Pramipexole-induced somnolence and episodes of daytime sleep.

Pramipexole is a non-ergot dopamine agonist used to treat Parkinson's disease (PD). Because of concern regarding driving safety, we evaluated the incidence and nature of somnolence experienced by patients receiving pramipexole in clinical trials at our center. A retrospective chart review was performed and structured interviews were conducted with patients who had reported moderate or severe somnolence. In addition, two patients underwent polysomnography (PSG) and multiple sleep latency tests (MSLT) while on and 2 weeks after discontinuation of pramipexole. Forty patients with PD participating in pramipexole clinical trials were identified. In the double-blind phases of the studies, 22 patients were randomized to pramipexole and 18 were randomized to placebo. Six patients assigned to pramipexole reported somnolence as an adverse event (1 moderate, 5 mild) compared with two patients assigned to placebo (1 severe, 1 moderate; p = 0.19, one-tailed Fisher's exact test). Thirty-seven patients participated in open-label extension studies. Twenty-one (57%) reported somnolence as an adverse event. Eleven (30%) patients reported moderate somnolence and three (8%) patients reported severe somnolence. For patients with moderate or severe somnolence, the onset of worst-reported somnolence occurred at a mean (+/- standard error) pramipexole dose of 4.0 +/- 0.4 mg (range, 0.75-4.5 mg) per day. Patients had been taking pramipexole for a total of 10.0 +/- 1.5 months (range, .03-22 mos) and at their maximal dose for 6.7 +/- 1.5 months (range, .03-20 mos). During structured interviews with 12 of the 14 patients reporting moderate or severe somnolence, seven reported falling asleep while driving and two reported minor motor vehicle accidents caused by falling asleep. Most patients reported relatively continuous drowsiness that led to falling asleep without acute warning during periods of inactivity. Three patients reported discreet waves of irresistible sleepiness heralded by prodromal symptoms occurring against a background of normal wakefulness. MSLT in two of these patients revealed decreased latency to sleep without early onset of rapid eye movements. Sleep latency normalized after withdrawal of pramipexole. Intensive patient education is necessary to prevent motor vehicle accidents in patients taking pramipexole. We recommend that patients who are experiencing generalized drowsiness and falling asleep during periods of inactivity be instructed not to drive because these patients do fall asleep without acute warning. Somnolence usually resolves with pramipexole dose reduction or discontinuation. Patients should also be alerted to pull over and stop driving immediately if they feel a wave of sleepiness coming on. Patient education and compliance are critical to maximize safety.

Whole-body bone marrow MRI in patients with metastatic disease to the skeletal system.

PURPOSE: The purpose of this study was to evaluate the diagnostic potential of a whole-body bone marrow MR protocol in the detection of bone metastases. METHOD: Whole-body bone marrow MRI was performed in 18 patients with known malignant tumors and suspected bone metastases. The imaging protocol consisted of fast T1-weighted and STIR sequences applied in different anatomical positions covering the whole skeleton. MRI findings indicating bone metastases were compared with findings from bone scintigraphy. Metastatic lesions were confirmed by follow-up MR examinations, bone scintigraphy, radiography, or CT. RESULTS: A total number of 216 lesions were detected with MRI in comparison with 159 lesions detected with bone scintigraphy. Follow-up examinations confirmed 105 lesions. MRI detected 96 (91.4%) of the confirmed lesions, whereas bone scintigraphy detected 89 (84.8%). The entire examination, including patient positioning and changing of imaging coils, required 45 min of room time. CONCLUSION: Whole-body bone marrow MRI as used in this study is an effective method for evaluating the entire skeletal system in patients with suspected metastatic disease.

Long-term evaluation of bilateral fetal nigral transplantation in Parkinson disease.

BACKGROUND: Parkinson disease (PD) is associated with a progressive loss of nigrostriatal dopamine neurons. Medication therapy provides adequate control of symptoms for several years, but long-term treatment is complicated by progressive disability and the development of motor fluctuations and dyskinesias. In animal models of PD, fetal nigral transplants have been shown to survive grafting into the striatum, provide extensive striatal reinnervation, and improve motor function. In patients with PD, cell survival and clinical benefit have been observed following fetal nigral grafting, but results have been inconsistent. OBJECTIVE: To evaluate the safety and efficacy of bilateral fetal nigral transplantation into the postcommissural putamen in patients with advanced PD complicated by motor fluctuations and dyskinesias. PATIENTS AND METHODS: Six patients with advanced PD underwent bilateral fetal nigral transplantation. Each patient received solid grafts derived from donors aged 6 1/2 to 9 weeks after conception stereotactically implanted into the postcommissural putamen using 3 to 4 donors per side. Cyclosporine was administered for approximately 6 months to provide immune suppression. Clinical evaluations included the Unified Parkinson's Disease Rating Scale (UPDRS), Schwab-England Activities of Daily Living Scale, and timed tests of motor function conducted during both the "off' and "on" states at baseline and at 1, 3, 6, 9, 12, 18, and 24 months following transplantation. Percentage of time off and percentage of time on with and without dyskinesia were recorded at half-hour intervals using home diaries during the week prior to each evaluation. 18F-fluorodopa positron emission tomographic scans were performed at baseline, and at 6 months and 1 year following transplantation. RESULTS: Patients have been followed up for a mean+/-SD of 20.5+/-5.5 months. Complications related to surgery were mild and transient. Activities of daily living, motor, and total (activities of daily living plus motor) UPDRS scores during the off state improved significantly (P<.05, Wilcoxon signed rank test) at final visit in comparison with baseline. Mean total UPDRS off score improved 32%, and each patient experienced at least a 19% improvement. Mean percentage of time on without dyskinesia during the waking day improved from 22% to 60% (P<.05). Mean putamenal fluorodopa uptake on positron emission tomography increased significantly at 6 and 12 months in comparison with baseline (P<.001, 2-tailed t test). This increase correlated with clinical improvement. Two patients died 18 months after transplantation from causes unrelated to the surgical procedure. In both cases, histopathological examination showed robust survival of tyrosine hydroxylase immunoreactive cells and abundant reinnervation of the postcommissural putamen. CONCLUSIONS: Fetal nigral tissue can be transplanted into the postcommissural putamen bilaterally in patients with advanced PD safely and with little morbidity. In this open-label pilot study we observed consistent long-term clinical benefit and increased fluorodopa uptake on positron emission tomography. Clinical improvement appears to be related to the survival and function of transplanted fetal tissue.

Clinical presentation and pharmacological therapy in corticobasal degeneration.

BACKGROUND: To date, to our knowledge, there is no systematic presentation of treatment outcome in large series of patients clinically diagnosed as having corticobasal degeneration. OBJECTIVE: To evaluate the clinical presentation and treatment outcome of patients clinically diagnosed as having corticobasal degeneration. SUBJECTS: We gathered case patients seen in 8 major movement disorder clinics during the last 5 years who were diagnosed as having corticobasal ganglionic degeneration. METHODS: Using a chart review method, we recorded the clinical presentation, medications used, response to medications, and adverse effects. RESULTS: A total of 147 case patients were reviewed, 7 were autopsy proven. Parkinsonian features were present in all, other movement disorders in 89%, and higher cortical dysfunction in 93%. The most common parkinsonian sign was rigidity (92%), followed by bradykinesia (80%), gait disorder (80%), and tremor (55%). Other movement disorders were dystonia in 71% and myoclonus in 55%. Higher cortical dysfunction included dyspraxia (82%), alien limb (42%), cortical sensory loss (33%), and dementia (25%). Ninety-two percent of the case patients received dopaminergic drugs, which resulted in a beneficial effect for 24%. Parkinsonian signs were the elements improving the most and levodopa was the most effective drug. Benzodiazepines, primarily clonazepam, were administered to 47 case patients, which resulted in improvement of myoclonus in 23% and dystonia in 9%. The most frequent disabling adverse effects of drug trials in these case patients were somnolence (n = 24), gastrointestinal complaints (n = 23), confusion (n = 16), dizziness (n =12), hallucinations (n = 5), and dry mouth (n = 5). CONCLUSIONS: Pharmacological intervention was largely ineffective in the management of corticobasal degeneration, and new treatments are needed for ameliorating the symptoms of this syndrome.

Living with a person who has Parkinson's disease: the spouse's perspective by stage of disease. Parkinson's Study Group.

The objective of this study was to examine the experience of spouses caregiving for their spouse with Parkinson's disease (PD) and to determine whether their experiences differed by stage of disease. By using a cross-sectional design and mail questionnaire data from 380 spouse caregivers across 23 sites of the Parkinson Study Group, key caregiver variables were examined by stage of PD. Three categories of variables--caregiver role strain (10 measures), caregiver situation (four measures), and caregiver characteristics (four measures)--were analyzed by using t tests with Bonferroni correction. Specific types and amounts of role strain accumulated as the disease progressed, and they differed significantly between stages (p < 0.05). In the caregiving situation, the mean number of caregiving tasks tripled by stage 4/5. Negative changes in lifestyle plus decreases in predictability in caregivers' lives increased significantly in late-stage disease (p < 0.05). Caregiver characteristics of physical health and preparedness did not significantly differ across stages of disease. Depression was significantly higher by stage 4/5. Mutuality, the positive quality of the relationship as perceived by the caregiving spouse, declined beginning at stage 2. Caregiver strain is experienced across all stages of PD and accumulates significantly as the disease progresses. This study defines types and amounts of strain by stage of disease, which will be helpful in designing formal intervention trials to provide more effective help for spouse caregivers.

Brain morphology in children with specific language impairment.

The planum temporale and pars triangularis have been found to be larger in the left hemisphere than the right in individuals with normal language skills. Brain morphology studies of individuals with developmental language disorders report reversed asymmetry or symmetry of the planum, although the bulk of this research has been completed on adults with dyslexia. Pars triangularis has not been studied in the developmental language impaired population. In this study, magnetic resonance imaging (MRI) was used for quantitative comparisons of the planum temporale (Wernicke's area) and pars triangularis (Broca's area) in children with specific language impairment (SLI) and children with normal language skills. The subjects were 11 children with SLI and 19 age- and sex-matched controls between 5.6 and 13.0 years old. Each subject received a neurolinguistic battery of tests and a high resolution volumetric MRI scan. Major results were that (a) pars triangularis was significantly smaller in the left hemisphere of children with SLI, and (b) children with SLI were more likely to have rightward asymmetry of language structures. Furthermore, anomalous morphology in these language areas correlated with depressed language ability. These findings support the hypothesis that language impairment is a consequence of an underlying neurobiological defect in areas of the brain known to subserve language.

The effect of deprenyl and levodopa on the progression of Parkinson's disease.

We have performed a 14-month, prospective, randomized, double-blind, placebo-controlled study to evaluate the effect of deprenyl and levodopa/carbidopa (Sinemet) on the progression of signs and symptoms in patients with mild Parkinson's disease (PD). One hundred one untreated PD patients were randomly assigned to one of the following four treatment groups: Group I, deprenyl + Sinemet; Group II, placebo-deprenyl + Sinemet; Group III, deprenyl + bromocriptine; and Group IV, placebo-deprenyl + bromocriptine. The final visit was performed at 14 months, i.e., 2 months after withdrawal of deprenyl or its placebo and 7 days after withdrawal of Sinemet or bromocriptine. Deterioration in Unified Parkinson's Disease Rating Score (UPDRS) between untreated baseline and final visits was used as an index of disease progression. Placebo-treated patients deteriorated by 5.8 +/- 1.4 points, while deprenyl-treated patients deteriorated by 0.4 +/- 1.3 points (p < 0.001). This effect was sufficiently powerful that a significant deprenyl effect could be detected in the subgroup of 41 patients randomized to Sinemet (p < 0.01) as well as in the 23 patients who completed a 14-day washout of Sinemet or bromocriptine (p < 0.05). No difference in the extent of deterioration was detected in patients randomized to Sinemet versus bromocriptine. This study demonstrates that deprenyl attenuates deterioration in UPDRS score in patients with early PD. These findings are not readily explained by the drug's symptomatic effects and are consistent with the hypothesis that deprenyl has a neuroprotective effect.

The effect of L-dopa infusions with and without phenylalanine challenges in parkinsonian patients: plasma and ventricular CSF L-dopa levels and clinical responses.

We monitored the motor response and plasma and ventricular CSF (CSFv) concentrations of L-dopa during IV infusions of L-dopa in two patients with advanced Parkinson's disease. Concentrations of L-dopa in CSFv mirrored, but lagged behind, those in plasma. In the fasting state, the duration, but not the magnitude, of the motor response was greater with increasing plasma and CSFv levels of L-dopa. During IV infusions of L-dopa following oral administration of phenylalanine, a large neutral amino acid that shares a transport system into the brain with L-dopa, the duration of the motor response was markedly attenuated despite undiminished CSFv levels of L-dopa. These observations suggest that either L-dopa entry into CSFv and the brain are differentially affected by phenylalanine or that phenylalanine affects other steps in the motor response. These observations demonstrate that, except in the fasting state, L-dopa in CSFv is not a reliable predictor of motor response.

Temporal relationships between plasma and cerebrospinal fluid pharmacokinetics of levodopa and clinical effect in Parkinson's disease.

We studied the pharmacokinetics of levodopa and its metabolites in plasma and ventricular cerebrospinal fluid in 4 parkinsonian patients with indwelling Ommaya reservoirs placed at the time of previous adrenal-medullary to caudate nucleus transplantation. Cerebrospinal fluid levodopa levels were 11.9% of those in plasma. Motor performance and dyskinesia correlated more closely with the time course of the appearance of levodopa in the ventricular cerebrospinal fluid than with the plasma levodopa concentration and did not correlate with plasma 3-O-methyldopa or cerebrospinal fluid 3-O-methyldopa or homovanillic acid. Our data confirm that the wearing off of the levodopa effect in patients with advanced Parkinson's disease is a function of drug concentration in the central nervous system.

Comparative efficacy of intravaginal prostaglandin E2 in the gel and suppository forms for cervical ripening.

Thirty-seven patients admitted for labor induction and presenting with unfavorable cervical features were randomized in a single-blind fashion to receive either 3 mg of prostaglandin E2 in an intravaginal gel or a 2-mg dose in a vaginal suppository. With the aid of previously reported placebo data, the intent was to compare the two dosage forms in terms of their ability to promote cervical ripening, and to see which dosage form was more effective in terms of influencing the overall incidence of cesarean section. The two groups showed a comparable improvement (alpha = 0.05) in cervical condition over that of the placebo group, with the mean Bishop score increasing by 2.0 points in the gel group, 2.5 points in the suppository group, and 0.7 points in the placebo group. As the suppository contained a lower dose of drug than the gel, the data support the concept that the type of drug vehicle and dosage form are important variables affecting product performance. No statistically significant difference in the incidence of cesarean section was noted between the two groups or between either group and placebo. This may be attributable to the small sample size and the relatively high proportion of women diagnosed as having cephalopelvic disproportion/failure to progress. Additional studies are warranted.

Autologous transplantation of adrenal medulla in Parkinson's disease. 18-month results.

Eighteen of 19 patients who underwent autologous adrenal medullary transplantation to the right caudate nucleus have been followed up for 18 months. During the course of this study, a statistically significant improvement was noted in percent "on" time, percent "on" time without dyskinesia, activity of daily living (ADL) scores during the "on" stages, and ADL, motor, and Schwab-England scores during the "off" stages. Benefits tended to be maximal at 6 months and to gradually lessen thereafter, although statistically significant improvement in comparison with baseline was still present at 18 months for ADL, motor, and Hoehn-Yahr scores during the "off" stages. Almost all parameters had deteriorated by 18 months compared with 12 months, including those remaining significantly improved in comparison with baseline. These patterns were similar for each of the three participating centers. Complications were largely restricted to the perioperative period.

CV 205-502: safety, tolerance to, and efficacy of increasing doses in patients with Parkinson's disease in a double-blind, placebo crossover study.

CV 205-502 (CV) is a long-acting dopamine agonist with potent D2 and weak D1 activity, which has not as yet been tested in patients with Parkinson's disease. We performed a dosage ranging and placebo crossover study in six patients to evaluate the efficacy and tolerance of CV when used as an adjunct to Sinemet in patients with Parkinson's disease. All patients had striking improvement. This effect was lost with placebo substitution and regained with reintroduction of CV. Benefits were sustained throughout the 6 month study. Single daily dosing could sustain the response in all but one patient. Adverse effects were mild and transient and resolved with dosage manipulation or a divided dosage regimen. CV is a promising drug for use in Parkinson's disease and further studies are indicated to test its long-term safety and efficacy.

Cervical ripening with intravaginal prostaglandin E2 gel.

Fifty-four patients were randomized in a double blind fashion into either a placebo group or a group treated with a 3 mg dose of an intravaginal prostaglandin E2 gel. The group receiving the prostaglandin E2 gel had a mean change in cervical score of 2.7 while the patients in the placebo group had no significant change. Even though a significantly higher number of patients in the prostaglandin group went into spontaneous labor, the incidence of cesarean section was not different between the two groups. Upon comparing the conflicting reports of various studies on the subject, it is concluded that the method of product preparation, particularly the source of prostaglandin E2 utilized and the choice of drug vehicle, may be important variables in determining treatment success, as measured in terms of decreased cesarean section rate.

Formulation of controlled-release products.

A substantial number of prolonged-release theophylline products are commercially available, each claiming some benefit over a competing product. This paper provides a brief overview of the controlled drug delivery area, starting with the theoretical base of such products, typical biologic constraints related to the oral route of administration, and finally an overview of the type and characteristics of the various sustained- or controlled-release products presently available. It is important to recognize that the preparation of most sustained-release products is on an empirical basis and that it is common to test such products in healthy volunteers under a protocol that bears very little relationship to expected performance in the clinic. Controlled drug delivery, a field that is at least 40 years old in terms of successful commercial products, is just beginning to emerge as a discipline with a strong theory and clinical base.

The theory and practice of retrograde infusion: influence of tube diameter on drug delivery.

This work identifies a model for the flow dynamics of retrograde drug infusion, thereby helping to clarify the influence of variables on drug dilution in the apparatus and hence drug infusion rate. The study is a 2(3) factorial design that focuses on the influence of tube diameter (0.065 vs. 0.120 inches) in conjunction with changes in injected drug volume (2.0 vs. 5.0 ml) and iv flow rate (2.0 vs. 10.0 ml h-1). Each of the three variables was shown to exert a statistically significant (p = 0.01) effect on the total volume of fluid necessary to clear a dose from the retrograde apparatus. In all cases studied, smaller diameter tubes, larger injected drug volumes, and slower iv flow rates decreased the total volume fraction (F0.95). Within the confines of the study, practitioners may use an F0.95 value of 1.5 to predict the time at which a patient's retrograde drug infusion is likely to be complete. This, in turn, may be used to facilitate proper timing of blood sampling for therapeutic drug monitoring as well as other pharmacokinetic manipulations.

Localization of alpha 1-adrenergic receptors in normal and weaver mouse brain with in vitro 125I-HEAT autoradiography.

Using 125I-HEAT, a specific alpha 1-adrenergic antagonist, we have autoradiographically localized alpha 1-adrenergic receptors in the normal and weaver mutant mouse. Highest levels of binding in both the normal and weaver mouse were seen in the dorsal thalamus, external plexiform layer of the olfactory bulb and intermediate layers of the frontoparietal cortex. These results essentially parallel those found in the rat, with some differences in the cortical pattern that are attributable to differences between the cytological organization in the two species. Reduced levels of binding in the agranular weaver cerebellum as compared to normals indicated that binding in the normal cerebellum was to receptors on granule cell dendrites.

Postnatal development of brain alpha 1-adrenergic receptors: in vitro autoradiography with [125I]HEAT in normal rats and rats treated with alpha-difluoromethylornithine, a specific, irreversible inhibitor of ornithine decarboxylase.

The postnatal development of brain alpha 1-adrenergic receptors was studied in the rat brain using in vitro autoradiography. In some regions, such as the globus pallidus, receptor-binding sites were present at birth and increased during the first week but then decreased to very low levels by adulthood. In contrast, other regions such as the olfactory bulb and cerebral cortex exhibited little binding at birth, with a subsequent increase in receptors during the second week of life that persisted into the mature stage. Several regions had an intermediate pattern with significant labelling at birth, an increase in the first few weeks and a smaller decrement in binding sites as adulthood was approached. The data suggested that there were two archetypal development patterns, one of which was potentially related to the arrival of noradrenergic nerve projections (olfactory bulb) and the other of which was determined intrinsically by differentiation (globus pallidus). The two patterns could be distinguished by their sensitivity to alpha-difluoromethylornithine, a drug that inhibits ornithine decarboxylase, leading to a slowing of cellular replication, differentiation and migration. Drug treatment dramatically delayed the developmental fall-off of binding in the globus pallidus such that receptor sites remained in high concentration well past the point at which they disappeared in control animals. In the olfactory bulb, however, alpha-difluoromethylornithine had little or no effect on the ontogeny of receptor binding. These studies provide evidence that alpha 1-adrenergic receptors in various brain regions develop at different rates and with at least two characteristic patterns. Autoradiographic techniques provide important insights into receptor development that cannot be garnered from biochemical methods using isolated membrane preparations.

Regional distribution of rat brain alpha 1-adrenergic receptors: correlation between (125I)-heat membrane binding and in vitro autoradiography.

[125I]-HEAT has proven useful for in vitro autoradiography as a specific alpha 1-adrenergic radioligand. We compared the binding of [125I]-HEAT to membranes from ten brain regions with the densitometric readings of these regions in autoradiographs. There was an excellent correlation between receptor numbers from membrane binding and relative optical densities from the autoradiography. The affinity of HEAT for binding to membranes from various regions was similar. The results of this direct comparison are further evidence that HEAT binds to alpha 1-adrenergic receptors in lightly fixed tissue sections. A further interesting observation is that in regions with a heterogeneous distribution of binding sites, membrane binding may not reflect the presence of a dense local population of receptors.

Anatomy of brain alpha 1-adrenergic receptors: in vitro autoradiography with [125I]-heat.

Much useful information on the localization of alpha 1-adrenergic binding sites has been gained by using tritiated radioligands for in vitro autoradiography. However, the iodinated alpha 1-adrenergic antagonist HEAT [( 2-beta (4-hydroxyphenyl)-ethylaminomethyl)-tetralone], BE 2254), a radioligand with high affinity and specificity, provides autoradiographs with a higher signal to noise ratio. This has allowed us to describe the anatomy of these binding sites in much greater detail than previously possible. Regions showing the highest levels of binding include external plexiform layer of the olfactory bulb, layers Va and Vc of frontoparietal cortex, lateral and central amygdaloid nuclei, thalamus, and inferior olive. Other regions were generally less intensely labeled, with the least evidence of labeling in white matter, such as corpus callosum. Some regions (e.g., hippocampus) had only moderate labeling, but the binding appeared in a discrete pattern that reflected the functional organization of the structure. Although the [125I]-HEAT binding sites were distributed in a pattern similar to that previously reported for [3H]-WB 4101 and [3H]-prazosin, the anatomical detail seen with the iodinated ligand is greater. As a result, an association of alpha 1-adrenergic antagonist binding sites with specific layers in the cortex and with some catecholamine-containing nuclei in the brainstem, such as the locus coeruleus, have been seen for the first time.