Changing dopamine agonist treatment in Parkinson's disease: experiences with switching to pramipexole.

1202 patients suffering from Parkinson's disease switched from other dopamine agonists to pramipexole under open conditions either abruptly or in an overlapping, gradual manner. Mostly insufficient effectiveness motivated the switch. The investigators gave equal preference to either an abrupt or an overlapping switch to pramipexole in this observational study. There was a tendency in favour of the overlapping switch procedure in those patients who were on a relatively higher dose of a dopamine agonist before the switch. The switch was performed because the investigators expected the effect of pramipexole on tremor, motor functions and depression/anhedonia to be better compared with previous dopamine agonists. The main reasons for switching to pramipexole (anti-tremor effect, anti-depressive/anti-anhedonic effect) as given by the physicians at baseline came up to expectations. The switch to pramipexole mostly yielded further improvements irrespective of the mode of switching.

[Pramipexole in Parkinson disease. Results of a treatment observation]. / Pramipexol bei der Parkinson-Krankheit. Ergebnisse einer Anwendungsbeobachtung.

Pramipexole is a novel, internationally available selective nonergot D2 dopamine agonist. The effectiveness, tolerability, and safety of pramipexole have been extensively proven in controlled trials in patients in the early and advanced stage of Parkinson's disease as monotherapy and in combination with L dopa. These trials indicated specific activity against tremor, anhedonia, and depression. Therefore, the present prospective, multicenter postmarketing surveillance study evaluated for the first time to what extent the results from the controlled pramipexole trials could be replicated under routine conditions in neurological practice and clinics. Modern scales were applied for the assessment of tremor and mood, i.e., the Short Parkinson's Evaluation Scale (SPES), the Tremor Impact Scale (TIS), and the German version of the Snaith-Hamilton Pleasure Scale (SHAPS-D). In 298 German Centers, 657 Parkinson's patients (365 men, 292 women) in advanced disease stages were treated with pramipexole in combination with levodopa. The average ages (+/- SD) were 67 (+/- 8.9) years for men and 69 (+/- 9.4) years for females. Motor functioning, especially tremor, motor complications, depression, and activities of daily living improved highly significantly (P < 0.0005), including self-rating by the patients. The dosage of levodopa could be reduced on average by 8% (P < 0.0001). This might contribute to a slowing of the disease progression in the long run. Dropouts due to side effects were observed only in 3.5% of the patients. Using new assessment scales suitable for routine application allowed confirmation of the results from controlled clinical trials with regard to tremor, anhedonia, and depression. The average daily dosage of pramipexole prescribed was 1.05 mg and thus was definitely lower than the average daily dosages of 2.35-2.66 mg used in controlled trials. This signifies that the option to adjust dosage according to effectiveness and tolerability under routine conditions yields a considerably lower incidence of adverse effects.

Platelet-activating factor receptor antagonist improves renal function and glomerular lesions in renal ablation.

In the renal ablation model hemodynamic changes, glomerular hypertrophy, and the release of inflammatory mediators contribute to structural damage and functional changes. Platelet-activating factor (PAF) has both hemodynamic and immune-mediating properties. We therefore examined the role for a PAF receptor antagonist (WEB 2170) on glomerular hemodynamic function, albuminuria, and structural alterations in a rat model of renal ablation (Nx). WEB 2170 treatment was started 10 weeks after renal ablation, and the variables were assessed at 36 weeks after surgery. WEB 2170 significantly improved inulin and PAH clearances at 36 weeks (inulin clearance: Nx, 182 +/- 28 microliters/min/100 gm body weight; Nx plus WEB, 284 +/- 19 microliters/min/100 gm body weight; p < 0.05; PAH clearance: Nx, 718 +/- 85 microliters/min/100 gm body weight; Nx plus WEB, 1215 +/- 103 microliters/min/100 gm body weight; p < 0.05). Glomerular prostaglandin E2 (PGE2) formation was significantly increased in nephrectomized rats treated with WEB 2170 when compared with nephrectomized animals not treated (PGE2: Nx, 103 +/- 16 pg/min/mg protein; Nx plus WEB, 182 +/- 19 pg/min/mg protein; p < 0.01). The PAF receptor antagonist did not change albuminuria (Nx, 205 +/- 56 mg/24 hr; Nx plus WEB, 178 +/- 48 mg/24 hr). Glomeruli of rats treated with WEB 2170 had significantly fewer sclerotic lesions at 36 weeks when compared with untreated animals (Nx, 36.5 +/- 4.4%; Nx plus WEB, 19.3 +/- 3.7%; p < 0.05). The results demonstrate that a PAF receptor antagonist significantly improves whole kidney clearances and glomerular morphology.(ABSTRACT TRUNCATED AT 250 WORDS)

The platelet activating factor receptor antagonist WEB 2170 improves glomerular hemodynamics and morphology in a proliferative model of mesangial cell injury.

Rats were treated with the platelet activating factor receptor antagonist WEB 2170 (15 mg/kg/day) in three different protocols to evaluate a possible role of platelet activating factor in an experimental proliferative model of glomerular disease. The glomerular immune injury was initiated by the i.v. administration of a rabbit anti-rat thymocyte antiserum. Anti-rat thymocyte antiserum induces a proliferative glomerulonephritis with reduction of glomerular filtration rate (614 +/- 94) compared with controls (1,120 +/- 192 microL/min/100 g body wt) when studied at day 7. Treatment of rats with WEB 2170 over 8 days (starting at day -1; protocol 1) ameliorated the loss in glomerular filtration rate (936 +/- 82 microL/min/100 g body wt) in nephritic rats at day 7; however, it had no effect on controls (1,142 +/- 104 microL/min/100 g body wt). Interventional treatment with WEB 2170 (starting at day 4 after anti-rat thymocyte antiserum; protocol 2) also improved glomerular function when glomerular filtration rate was already reduced (410 +/- 41 microL/min/100 g body wt) at day 4. The platelet activating factor receptor antagonist given at day 7 after induction of disease (protocol 3) did not improve impaired glomerular filtration rate. Preinterventional and interventional treatment with WEB 2170 reduced the infiltration of polymorphonuclear granulocytes in glomeruli. Interventional treatment with WEB 2170 also reduced glomerular morphologic damage in nephritic glomeruli. The data demonstrate a beneficial effect of the platelet activating factor receptor antagonist in this animal model of proliferative glomerulonephritis which suggests that platelet activating factor might play an important role in the mediation of this disease.

Pharmacodynamics, pharmacokinetics and safety profile of the new platelet-activating factor antagonist apafant in man.

Platelet-activating factor (PAF) is a unique phospholipid mediator with multifunctional properties. Evidence generated in experimental studies suggests that PAF plays a pathogenetic role in anaphylactic, inflammatory and immunogenic reactions. Apafant (WEB 2086, CAS 105219-56-5), a novel synthetic PAF receptor antagonist, was administered to a total of 101 healthy volunteers within 5 studies to investigate its pharmacologic activity, pharmacokinetic behaviour and safety profile. Pharmacologic activity was monitored by inhibition of 5 x 10(-8) mol/l PAF-induced platelet aggregation ex vivo. The following treatment schedules were studied: oral single dose 1.25 to 400 mg; oral multiple dose 100 mg t.i.d. over 7 days; i.v. infusion 0.5 to 50 mg (over 30 min); inhalative administration up to 1.0 mg. PAF induced platelet aggregation was virtually completely inhibited by single oral doses of 20 mg upwards, throughout during the multiple oral dose study, at all dose levels tested in the i.v. study and (significantly but not completely) at 0.5 and 1.0 mg in the inhalative study. Following oral administrations (capsules) apafant is absorbed rapidly (tmax 1 to 2 h), there is linear pharmacokinetics for the mean plasma concentrations of apafant measured by RIA as well as for the areas under the curve (AUCs). Approximately 60% of apafant is bound to plasma protein, the mean volume of distribution is 28 l, about 44% of an oral dose is excreted in the urine, the mean renal clearance is 192 ml/min. No accumulation of the drug occurred in volunteers with normal kidney function. No clinically relevant drug related adverse events or changes in laboratory or vital parameters such as blood pressure, heart rate, respiratory rate and ECG were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Safety, tolerability, and pharmacologic activity of multiple doses of the new platelet activating factor antagonist WEB 2086 in human subjects.

The safety, tolerability, and pharmacologic activity of WEB 2086, a novel, specific platelet activating factor antagonist, were examined in two double-blind, placebo-controlled, within-subject crossover studies. In each study, WEB 2086 (three times 40 mg/day or three times 100 mg/day) was administered for 7 days to 12 healthy volunteers. Pharmacologic activity of the compound was monitored with ex vivo platelet activating factor-induced platelet aggregation. Multiple administration of WEB 2086 resulted in a continuous, almost complete inhibition of this aggregation. Nevertheless, no clinically significant drug-related effects on vital and laboratory parameters or obvious drug-dependent adverse reactions were observed. In conclusion, the performed studies confirmed earlier findings that WEB 2086 was an effective platelet activating factor antagonist in human beings and, furthermore, showed no side effects that would provide objections against further clinical trials with this substance in patients.

Inhibitory effect of oral WEB 2086, a novel selective PAF-acether antagonist, on ex vivo platelet aggregation.

WEB 2086 is a novel PAF-acether antagonist, whose pharmacological action in man has only been preliminarily defined. Twelve healthy male volunteers received oral doses of 5, 30 and 90 mg and over the following 24 h inhibition of 5 x 10(-8) M PAF-acether-induced platelet aggregation ex vivo was studied as an indicator of pharmacological activity. WEB 2086 inhibited PAF-acether-induced platelet aggregation in all the doses tested, with the maximum effect 1 to 2 h after administration. After 2 h 5- 30- and 90-mg doses caused, respectively, 87, 98 and 100% inhibition. The magnitude and duration of the inhibitory effect was dose-dependent, with a significant action still detectable 10 h after administration of all three doses, and 12 h after administration of the two highest doses (30 and 90 mg). The subjects did not complain of any significant adverse effect and all completed the study.

The influence of sympathetic nervous activity on regression of cardiac hypertrophy.

Pharmacotherapeutical means of reversing cardiac hypertrophy (prazosin, clonidine and nifedipine) were analysed in concentrically, as well as eccentrically, hypertrophied left ventricles. Regression of cardiac hypertrophy, i.e. a therapeutic intervention on a critical precursor of hypertensive congestive heart failure, can be obtained by various antihypertensive agents. Prazosin, calcium channel blockers, clonidine and angiotensin converting enzyme inhibitors as well as a combined treatment regimen using alpha-receptor blockers together with diuretics and vasodilators can all induce regression of hypertrophy associated with an improvement in left ventricular function. Moreover, an improved coronary reserve may reduce the ischaemic risk of the hypertrophied myocardium. However, not all antihypertensive drugs seem equally effective in bringing about coronary regression of left ventricular hypertrophy (LVH). No regression or little regression has been found with diuretic monotherapy despite a satisfactory reduction in blood pressure. On the other hand, a trend towards a regression has been observed in patients in whom treatment with clonidine significantly reduced catecholamines.

Hormonal and metabolic parameters following insulin-induced hypoglycemia.

The present study was conducted in 12 healthy volunteers to determine the effect of porcine insulin (0.15 U/kg i.v.) on a number of different metabolic and hormonal parameters measured simultaneously. The nadir of blood glucose (19.0 +/- 2.7 ng/100 ml) is detected 30 min following insulin application, paralleled by suppressed levels of FFA and beta-hydroxybutyrate. The lowest level of potassium (3.39 +/- 0.09 mval/l) is observed 45 min following insulin application. The hormones of counterregulation show an uniform pattern of response. Peak levels of norepinephrine (228.9 +/- 36.0 ng/l) and epinephrine (720.6 +/- 125.6 ng/l) are observed at 30 and 45 min, those of cAMP (33.4 +/- 2.5 pmol/ml), glucagon (0.209 +/- 0.024 ng/ml), ACTH (166.0 +/- 40.1 ng/ml), and prolactin (28.1 +/- 7.8 ng/ml) at 45 min and finally those of cortisol (26.1 +/- 3.3 micrograms/100 ml) and growth hormone (21.6 +/- 3.1 ng/ml) at 60 min following insulin injection. As the blood glucose level is already rising after 30 min it is concluded that the catecholamines and glucagon play a major part in the restitution of normal blood glucose levels. At the end of the test, blood glucose and hormone levels have almost normalized, but FFA and beta-hydroxybutyrate levels are doubled and almost triplicated as compared to the starting point levels.

[Autonomic circulatory regulation in uremia (author's transl)]. / Autonome Kreislaufregulation in der Urämie.

Uremic autonomic neuropathy leads to impaired function of the baroreflex. The main defect, according to literature, is located in the afferent limb of the reflex arc and in the efferent cardiac vagus nerve, whereas the sympathetic part of the efferent arc is still intact. Own results, obtained in hemodialysis patients during orthostasis and volume removal induced sympathetic stimulation, showed qualitatively and quantitatively adequate sympathetic response and also an adequate end organ receptor response. Autonomic nervous neuropathy predisposes to volume removal related symptomatic hypotension during hemodialysis treatment. In addition hemodialysis treatment per se induces a so far unexplained interference with sympathetic response to volume removal. The autonomic neuropathy also predisposes to development of hypertension in response to volume load.

Differences in psychic performance with guanfacine and clonidine in normotensive subjects.

1. Doses of clonidine 0.15 mg or guanfacine 1.0 mg, respectively, and 2 h later additional doses of clonidine 0.3 mg or guanfacine 2.0 mg, respectively, were given to 24 healthy students. 2. Blood pressure was reduced by the same amount by both drugs. 3. Plasma noradrenaline concentrations decreased with both drugs, but the reduction was significantly greater following the administration of clonidine. 4. Mental activity in the EEG was less suppressed in the guanfacine group than in the clonidine group. The differences were statistically significant. 5. Self-estimations for well-being and mood showed only small changes due to guanfacine but significant changes due to clonidine. 6. The decrease of information processing and the increase in reaction time, measured by performance in different psychometric tests, were significantly more pronounced after clonidine treatment than guanfacine. 7. A dose-response relationship could only be observed in vigilosomnograms, in the tests of self-estimation related to well-being and mood and in the decrease in plasma noradrenaline in the clonidine group. 8. It was concluded that guanfacine had a lesser CNS depressant action than clonidine, when administered in equipotent hypotensive doses.

Guanfacine in essential hypertension: effect on blood pressure, plasma noradrenaline concentration and plasma renin activity.

1. The acute and chronic effects of guanfacine on blood pressure, plasma noradrenaline concentration and plasma renin activity were investigated in 23 patients (15 males, 8 females) with essential hypertension (WHO grade I-II). 2. Guanfacine induced a decrease in plasma noradrenaline concentration and plasma renin activity concomitant with a fall in blood pressure and heart rate in both the acute and the chronic study. 3. The adrenergic response to upright posture, reflected by an increase in plasma noradrenaline concentration and plasma renin activity, was not abolished after chronic guanfacine therapy. 4. The decrease in blood pressure 15 min after intravenous administration of guanfacine was inversely correlated with the basal sympathetic activity before treatment and with the decrease in plasma noradrenaline. 5. After chronic treatment with guanfacine no significant correlation existed between blood pressure reduction and the concomitant changes in peripheral sympathetic and/or plasma renin activity. 6. Despite the lack of a close correlation it is suggested that the antihypertensive effect of guanfacine in patients with essential hypertension is at least partially mediated by an inhibition of the sympathetic nervous and plasma renin activity.

Relation of plasma noradrenaline to blood pressure, age, sex and sodium balance in patients with stable essential hypertension and in normotensive subjects.

1. Plasma noradrenaline was measured in 125 patients with stable essential hypertension (WHO I-II) and in 107 normotensive control subjects lying and standing. 2. In normotensive subjects and in patients with essential hypertension no sex-related differences of plasma noradrenaline were found between age-matched groups. 3. Plasma noradrenaline was not related to sodium balance indexed by urinary sodium/creatinine ratio. 4. In patients with essential hypertension plasma noradrenaline increases with age. 5. Mean plasma noradrenaline concentrations are significantly higher in patients with essential hypertension compared with age-matched normotensive subjects both lying and standing. 6. In patients with essential hypertension diastolic blood pressure and heart rate correlated significantly with supine plasma noradrenaline concentrations.

Plasma catecholamines in exercise induced bronchoconstriction.

Plasma nor-epinephrine (NE) and epinephrine (E) levels at rest and immediately after exercise were estimated in 8 patients with asymptomatic extrinsic allergic bronchial asthma. The patients had a normal airway resistance at rest and developed a marked bronchoconstriction (EIB) during exercise, which could be prevented by previous alpha-adrenergic blockade with phentolamine. In 7 control persons NE and E levels were measured also after beta-adrenergic blockade with propranolol. The following results were obtained: 1. At rest NE levels showed no significant differences between the groups. After exercise an increase of NE was observed in all groups, but in patients, even after phentolamine, and in normals after propranolol the increase was significantly higher than in the normal group within the control test. 2. No significant differences between the groups were found in E levels at rest and after exercise. Exercise caused no significant increase of E levels, except in the normals after propranolol application. 3. No significant correlation existed between NE levels and the increase of airway resistance after exercise. It is concluded that during exercise in asthmatics the sympathetic activity is enhanced, but the provocation of an EIB does not seem to be mediated by enhanced plasma NE levels.