Jean-Michel Senard

Deciphering biased-agonism complexity reveals a new active AT1 receptor entity.

Functional selectivity of G protein-coupled receptor (GPCR) ligands toward different downstream signals has recently emerged as a general hallmark of this receptor class. However, pleiotropic and crosstalk signaling of GPCRs makes functional selectivity difficult to decode. To look from the initial active receptor point of view, we developed new, highly sensitive and direct bioluminescence resonance energy transfer-based G protein activation probes specific for all G protein isoforms, and we used them to evaluate the G protein-coupling activity of [(1)Sar(4)Ile(8)Ile]-angiotensin II (SII), previously described as an angiotensin II type 1 (AT(1)) receptor-biased agonist that is G protein independent but β-arrestin selective. By multiplexing assays sensing sequential signaling events, from receptor conformations to downstream signaling, we decoded SII as an agonist stabilizing a G protein-dependent AT(1A) receptor signaling module different from that of the physiological agonist angiotensin II, both in recombinant and primary cells. Thus, a biased agonist does not necessarily select effects from the physiological agonist but may instead stabilize and create a new distinct active pharmacological receptor entity.

L-threo-dihydroxyphenylserine (L-threo-DOPS; droxidopa) in the management of neurogenic orthostatic hypotension: a multi-national, multi-center, dose-ranging study in multiple system atrophy and pure autonomic failure.

This study was designed to determine the efficacy and tolerability of increasing doses ofl-threo-dihydroxyphenylserine (l-threo-DOPS) in treating symptomatic orthostatic hypotension associated with multiple system atrophy (MSA) and pure autonomic failure (PAF). Following a one-week run-in, patients (26 MSA; 6 PAF) with symptomatic orthostatic hypotension received increasing doses ofl-threo-DOPS (100, 200 and 300 mg, twice daily) in an open, dose-ranging study. Incremental dose adjustment (after weeks two and four of outpatient treatment) was based on clinical need until blood pressure (BP), and symptoms improved. Final dosage was maintained for six weeks. Withl-threo-DOPS, systolic BP decrease was reduced during orthostatic challenge (−22±28 mm Hg reduction from a baseline decrease of 54.3±27.7 mm Hg, p=0.0001, n=32; supine systolic BP at final visit was 118.9±28.2 mm Hg). By the end of the study, 25 patients (78%) improved, and in 14 patients (44%) orthostatic hypotension was no longer observed. Decreased orthostatic systolic BP decrease occurred in 22% (7/32), 24% (6/25) and 61% (11/18) of patients treated with 100, 200, and 300 mgl-threo-DOPS twice daily, respectively. An improvement occurred in symptoms associated with orthostatic hypotension, such as light-headedness, dizziness (p=0.0125), and blurred vision (p=0.0290).l-threo-DOPS was well tolerated, with the 2 serious adverse events reported being a possible complication of the disease under study, and with no reports of supine hypertension. I conclusion,l-threo-DOPS (100, 200, and 300 mg, twice daily) was well tolerated. The dosage of 300 mg twice dailyl-threo-DOPS seemed to offer the most effective control of symptomatic orthostatic hypotension in MSA and PAF.

Ropinirole in the treatment of levodopa-induced motor fluctuations in patients with Parkinson's disease.

Forty-six patients with Parkinsons disease experiencing motor fluctuations and not optimally controlled on levodopa received as adjunct therapy a new nonergoline dopamine agonist, ropinirole, in a 3-month randomized placebo-controlled trial. Ropinirole significantly reduced the duration of off periods as assessed by self-scoring diary cards. There were more nonserious dopaminergic adverse events in the ropinirole group. More patients withdrew because of adverse events or insufficient therapeutic effect in the placebo group. Ropinirole has beneficial adjuvant effects in parkinsonian patients with moderate motor disability and motor fluctuations.

Drug-induced parkinsonism: a review

Summary— The main clinical features, pathophysiology and underlying mechanisms of drug‐induced parkinsonism are reviewed. The clinical manifestations of drug‐induced parkinsonism are often indistinguishable from idiopathic Parkinsons disease. However, some subtle differences may exist: for example drug‐induced parkinsonism is often associated with tardive dyskinesias, bilateral symptoms and the absence of resting tremor, etc. Besides toxins (eg manganese, carbon monoxide or MPTP), many drugs are known to produce parkinsonism: dopamine blocking drugs (true neuroleptics used as antipsychotics: phenothiazines, butyrophenones, thioxanthenes but also sulpiride, “hidden” neuroleptics prescribed as anti‐nausea or anti‐vomiting drugs (such as metoclopramide and other benzamide derivatives), dopamine depleting drugs (reserpine, tetrabenazine), alpha‐methyldopa, calcium channel blockers (flunarizine, cinnari‐zine, etc). The putative role of other drugs (eg fluoxetine, lithium, amiodarone) as well as the therapeutic management of this side effect are reviewed.

L-dopa-induced sedation : a double-blind cross-over controlled study versus triazolam and placebo in healthy volunteers

Incidental case reports suggest that some parkinsonian patients treated with dopaminergic drugs complain of drowsiness but few controlled data are available. We compared the sedative effects of L-Dopa (200 mg + 50 mg benserazide, PO), triazolam (0.125 mg) and placebo in a randomized double-blind cross-over design in 22 healthy volunteers pretreated with domperidone (60 mg/day). Drowsiness was assessed using a visual analog scale (VAS), a computerized choice reaction time test (CRT) and an electro-oculogram (EOG). L-Dopa and triazolam induced significant drowsiness, compared to placebo, on VAS, CRT and some EOG parameters. After this first evaluation session, all subjects were chronically treated for 11 days with 600 mg/d of L-Dopa. Drowsiness induced by L-Dopa, triazolam or placebo was then tested again on three consecutive days to assess putative dopaminergic tolerance. After chronic L-Dopa treatment, triazolam-induced sedation remained unchanged while L-Dopa sedative effects were no longer significant except on the VAS, preventing the conclusion that tolerance occurred. These data suggest that an acute dose of L-Dopa induces sedation in L-Dopa-naive subjects. This sedative effect must be considered in clinical practice and when studying the effects of L-Dopa on motor or neuropsychological performance, especially in acute tests.

Sleep attacks and antiparkinsonian drugs: a pilot prospective pharmacoepidemiologic study.

A prospective survey was performed to characterize the prevalence of sleep attacks and to evaluate precipitating factors in a group of 236 patients with idiopathic Parkinsons disease. Sleep attacks were reported by 72 patients (30.5%). Multivariate analysis showed a marked association between the occurrence of sudden sleep episodes and first autonomic failure, followed by treatment with ropinirole and bromocriptine. The present work underlines the major contributing role of autonomic failure followed by dopamine agonists in the occurrence of such an event. Because a relationship between sleep attacks and not only ropinirole but also bromocriptine treatment was described, the present work suggests that sleep attacks are a common side effect of all dopamine agonists.

Treatment of Parkinson's disease should begin with a dopamine agonist

The occurrence of side effects with long‐term levodopa therapy, such as fluctuations in motor performance or abnormal movements, led to a search for new antiparkinsonian drugs. Dopamine agonists include ergot derivatives such as bromocriptine, lisuride, pergolide, and cabergoline and other agents which do not possess the ergot structure such as pramipexole and ropinirole. They all are powerful stimulators of the D2 dopamine receptor which probably underlies their therapeutic effects. The clinical consequences of their binding to other dopamine receptor subtypes (D1 or D3) remains unknown. They are usually prescribed in combination with levodopa when late side effects begin to occur. This review summarizes the available pharmacologic and clinical data to support the early use of dopamine agonists in Parkinsons disease. Several strategies can be used, such as monotherapy or “early” or “late” combination with levodopa. Results of recent well‐performed, modern clinical trials show that early use of the new dopamine agonists is able to effectively control the clinical symptoms for more than 3 years thereby offering the possibility of delaying the occurrence of levodopa‐induced late motor side effects.

α2-Adrenoceptor Antagonists

Postmortem studies have shown that noradrenergic neurotransmission is impaired in Parkinson’s disease. This abnormality may have functional importance because (α2-adrenoceptor antagonists, which increase central noradrenergic transmission, improve motor behaviour in various animal models of this disease.Pilot clinical data suggest that (α2-antagonists may indeed have several potential indications in the treatment of Parkinson’s disease: (i) 3 recent placebocontrolled studies reported an improvement in motor scores following short term intravenous or long term oral administration of two different (α2-antagonists (idazoxan and efaroxan), suggesting that both drugs provide symptomatic benefit with regard to motor symptoms, especially rigidity and akinesia; (ii) an acute oral challenge with idazoxan reduced the severity of ‘peak-dose’ levodopa-induced dyskinesia, one of the most disabling complications of long term therapy with that drug, in a placebo-controlled study; (iii) biochemical and pharmacological experiments have suggested that levodopa-resistant parkinsonian symptoms, such as frozen gait, cognitive dysfunction, depressive state and dysautonomia, could be improved by enhancing central noradrenergic function; however, controlled clinical studies are necessary to evaluate the usefulness of (α2-adrenoceptor antagonists in these indications; and (iv) some preliminary experimental data support the hypothesis that noradrenergic mechanisms could be involved in the progression of Parkinson’s disease; thus, there is a rationale for testing the putative neuroprotective effects of (α2-adrenoceptor antagonists in this disorder.It has yet to be determined whether the antiparkisonian effects of (α2-antagonists are due to a direct effect of noradrenaline (norepinephrine) on motor systems or to an indirect effect, by means of noradrenergic interactions with dopamine or other neurotransmitters controlling motor behaviour or via other mechanisms.A careful evaluation of (α2-antagonists in the treatment of Parkinson’s disease must also consider their potential adverse effects, because these drugs possess cardiovascular and psychiatric properties which might compromise their risk-benefit ratio.

Sleep disruption, daytime somnolence and ‘sleep attacks’ in Parkinson's disease: a clinical survey in PD patients and age-matched healthy volunteers

Recent case reports of ‘sleep attacks’ (SA) in patients with Parkinsons disease (PD) generated concerns about drug‐induced daytime somnolence in this population. However, there are nearly no comparative data on sleep and vigilance problems between PD patients and normal controls. We performed a cross‐sectional survey in PD patients and age‐matched controls using a structured questionnaire on PD history, treatments, co‐morbidity, activities of daily living, habits, exercise, sleep pattern, driving, pre‐existing nocturnal problems, daytime somnolence, episodes of SA and the circumstances in which such episodes occurred. Daytime somnolence was also measured with the Epworth Sleepiness Scale (ESS) and sleep quality with the Pittsburgh Sleep Quality Index (PSQI). 176 PD patients and 174 controls were included. The same proportion of PD patients (27%) and controls (32%) reported episodes of SA, but these were more frequent in PD patients and occurred more frequently during situations requiring attention (10.8% vs. 1.7%, p<10−3). More PD patients had abnormal daytime somnolence (ESS) and poor sleeping quality (PSQI). The most consistent factor associated with SA was the duration of levodopa therapy and the predictive value of an abnormal ESS score was rather poor (40.7%). Abnormal daytime somnolence and poor sleep quality at night are more frequent in PD patients than in normals. However, SA are reported in both groups, although less frequently in the normals during activities that requires attention.

Changes in short-term variability of blood pressure and heart rate during the development of obesity-associated hypertension in high-fat fed dogs

OBJECTIVE To investigate the nature and time course of autonomic nervous system changes elicited by a 21-week ad libitum high-fat diet (HFD) in dogs. RESULTS The HFD increased body weight (+22.0+/-2.8% at week 21) with an abdominal circumference gain significantly more elevated than the thoracic one. The increases in insulin and free fatty acid plasma levels were correlated with body weight changes. Systolic and diastolic blood pressures and heart rate significantly increased (+23+/-6, +28+/-5 and 19+/-9% respectively). Arterial hypertension was characterized by an increase in cardiac output (+22.3+/-7.7%), in left ventricular mass (+18.1+/-5.0% at week 21) and a decrease in spontaneous baroreflex efficiency (-55+/-6%). The time course of autonomic changes (using spectral analysis of systolic blood pressure and heart rate) showed the existence of time-dependent modifications, which were linked with food intake. The initial rise in arterial blood pressure during body weight increment (observed between the 1st and 8th week of HFD) was associated with a transient increase in the low frequency band of systolic blood pressure variability and noradrenaline plasma levels associated with a long-lasting decrease in the high frequency band of heart rate variability. Early changes in short-term variability were significantly correlated with free fatty acid plasma levels. In contrast, the steady-state of obesity-related hypertension was associated with a decreased high frequency band of heart rate variability, without significant changes in noradrenaline plasma levels. CONCLUSIONS This study shows that the HFD induces abdominal obesity, hyperinsulinaemia and arterial hypertension, with a left ventricular hypertrophy associated with a biphasic changes in autonomic activity: an early and long-lasting decrease in parasympathetic nervous system activity and an early but transient increase in sympathetic activity. The present data suggest that autonomic nervous system changes are dependent on the time course of obesity development.