Parkinsonism from DP, these effects were insufficient to account for the DP-treated group's delay at reaching the study end-point. In addition to DP, this placebo-controlled double-blind study also assessed the possibility of protective effects from another antioxidative strategy, a 2,000 I.U./day regimen of alpha-tocopherol. To date, results of the latter trial have not been reported. Monoamine oxidase type-B (MAO-B) metabolism of dopamine generates hydrogen peroxide and, thereby, an oxidative stress on the nigrostriatal dopaminergic neuron. The inhibition of MAO-B by DP may have been the means by which progression of Parkinsonism was attenuated, although other mechanisms are also tenable. DATATOP has pointed to the potential for arresting the progression of Parkinson's disease, and has provided an unparalleled opportunity to study the clinical course and neurochemical indices of untreated Parkinsonism.(ABSTRACT TRUNCATED AT 250 WORDS)

CSF corticotropin-releasing factor (CRF) in Alzheimer's disease: its relationship to severity of dementia and monoamine metabolites.

The concentration of corticotropin-releasing factor-like immunoreactivity (CRF-LI) in the cerebrospinal fluid (CSF) of 15 probable Alzheimer's disease (AD) patients with mild to moderate dementia and 10 neurologically normal age-matched controls was examined. There were no significant alterations in the mean CSF CRF-LI concentration in AD compared to controls. However, in the AD group, CSF CRF-LI correlated significantly with the global neuropsychological impairment ratings, suggesting that greater cognitive impairment was associated with lower CSF CRF-LI concentrations. There was a significant reduction in the CSF concentration of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the AD patients, and there was a positive correlation between the concentration of CRF-LI and 5-HIAA in CSF. This latter finding suggests that serotoninergic neuronal systems may interact with CRF-containing neurons.

Cerebrospinal fluid C3a increases with age, but does not increase further in Alzheimer's disease.

Complement activation is present in the brain in Alzheimer's disease (AD), and C1q concentrations are decreased in AD cerebrospinal fluid (CSF). To determine whether concentrations of other complement proteins are also altered in AD CSF, we measured concentrations of C3a and SC5b-9 in CSF from patients with probable AD (n = 19), normal aged controls (n = 11), and normal younger controls (n = 15). C3a concentrations were similar between AD and aged controls, but threefold higher than in younger controls (p < 0.05 vs. both groups). A similar pattern was found with SC5b-9, though the increase was only twofold and statistically significant only for AD vs. younger controls. These results suggest that an increased generation of complement proteins in localized areas of the AD brain does not result in elevated concentrations of these proteins in CSF, compared with age-matched controls. Increased C3a (and, to a lesser extent, SC5b-9) in aged controls may be due to increased complement activation, increased central nervous system production, and/or blood-brain barrier leakage of these proteins.

Pharmacokinetic evaluation of erythromycin and caffeine administered with bromocriptine.

A study was performed to determine if the pharmacokinetics of bromocriptine is altered by factors that have been shown to interact with other ergot compounds. The effects on bromocriptine plasma concentrations by bromocriptine coadministration with caffeine and erythromycin were evaluated in five male volunteers. Serial blood samples were obtained during a 12-hour period after a single 5 mg oral dose of bromocriptine (alone and after 4-day treatments of either erythromycin estolate, 250 mg four times/day, or caffeine, 200 mg four times/day). There were no significant alterations of bromocriptine pharmacokinetic parameters after caffeine, although statistical power was very low. With the use of erythromycin, the bromocriptine area under the concentration-time curve standardized to body weight increased significantly by 268%, whereas peak bromocriptine plasma concentration (Cmax) increased to 4.6 times the Cmax from bromocriptine alone. Time to achieve Cmax was not altered by erythromycin. We conclude that erythromycin can markedly increase the systemic bioavailability of bromocriptine, which can lead to increased therapeutic or adverse effects, whereas the effects of caffeine require further study.

A comparison of two iatrogenic dyskinesias.

The authors compared the regions of motor involvement in levodopa-induced dyskinesia and neuroleptic-induced tardive dyskinesia. Significantly more patients with tardive dyskinesia than parkinsonian patients with levodopa-induced dyskinesia had lip and tongue movements. Patients with tardive dyskinesia had significantly higher mean AIMS scores in the orofacial region than parkinsonian patients with levodopa-induced dyskinesia. More patients with levodopa-induced dyskinesia than those with tardive dyskinesia demonstrated hyperkinesia in the lower extremities. Limb and truncal movements in levodopa-induced dyskinesia were worse in patients with more severe parkinsonism and correlated positively with the length of Parkinson's disease. These findings suggest that these dyskinesias may involve different pathophysiological mechanisms.

CSF GABA in caregiver spouses of Alzheimer patients.

The authors studied CSF gamma-aminobutyric acid (GABA) in 14 Alzheimer patients and nine age-matched normal subjects. The five normal subjects who were wives of the demented patients had higher CSF GABA concentrations than the four normal subjects without demented spouses.

Glutamate and other CSF amino acids in Alzheimer's disease.

The authors compared CSF amino acid levels of 10 patients with mild to moderate dementia and probable Alzheimer's disease who had never received antidepressant or neuroleptic medication with those of 10 normal subjects of similar age. The Alzheimer's patients had significantly higher levels of CSF glutamate. This finding was not related to age, sex, or severity of dementia. Elevated CSF glutamate may reflect greater glutamatergic activity early in the course of Alzheimer's disease. The authors speculate that the excitotoxic effects of glutamate may contribute to progressive neuronal loss in Alzheimer's disease.

Neuropsychological performance in lateralized parkinsonism.

Seven dextral patients with Parkinson's disease (PD) who had predominant right-sided motor signs were compared on neuropsychological tests with eight dextral patients with PD who had predominant left-sided signs. Objective criteria for group designation were developed from clinical ratings. The patient subgroups were matched on age, education, estimated premorbid IQ, severity of motor signs, and medication usage. Patients with signs lateralized to the right were more impaired on tests of dominant hemisphere function (serial digit learning, confrontation naming, and verbal associative fluency), but no differences were found on tests of nondominant hemisphere function (form sequence learning, line orientation, facial recognition), indicating some correlation of neuropsychological performance with lateralization of predominant motor signs. Findings demonstrate that the cognitive deficits (particularly visuospatial) previously reported in the literature are not seen consistently in all subjects with PD.

Cholecystokinin and neurotensin gradients in human CSF.

In successive samples of human lumbar CSF, concentrations of two neurally active peptides, cholecystokinin (CCK) and neurotensin (NT), were compared with levels of homovanillic acid (HVA), the major metabolite of dopamine. Although HVA values progressively increased between the first and 20th milliliter samples, no significant change occurred in the concentration of either peptide. Thus, lumbar CSF levels of CCK and NT, unlike levels of HVA, may not closely reflect amounts of these peptides in supraspinal CSF or brain.

A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events.

OBJECTIVE: To assess the safety and efficacy of subcutaneous apomorphine hydrochloride administration for off-state (poor motor function) periods in patients with Parkinson disease with motor fluctuations under both inpatient titration and outpatient therapeutic conditions. PATIENTS AND METHODS: Twenty-nine patients had advanced Parkinson disease with 2 hours or more off time despite aggressive oral therapy. Patients randomly received titrated doses of subcutaneous apomorphine hydrochloride (2-10 mg, n = 20) or pH-matched vehicle placebo (n = 9) during an inpatient and 1-month outpatient phase. A change in the United Parkinson Disease Rating Scale motor score 20 minutes after inpatient dosing during a practically defined off-state event and the percentage of injections successfully aborting off-state events were the primary inpatient and outpatient efficacy factors. RESULTS: The average (SEM) levodopa equivalent dose of apomorphine hydrochloride was 5.4 +/- 0.5 mg and the mean placebo dose was 1.0 mL. Mean inpatient United Parkinson Disease Rating Scale motor scores were reduced by 23.9 and 0.1 points (62% and 1%) by apomorphine treatment and placebo, respectively (P<.001). The mean percentage of outpatient injections resulting in successful abortion of off-state events was 95% for apomorphine and 23% for placebo (P<.001). Inpatient response was significantly correlated with and predictive of outpatient efficacy (P<.001). The levodopa dose was not predictive of the apomorphine dose requirement. Frequent adverse events included dyskinesia, yawning, and injection site reactions. CONCLUSION: Apomorphine by intermittent subcutaneous injection is effective and safe for outpatient use to reverse off-state events that occur despite optimized oral therapy.

Clinical studies with and pharmacokinetic considerations of sustained-release levodopa.

Although levodopa is the most effective antiparkinson agent yet available, strategies for improving the constancy of levodopa delivery to the brain are sometimes needed to optimize its actions. Its most common formulation is Sinemet, a combination of levodopa and carbidopa. Conventional Sinemet is absorbed and metabolized over 3 to 4 hours; however, Sinemet CR, a sustained-release preparation of 200 mg of levodopa and 50 mg of carbidopa, offers a duration of effect almost double that of Sinemet 25/100. In an 8-week trial with 25 parkinsonian patients, those treated with Sinemet CR required fewer daily doses than with the conventional Sinemet formulation and experienced improved "on" times (although improvements were not evident in all motor-fluctuation situations). The best therapeutic strategy may be a combination of the two Sinemet preparations, conventional Sinemet 25/100 as a booster dose and Sinemet CR for more sustained effect.

Levodopa therapeutics: new treatment strategies.

Even though levodopa can provide effective therapy for symptomatic relief of parkinsonism, many patients deteriorate over time. This change may be related to a loss of storage capability for dopamine in the brain affected by parkinsonian changes. Some of the variability in drug action is determined by its peripheral pharmacokinetics. Methods that can enhance dose-by-dose effectiveness, including controlled-release preparations and enteral infusions, have practical applications for managing "wearing-off" or peak-effect problems.

Severity of Parkinson's disease and the dosage of bromocriptine.

In view of reports that low-dose bromocriptine (15 mg or less daily) therapy is effective in Parkinson's disease, we undertook a retrospective study of 79 patients with Parkinson's disease to evaluate factors that affect the optimal daily dose of bromocriptine in subjects whose intake of levodopa was decreased as bromocriptine was introduced. Doses of bromocriptine 15 mg or less daily were seldom therapeutic; doses of over 15 mg, up to 30 mg, were appropriate for patients with mild, early disease. Those with more severe symptoms of longer duration usually required larger doses. The optimal daily requirement of bromocriptine was correlated to the severity and duration of the illness, but not to the age of the patient.

Neoplastic angioendotheliosis: a case with spontaneous regression and radiographic appearance of cerebral arteritis.

Neoplastic angioendotheliosis (NA) of the CNS is usually characterized by systemic vascular disease and a rapidly fatal course. We report a 52-year-old woman with dementia, spasticity, and sensory deficits developing insidiously over a year. Diagnostic findings included small CT lucencies in the brain and angiographic irregularities of medium-sized arteries (resembling cerebral arteritis). Brain biopsy revealed numerous small infarcts as well as pleomorphic, highly malignant tumor cells within cerebral meningeal vessels. Without treatment, she experienced only slight increase of dementia before death from pneumonia. At autopsy, there was almost complete regression of the intravascular cerebral tumor. The clinical course was unusual for the length of illness and the radiographic picture of cerebral vasculitis. Clinical features often present with NA--such as strokelike events, elevated sedimentation rate, renal impairment, and fever--were notably absent.

CSF dopamine-beta-hydroxylase activity in Parkinson's disease.

Although the most prominent neurochemical change in parkinsonism is nigrostriatal dopamine deficiency, norepinephrine content is also diminished in the CNS. In this study, dopamine-beta-hydroxylase (DBH) activity, a marker of central noradrenergic activity, was measured in the CSF of previously unmedicated parkinsonian patients and normal controls. The parkinsonian patients showed a reduction in CSF DBH levels to 41% of control values (p less than 0.01). Possible explanations for the decrease included a decreased noradrenergic nerve pool or a diminished rate of synthesis of catecholamines.

Motor function in the normal aging population: treatment with levodopa.

In normal elderly humans there is progressive motor dysfunction and loss of nigrostriatal neurons and brain dopamine similar to, although of a milder degree than, that seen in Parkinson's disease. Ten healthy elderly volunteers were given carbidopa/levodopa or placebo in a double-blind crossover study. We measured movement velocity, reaction time, tremor, visual evoked response (VER), and electroretinography (ERG). Significant changes were seen only in ERG. Motor functions and VER were unchanged. Although there appeared to be pharmacologic activity (ie, changes in ERG), levodopa, in adequate antiparkinson dosage, had no impact on the mild extrapyramidal impairment of normal elderly subjects.

Blink rates and disorders of movement.

Blink rate, a putative noninvasive marker of central dopamine activity, was assessed in medication-free patients with Parkinson's disease, progressive supranuclear palsy, Huntington's disease, and dystonia. The normal control rate of 24 blinks per minute was significantly higher than the rate of 12 and 4 blinks per minute recorded for patients with Parkinson's disease and progressive supranuclear palsy, respectively. The rates for patients with Huntington's disease and dystonia did not differ significantly from those of controls (36 and 26 blinks per minute, respectively).

Pharmacodynamic modeling of concentration-effect relationships after controlled-release carbidopa/levodopa (Sinemet CR4) in Parkinson's disease.

Eight parkinsonian patients participated in a pharmacokinetic pharmacodynamic study of sequential doses of controlled-release carbidopa (CD)/levodopa (LD) at 4-hour intervals, with serial blood samples obtained before and after each dose. Effect measurements obtained with each blood sample included tapping and walking speed as well as a global assessment of motor function. Analysis of the data by extended least squares regression for linear, Emax, and sigmoid Emax pharmacodynamic models revealed that linear relationships do not provide the best fit between LD plasma concentrations and clinical effects after controlled-release CD/LD. The data are fit best to models that are curvilinear in nature. LD plasma concentrations greater than 2.0 micrograms/ml resulted in sustained effects on walking and global scores while the greatest rate of change in walking and global scores occurred at 0.9 micrograms/ml. LD plasma concentrations fluctuating around 0.9 micrograms/ml may result in the "on/off" effects seen in Parkinson's disease.