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Biomedical subjects

R A Hauser

Publications and source records attributed to R A Hauser.

At least 37 records · Page 2Linked to original sources
PubMed1999

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.

Adult↗
PubMed1999

Management of early Parkinson's disease.

The two major questions in the treatment of early PD are (1) Does selegiline slow neuronal loss and delay the progression of clinical disability? and (2) Should dopamine agonists be used as initial symptomatic therapy in early disease rather than levodopa/PDI to reduce long-term disability and delay the onset of motor fluctuations and dyskinesia? Selegiline affords neuroprotection for dopamine neurons in cell culture systems and the results of several clinical trials are consistent with the hypothesis that it is neuroprotective in Parkinson's disease. Several clinical trials have found that initial symptomatic therapy with dopamine agonist to which levodopa/carbidopa is later added when needed leads to a lower incidence of long-term motor complications. These strategies are now being tested in prospective, randomized, blinded trials, many of which include PET or SPECT scans to assess the rate of dopamine neuron loss. These trials will provide more definitive answers to guide the early medial management of Parkinson's disease in the future.

Animals↗
PubMed1999

Ropinirole in the treatment of Parkinson's disease.

In this review, the pharmacokinetics, safety and tolerability, and clinical efficacy of ropinirole (Requip), a non-ergoline dopamine agonist approved for use in the treatment of Parkinson's disease (PD) are examined. A summary of preclinical and clinical studies is presented. Ropinirole is safe and efficacious as monotherapy in the treatment of early PD and as an adjunct to levodopa in more advanced cases.

Journal Article↗
PubMed1999

Current issues in depression in Parkinson's disease.

Depression affects 40%-50% of Parkinson's disease (PD) patients. The authors, by use of a Mednet and manual search of pertinent literature, summarize current issues in the treatment of depression in PD. Open-label studies suggest that antidepressants may be effective for treating depression in PD. Although case reports indicate that selective serotonin reuptake inhibitors (SSRIs) can potentially worsen the motor symptoms of PD, this effect has not been confirmed in the small number of open-label studies that have been performed to date. The occurrence of the serotonin syndrome resulting from a combination of selegiline and an SSRI appears to be rare. Double-blind prospective studies are needed to evaluate the safety and efficacy of antidepressants in PD and their effect on motor function.

Aged↗
PubMed1998

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.

Antiparkinson Agents↗
PubMed1998

Randomized, placebo-controlled study of tolcapone in patients with fluctuating Parkinson disease treated with levodopa-carbidopa. Tolcapone Fluctuator Study Group III.

OBJECTIVE: To assess the efficacy and tolerability of the catechol-O-methyltransferase inhibitor tolcapone in reducing "off/on" fluctuations in levodopa-treated parkinsonian patients. DESIGN: A randomized, double-blind, placebo-controlled, parallel-group study. SETTING: Fifteen Parkinson disease clinics. PATIENTS: Two hundred fifteen referred outpatients with Parkinson disease who showed predictable end-of-dose motor fluctuations that were not controlled by a stable levodopa-carbidopa (Sinemet) regimen of at least 4 weeks' duration. INTERVENTIONS: In addition to their usual levodopa-carbidopa regimen, patients received placebo or tolcapone, 100 or 200 mg, 3 times daily orally for 6 weeks. PRIMARY OUTCOME MEASURE: Change in daily off/on time. RESULTS: Tolcapone, 100 and 200 mg 3 times daily, reduced off time by 2.0 and 2.5 hours per day, respectively, and increased on time by 2.1 and 2.3 hours per day, respectively (P<.001 vs placebo). Investigators' global measures of disease severity indicated that significantly more tolcapone-treated patients had reduced wearing off and symptom severity (P<.001 vs placebo). No significant change in quality-of-life measures occurred. Clinical improvements occurred despite a reduction in total daily levodopa dose of 185.5 mg (23%) in the tolcapone, 100 mg 3 times daily, group and 251.5 mg (29%) in the 200 mg 3 times daily group. Principal adverse events (mainly dyskinesia and nausea) were levodopa related, were not treatment limiting, and were seldom reported as reasons for withdrawal. The frequency of withdrawals because of adverse events was similar in all groups (3% to 7%). CONCLUSIONS: Tolcapone was well tolerated and substantially increased on time and reduced off time in patients with fluctuating Parkinson disease. Additionally, levodopa requirements were significantly decreased.

Aged↗
PubMed1998

Ropinirole for the treatment of early Parkinson disease: a 12-month experience. Ropinirole Study Group.

OBJECTIVE: To evaluate ropinirole hydrochloride as dopaminergic monotherapy in patients with early Parkinson disease. DESIGN: A 6-month extension of a double-blind, placebo-controlled study. SETTING: Ambulatory care at 22 different sites in the United States. PATIENTS: Patients who successfully completed the initial 6-month study could enter the 6-month extension study (ropinirole, n = 70; placebo, n = 77). INTERVENTION: Use of ropinirole or placebo therapy. MAIN OUTCOME MEASURES: The efficacy variables were the number of patients who successfully completed the 12-month study and did not require supplemental levodopa, the number of patients requiring supplemental levodopa, and the proportion of patients having an insufficient therapeutic response. RESULTS: Significantly fewer ropinirole-treated patients met criteria for insufficient therapeutic response (23 [19.8%] of 116) or required the initiation of levodopa therapy (22 [19%] of 116) compared with placebo-treated patients (60 [48%] of 125 patients for insufficient therapeutic response; 57 [45.6%] of 125 patients for additional levodopa). Significantly more ropinirole-treated patients (51 [44.0%] of 116) successfully completed the 12-month study and did not require supplemental levodopa compared with placebo-treated patients (28 [22.4%] of 125). The incidence of adverse experiences and patient withdrawals was low. CONCLUSION: Ropinirole was effective and well tolerated as monotherapy for 12 months in patients with early Parkinson disease.

Adult↗
PubMed1998

Fetal nigral grafts survive and mediate clinical benefit in a patient with Parkinson's disease.

We have previously demonstrated that fetal nigral grafts can survive, reinnervate the striatum, and mediate clinically relevant recovery in a patient with Parkinson's disease (PD). Most previous autopsy cases have failed to identify meaningful numbers of viable grafted cells suggesting that differences in critical transplant variables determine graft viability. The present study evaluated the structural and functional correlates of fetal nigral transplantation in a second PD patient who received fetal nigral grafts according to our previously published transplant protocol. A 61-year-old woman with severe PD received bilateral fetal nigral grafts to the postcommissural putamen from seven donor fetuses (four right side and three left side) aged 6.5-9 weeks postconception. This patient died 19 months after surgery from a cause unrelated to the transplant surgery. Her postoperative clinical course was characterized by improved motor and activities of daily living scores during "off time," reduced "off time," and increased "on" time without dyskinesia. Positron emission tomography (PET) scans revealed a bilateral and progressive increase in fluorodopa (FD) uptake within the grafted putamen. Postmortem examination of the right hemisphere revealed large oval-shaped grafts containing more than 138,000 tyrosine-hydroxylase-immunoreactive (TH-ir) neurons. Grafted cells formed a seamless border with the host and provided dense TH-ir innervation to 78% of the host postcommissural putamen. Graft-mediated sprouting of host fibers was not observed. These data provide essential confirmation that, under appropriate transplant conditions, grafted nigral neurons can survive, reinnervate the host striatum, and provide clinical benefit to PD patients. These findings also support the concept that improved motor function and striatal FD uptake on PET after nigral grafting in PD are the result of the viability of grafted neurons and graft-derived reinnervation of the host striatum.

Brain Tissue Transplantation↗
PubMed1998

A pilot evaluation of the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in untreated Parkinson's disease patients. Tolcapone De Novo Study Group.

Tolcapone is a potent, reversible catechol-O-methyltransferase (COMT) inhibitor with both peripheral and central activity. It has been demonstrated to improve motor function and allow levodopa dose reductions in Parkinson's disease (PD) patients who are experiencing either a stable response or motor fluctuations while on levodopa/dopa decarboxylase inhibitor therapy. Because striatal dopamine is metabolized by COMT and monoamine oxidase (MAO), central COMT inhibition alone or in combination with MAO inhibition might provide symptomatic benefit for patients not receiving levodopa. We conducted a pilot study to evaluate the tolerability, safety, and efficacy of tolcapone alone and in combination with oral selegiline in early untreated PD patients. Patients were randomized to receive 200 mg tolcapone three times a day or placebo for the 8 weeks of the study. Open-label oral selegiline (5 mg in the morning and midday) was administered to all patients during the second 4 weeks of the study. There was no difference between treatment groups according to the investigator's assessment of tolerability at week 4. Ninety-five percent of tolcapone-treated patients and 98% of placebo-treated patients experienced excellent or good tolerability during the first 4 weeks (95% confidence interval [CI]: -10.3, 5.7; p = 0.57). A decrease in tolerability occurred in the tolcapone group during the second 4 weeks of the study following the addition of selegiline. The most commonly reported side effects were diarrhea (31% tolcapone, 7% placebo), nausea (21% tolcapone, 2% placebo), urine discoloration (12% tolcapone, 0% placebo), dizziness (12% tolcapone, 5% placebo), headaches (12% tolcapone, 10% placebo), and abdominal pain (10% tolcapone, 5% placebo). We did not identify symptomatic benefit associated with tolcapone alone or in combination with oral selegiline in this group of otherwise untreated PD patients.

Administration, Oral↗
PubMed1998

Plasma thiamine deficiency associated with Alzheimer's disease but not Parkinson's disease.

In this study we compared plasma and erythrocyte thiamine levels in a group of patients with idiopathic Parkinson's Disease (iPD) to a group of patients with probable Alzheimer's Disease (pAD). pAD patients had significantly lower plasma thiamine levels (raw and z-score) than iPD patients. A significantly higher number of pAD patients had plasma thiamine deficiencies than iPD patients. The demographics of our patient groups were similar to those reported by other investigators, making age, sex and nutritional status unlikely explanations for our findings. These results suggest that plasma thiamine deficiency is associated with pAD but not with iPD.

Adult↗
PubMed1997

Sertraline for the treatment of depression in Parkinson's disease.

Although antidepressant medications are commonly used to treat depression in Parkinson's disease (PD), little information is available regarding their safety and efficacy in this condition. Sertraline is a relatively selective serotonin reuptake inhibitor with some dopamine reuptake inhibitor activity. It has a favorable tolerability profile, especially in the elderly. We undertook an open-label pilot evaluation of the safety and efficacy of sertraline to treat depression in PD. A total of 15 patients with PD and depression participated in the study. Sertraline was introduced at a daily dose of 25 mg for 1 week and then increased to 50 mg/day. Patients underwent evaluation at baseline and at a final visit approximately 7 weeks later. Sertraline was generally well tolerated, but five patients experienced side effects, and two discontinued medication. Patients taking selegiline experienced more adverse effects. Beck Depression Inventory scores improved significantly (mean +/- SE = 16.0 +/- 2.0 vs 11.7 +/- 1.9, p = 0.03), and Unified Parkinson's Disease Rating Scale and energy-level scores were unchanged. These results suggest that sertraline may be a useful treatment for depression in PD. As substantial placebo effects can occur in studies of PD and depression, placebo-controlled, double-blind studies are warranted.

1-Naphthylamine↗
PubMed1997

Hyperactivity and hypoactivity in a rat model of Huntington's disease: the systemic 3-nitropropionic acid model.

The present study proposes the use of systemic 3-nitropropionic acid (3-NP) treatment in rats as a model of Huntington's disease (HD). The systemic 3-NP model involves chronic injection of low dose intraperitoneal (i.p.) injections of 3-NP to rats once every 4 days over a period of time. Evidence from our experimental studies suggests that manipulating the number of injections can result in either increased nocturnal spontaneous locomotor activity (hyperactivity) or nocturnal akinesia (hypoactivity) [1]. For example, two injections of 3-NP (using the treatment of one injection every 4 days) result in hyperactivity, while four injections or more of 3-NP lead to hypoactivity [1]. The locomotor activity is recorded by Digiscan locomotor activity monitors [11]. The observation of these two types of locomotor activity is unique since no excitotoxin model has replicated a two-stage progression of a HD-like behavioral alteration. Most studies using excitotoxins like quinolinic acid (QA) and kainic acid (KA) have only reproduced the hyperactivity stage [4,5,7]. With the systemic 3-NP model, investigations into at least two stages of the disease are made possible. This allows for better assessment of intervention strategies such as neural transplants across different stages of the disease. The systemic 3-NP rat model is believed to be an improved animal model of HD.

Animals↗
PubMed1997

Ropinirole for the treatment of early Parkinson's disease. The Ropinirole Study Group.

A prospective, randomized, placebo-controlled, double-blind, parallel-group, 6-month study assessed the efficacy and safety of ropinirole, a nonergoline D2-dopamine agonist, in patients with early Parkinson's disease (n = 241; Hoehn & Yahr stages I to III) with limited or no prior dopaminergic therapy. Patients (mean age, 62.8 years), stratified by concomitant use of selegiline, were randomized to ropinirole (n = 116) or placebo (n = 125). The starting dose of ropinirole was 0.25 mg tid with titration to at least 1.5 mg tid (maximum dose, 8 mg tid). Primary efficacy endpoint was the percentage improvement in Unified Parkinson's Disease Rating Scale (UPDRS) motor score. Ropinirole-treated patients had a significantly greater percentage improvement in UPDRS motor score than patients who received placebo (+24% vs -3%; p < 0.001). Ropinirole was well tolerated and patient withdrawals were infrequent. Most adverse experiences were related to peripheral dopaminergic activity. Ropinirole monotherapy is an effective and well-tolerated therapeutic option for treatment of early Parkinson's disease.

Aged↗