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Biomedical subjects

Guy Arnold

Publications and source records attributed to Guy Arnold.

16 recordsLinked to original sources
PubMed2006

Pergolide versus levodopa monotherapy in early Parkinson's disease patients: The PELMOPET study.

Dopamine agonists are used as initial treatment in patients with Parkinson's disease (PD) to reduce incidence and severity of motor complications. This paradigm is based on long-term studies, allowing "rescue" therapy with levodopa. The present strict monotherapy study (PELMOPET, the acronym for the pergolide-versus-L-dopa-monotherapy-and-positron-emission-tomography trial) evaluated the efficacy and safety of pergolide versus levodopa without levodopa "rescue" medication. This multicenter, double-blind, randomized, 3-year trial compared pergolide monotherapy (n=148) with levodopa monotherapy (n=146) in dopamine-naive patients with early PD (Hoehn and Yahr stage 1-2.5). Primary efficacy measures were clinical efficacy, severity and time to onset of motor complications, and disease progression. During the 3 years, severity of motor complications was significantly lower and time to onset of dyskinesia was significantly delayed in the group receiving pergolide (3.23 mg/day) compared with those receiving levodopa (504 mg/day). However, time to onset of motor complications was not longer in patients receiving pergolide after 3 years. Symptomatic relief (assessed by Unified Parkinson's Disease Rating Scale [UPDRS], UPDRS II, and III, Clinical Global Impressions [CGI] severity, and CGI and Patient Global Impressions [PGI] improvement) was significantly greater in patients receiving levodopa. Adverse events led to discontinuation of therapy in 17.6% of pergolide patients and 9.6% of levodopa patients. This is the first study comparing strict monotherapy with a dopamine agonist versus levodopa in previously untreated early PD. In principle, both levodopa and a dopamine agonist such as pergolide seem to be suitable options as initial PD therapy. The choice remains with the treating physician based on the different efficacy and adverse event profiles.

Adult↗
PubMed2006

Effects of parecoxib on plasma protein extravasation and c-fos expression in the rat.

OBJECTIVE: We aimed to investigate the effects of the cyclooxygenases-2 (COX-2) inhibitor parecoxib on meningeal plasma protein extravasation (PPE) and on c-fos expression in the nucleus trigeminalis caudalis in an animal model of trigeminovascular activation. Background.-Recent reports about the efficacy of COX-2 inhibitors in migraine treatment suggest the involvement of COX-2 in migraine pathophysiology. So far, studies on the role of COX-2 in animal models of migraine are lacking. METHODS: Unilateral electrical stimulation of the trigeminal ganglion was performed in anesthetized male Sprague Dawley rats. We assessed PPE in the ipsilateral dura mater and expression of c-fos within the ipsilateral trigeminal nucleus caudalis (TNC) under control conditions and after pretreatment with parecoxib. RESULTS: Parecoxib significantly attenuated PPE in the rat dura mater. The PPE ratio under control conditions (1.73 +/- 0.19 (mean +/- SD)) was reduced by 58.9 +/- 30% after pretreatment with 10 mg/kg parecoxib and by 78.1 +/- 23% after pretreatment with 50 mg/kg. c-fos experiments: Compared with vehicle, all doses of parecoxib (1 mg/kg, 10 mg/kg, 50 mg/kg) significantly reduced the number of c-fos positive cells in the ipsilateral TNC (P < .05). The number of c-fos positive cells in the ipsilateral TNC was 50 +/- 2.7 (mean +/- SEM) under control conditions and 9.1 +/- 0.6 after pretreatment with 50 mg/kg parecoxib. CONCLUSION: Our study results suggest that COX-2 is involved in neurogenic inflammation of the rat dura mater. Moreover, the study points to a role of COX-2 inhibitors in trigeminal nociception at the second-order level.

Animals↗
PubMed2005

High doses of pergolide improve clinical global impression in advanced Parkinson's disease:- a preliminary open label study.

We evaluated the efficacy and safety of high-dose pergolide treatment in patients with moderate to severe Parkinson's disease (PD) in an open-label multicenter clinical trial. The primary objective was to assess the amount of reduction in levodopa, the improvement in Unified Parkinson's Disease Rating Scale (UPDRS) and adverse reactions. We treated 32 patients with PD presenting with motor fluctuations. Pergolide treatment started with a dose escalation period of 12 weeks followed by a 12-week continuation period. Pergolide doses were increased up to a maximum of 12 mg/day in combination with a simultaneous decrease of levodopa doses in 100mg steps. Levodopa was reduced from 500 mg/day (median) to 250 mg/day. Mean UPDRS part III improved significantly (p=0.01). Clinical global impression improved significantly after 24 weeks (p<0.01). Most frequent adverse events were hallucinations, asthenia, anxiety, abdominal pain, and peripheral edema. Twenty-two patients finished the complete study according to protocol. A possible relationship to the study medication was assumed for two serious adverse events reporting psychosis. We conclude that high doses of pergolide are efficacious in advanced stages of PD if given in appropriate regimens.

Adult↗
PubMed2005

Egocentric and allocentric spatial memory in idiopathic cervical dystonia.

OBJECTIVE: To investigate whether impaired spatial memory contributes to cognitive deficits in idiopathic cervical dystonia (ICD). METHODS: The authors tested 16 untreated patients with ICD and 16 healthy controls with four variants of a classic spatial memory task, in which subjects were requested to recall the locations of 16 toy objects either immediately after their presentation or after an unfilled delay of 10 minutes. By varying the spatial relationship between subject and toy object array, we tested encoding and memory of spatial relationships between subject and toy objects (egocentric tasks) and of spatial relationships between toy objects and environment (allocentric tasks). RESULTS: In all four tasks, absolute performance of patients did not differ significantly from controls, suggesting that there are no significant spatial memory deficits in ICD. However, significant correlations between egocentric and allocentric task performance were found in patients but not in controls. CONCLUSIONS: While control subjects flexibly used egocentric or allocentric spatial representations in memory tasks, patients with idiopathic cervical dystonia (ICD) solved both task types with a single allocentric strategy. Our findings point to the existence of compensatory mechanisms between distinct neural systems supporting egocentric and allocentric spatial representations in ICD.

Adaptation, Physiological↗
PubMed2004

Subthalamic stimulation differentially modulates declarative and nondeclarative memory.

Declarative memory has been reported to rely on the medial temporal lobe system, whereas non-declarative memory depends on basal ganglia structures. We investigated the functional role of the subthalamic nucleus (STN), a structure closely connected with the basal ganglia for both types of memory. Via deep brain high frequency stimulation (DBS) we manipulated neural activity of the STN in humans. We found that DBS-STN differentially modulated memory performance: declarative memory was impaired, whereas non-declarative memory was improved in the presence of STN-DBS indicating a specific role of the STN in the activation of memory systems.

Aged↗
PubMed2003

Deep brain stimulation in dystonia.

Renewed interest in stereotaxy for dystonia followed the introduction of deep brain stimulation (DBS) in Parkinson's disease and essential tremor in the 1990s. DBS evolved from ablative surgery, which was applied with varying results in the 1950s in patients with movement disorders such as Parkinson's disease, essential tremor and dystonia. The present review summarizes the current knowledge on clinical aspects of DBS in dystonia (Dec. 2002). Excellent results have been achieved in dystonic patients carrying a mutation in the DYT1 gene with improvements up to 90 %. Similar results may also be obtained in patients with idiopathic generalized dystonia, myoclonus-dystonia syndrome, and tardive dystonia. Substantial improvement has been observed in patients with focal dystonia (for instance cervical dystonia). Patients with secondary dystonia often display a lesser and more variable degree of improvement. Long-term studies are warranted to assess both motor and neuropsychological sequelae of DBS in dystonia. Furthermore, the optimal target for different dystonic disorders remains to be determined, although the globus pallidus internus has currently emerged as the most promising target for dystonia.

Dystonia↗
PubMed2003

Riluzole and blood pressure in multiple system atrophy.

Riluzole is a neuroprotective agent that is currently tested for the treatment of multiple system atrophy (MSA). Riluzole may influence afferent and efferent parts of the baroreflex due to glutamate antagonistic effects. The effect of riluzole on the efferent part may be unmasked in MSA patients with dysfunction of afferent structures of the baroreflex. We compared the effect of a single dose of 200 mg riluzole with placebo in 10 patients with probable MSA. Brachial blood pressure and heart rate were recorded at baseline and for 120 minutes every 5 minutes after ingestion of riluzole. For determination of spontaneous baroreflex sensitivity, continuous finger blood pressure and ECG were recorded. Cardiac stroke volume was monitored using impedance cardiography. The change in blood pressure over a two hour period was significantly greater with riluzole than with placebo (5 +/- 5/2 +/- 3 mmHg with placebo, 16 +/- 6/10 +/- 2 mmHg with riluzole, p < 0.001 by ANOVA). Systemic vascular resistance increased 32 +/- 6% with riluzole. Baroreflex sensitivity, the high and low frequency components of heart rate variability, and the low frequency component of systolic blood pressure variability were not different between placebo and riluzole treatment. We conclude that in MSA patients, manipulation of glutamatergic transmission with riluzole elicits a moderate pressor response. The response is explained by a marked increase in systemic vascular resistance. We propose that decreased inhibition of efferent sympathetic neurons may contribute to the response.

Aged↗
PubMed2003

A fluorescence-based method to assess plasma protein extravasation in rat dura mater using confocal laser scanning microscopy.

We describe a nonradioactive, fluorescence-based method to assess plasma protein extravasation (PPE) in rat dura mater using confocal laser scanning microscopy (CLSM). Unilateral PPE can be induced by electrical stimulation of the ipsilateral trigeminal ganglion (TG) and is widely used as an experimental migraine model. The gold standard to determine PPE in the meninges is based on the detection of radiolabeled albumin ([125]I-BSA). The aim of this study was to develop a nonradioactive, histological method to quantify PPE in the meninges. The fluorescent dye Evans Blue (50 mg/kg) was injected intravenously to the rat 7 min prior to TG stimulation. PPE in dura mater was detected by a CLSM. The amount of extravasated Evans Blue in the dura mater was measured at six to eight regions of interest (ROIs) in the vicinity of large meningeal vessels. The ratio of the average fluorescence intensity within dura mater of the "stimulus side", compared to the contralateral "control side", was calculated for each animal. By using this method, The PPE ratio was 1.67+/-0.12 (n=5). Intravenous injection of three different dosages of the 5HT(1B/1D)-receptor agonist sumatriptan (25, 50, and 100 microg/kg) 15 min prior to stimulation attenuated PPE by 42+/-12%, 49+/-9%, and 86+/-15%, respectively (p<0.01). The approximated ED(50) value was 48 microg/kg. Our results are in accordance with previous reports in the literature using the radioactive approach. We conclude that CLSM is a safe, sensitive, and reliable method to assess PPE in rat meninges in an experimental migaine model.

Animals↗
PubMed2002

Catechol-o-methyltransferase and blood pressure in humans.

BACKGROUND: Whether catechol-O-methyltransferase (COMT), the enzyme that metabolizes extraneuronal norepinephrine, contributes to blood pressure regulation in humans is unknown. METHODS AND RESULTS: We studied incremental doses of the COMT inhibitor entacapone, the sympathetic stimulant yohimbine, and placebo in 7 patients with multiple system atrophy (Shy Drager syndrome). We selected these unique subjects because norepinephrine exerts an exaggerated increase in blood pressure in these patients. Autonomic regulation was characterized with intravenous phenylephrine, nitroprusside, and trimethaphan. Patients were extremely hypersensitive to phenylephrine and nitroprusside. Trimethaphan elicited a profound depressor response. Phenylephrine sensitivity increased only slightly during ganglionic blockade. Entacapone increased systolic blood pressure dose-dependently; however, the pressor response to yohimbine was approximately 3.5 times greater than the maximal response to entacapone. CONCLUSIONS: COMT inhibition elicits a moderate, dose-dependent pressor response in the setting of severely impaired baroreflex buffering. Patients with multiple system atrophy allow for the characterization of subtle manipulations of norepinephrine turnover and blood pressure regulation in small numbers of subjects.

Baroreflex↗
PubMed2002

Baroreflex buffering and susceptibility to vasoactive drugs.

BACKGROUND: The overall effect of vasoactive drugs on blood pressure is determined by a combination of the direct effect on vascular tone and an indirect baroreflex-mediated effect, a baroreflex buffering of blood pressure. Differences in baroreflex function affect the responsiveness to vasoactive medications, particularly baroreflex buffering of blood pressure; however, the magnitude is not known. METHODS AND RESULTS: We characterized baroreflex function and responses to vasoactive drugs in patients with idiopathic orthostatic intolerance, patients with essential hypertension, patients with monogenic hypertension and brachydactyly, patients with multiple system atrophy, and control subjects. We used phenylephrine sensitivity during ganglionic blockade as a measure of baroreflex buffering. Phenylephrine (25 microg) increased systolic blood pressure 6+/-1.6 mm Hg in control subjects, 6+/-1.1 mm Hg in orthostatic intolerance patients, 18+/-3.9 mm Hg in patients with essential hypertension, 31+/-3.4 mm Hg in patients with monogenic hypertension, and 25+/-3.4 mm Hg in patients with multiple system atrophy. Similar differences in sensitivities between groups were observed with nitroprusside. The sensitivity to vasoactive drugs was highly correlated with baroreflex buffering function and to a lesser degree with baroreflex control of heart rate. In control subjects, sensitivities to nitroprusside and phenylephrine infusions were correlated with baroreflex heart rate control and sympathetic nerve traffic. CONCLUSIONS: Our findings are consistent with an important effect of baroreflex blood pressure buffering on the sensitivity to vasoactive drugs. They suggest that even moderate changes in baroreflex function may have a substantial effect on the sensitivity to vasoactive medications.

Adrenergic beta-Agonists↗
PubMed2002

Steele-Richardson-Olszewski-syndrome: reduction of dopamine D2 receptor binding relates to the severity of midbrain atrophy in vivo: (123)IBZM SPECT and MRI study.

Patients with the clinical diagnosis of progressive supranuclear palsy (PSP) show heterogeneous neuropathological findings. In neuropathologically proven cases with numerous neurofibrillary tangles of neuropil threads, the brainstem and striatum are always affected. We compared (123)I-iodobenzamide single photon emission computed tomography (IBZM-SPECT) for imaging of striatal dopamine D(2) receptors in vivo with high-resolution magnetic resonance imaging (MRI) in 13 patients with possible or probable PSP. Clinically, all patients exhibited similar signs including supranuclear vertical-down-gaze palsy, axial rigidity especially involving the neck, bradykinesia, instability of balance with easy falls, and a poor response to dopaminergic drugs. Specific striatal dopamine D(2) receptor binding in IBZM-SPECT was reduced in 10 patients but was normal in three patients. Mean midbrain diameter was 23.7 mm. The reduction of IBZM-binding was statistically significantly correlated to midbrain atrophy (P = 0.010) either in all 13 patients or in those without striatal or white matter lesions (P = 0.015). We suggest that technical investigations, mainly MRI, are able to corroborate the in vivo diagnosis, if PSP is clinically suspected.

Aged↗
PubMed2002

Habituation of the visually evoked potential and its vascular response: implications for neurovascular coupling in the healthy adult.

In the human, visually evoked potentials (VEP) and cerebral oxygenation changes, as measured by near-infrared spectroscopy (NIRS), are assessed to elucidate the relation between electrophysiological and vascular responses to a checkerboard stimulus reversing at 3 Hz. Habituation of either response is analysed on two time scales. Within the 1-min stimulation period we find a decrease in P100N135-component amplitude, closely coupled to a decrease in the amplitude of the oxygenation parameters (concentration changes in oxygenated and deoxygenated haemoglobin, [oxy-Hb] and [deoxy-Hb]). The N75P100-component amplitude exhibits a different behaviour along the 1-min stimulation period. An initial increase is overridden by an overall decrease, the latter not reaching statistical significance. The analysis across the 13 successive stimulation blocks separated by resting periods of equal duration yields a trend for an decrease in the VEP-components' amplitude, not reflected in the vascular response. When calculating a ratio between the amplitude of the P100N135-component and the concentration changes in the haemoglobins a "coupling index" of a 0.2 microM decrease in [deoxy-Hb] and an increase of 0.6 microM in [oxy-Hb] is found per 1 microV increase in VEP-component amplitude. The ratio is the same irrespective of its assessment from the difference stimulation/ rest or from the habituation effect, i.e., the difference between the amplitudes at the beginning and towards the end of the stimulation period. Although supporting the notion that the coupling between neuronal activation and the vascular response exhibits linear aspects, our findings cannot be taken as a proof of such a linearity across all brain regions and activation types. On the contrary, tentatively calculating a coupling index for the data assessed in the visual system, we intend to stress the necessity to assess both neuronal and vascular response to allow for a comparison between different systems and conditions in whom neurovascular coupling is expected to be altered (Miller et al, 2001; Mechelli et al, 2001).

Adult↗
PubMed2002

Treatment of acute cluster headache with 20 mg sumatriptan nasal spray--an open pilot study.

We investigated the efficacy and tolerability of 20 mg sumatriptan nasal spray in the acute treatment of cluster headache attacks in an open-label study. 10 patients met the criteria of the International Headache Society (IHS) for episodic or chronic cluster headache and were enrolled in our study. The primary efficacy measure was "pain free" 30 minutes after treatment. Secondary end-points included "headache response" (defined as headache improvement from "very severe", "severe" or moderate" pain to "mild" or "no" pain) 15, 30, 45 and 60 minutes after treatment. We also assessed the participant's overall treatment satisfaction at the end of the study. Sumatriptan nasal spray was applied in 154 "moderate" to "very severe" cluster headache attacks. 30 minutes after nasal spray application, 50% of attacks were completely aborted and 58% of attacks responded to treatment. The overall efficacy of sumatriptan nasal spray was considered "excellent" in two, "good" in four, "reasonable" in two and "poor" in two patients. Eight patients indicated their intention to treat further attacks with intranasal sumatriptan. Seven patients were interviewed after a follow-up period of six months. Four patients continued to treat all cluster headache attacks with the intranasal sumatriptan formula, two patients had switched to subcutaneous sumatriptan and one patient was in remission since the end of the study. We conclude that 20 mg sumatriptan nasal spray might be an alternative therapy for the treatment of cluster headache attacks, but double-blind studies are needed to further evaluate its efficacy.

Administration, Intranasal↗