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R Horowski

Publications and source records attributed to R Horowski.

At least 19 recordsLinked to original sources
PubMed2005

Proterguride, a highly potent dopamine receptor agonist promising for transdermal administration in Parkinson's disease: interactions with alpha(1)-, 5-HT(2)- and H(1)-receptors.

Dopamine receptor agonists play an important role in the treatment of Parkinson's disease and hyperprolactinemic conditions. Proterguride (n-propyldihydrolisuride) was already reported to be a highly potent dopamine receptor agonist, thus its action at different non-dopaminergic monoamine receptors, alpha(1A/1B/1D), 5-HT(2A/2B)- and histamine H(1), was investigated using different functional in vitro assays. The drug behaved as an antagonist at alpha(1)-adrenoceptors without the ability to discriminate between the subtypes (pA(2) values: alpha(1A) 7.31; alpha(1B) 7.37; alpha(1D) 7.35) and showed antagonistic properties at the histamine H(1) receptor. In contrast, at serotonergic receptors (5-HT(2A), 5-HT(2B)) proterguride acted as a partial agonist. The drug stimulated 5-HT(2A) receptors of rat tail artery in lower concentrations than 5-HT itself but failed to evoke comparable efficacy (proterguride: pEC(50) 8.34, E(max) 53% related to the maximum response to 5-HT; 5-HT: pEC(50) 7.03). Agonism at 5-HT(2B) receptors is presently considered to be involved in drug-induced valvular heart disease. Activation of 5-HT(2B) receptors in porcine pulmonary arteries by proterguride (pEC(50) 7.13, E(max) 49%; E(max) (5-HT) 69%), however, occurred at concentrations much higher than plasma concentrations achieving dopaminergic efficacy in humans. The results are discussed focussing on the relevance of action at 5-HT(2B) receptors as well as their significance for a transdermal administration of proterguride. Since it is well accepted that pulsatile dopaminergic stimulation is associated with treatment-related motor complications in the dopaminergic therapy of Parkinson's disease, the transdermal route of administration is of great clinical interest due to the possibility to achieve constant plasma concentrations.

Administration, Cutaneous↗
PubMed2004

High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study.

UNLABELLED: Increasing evidence has suggested that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E (alpha-tocopherol) has been shown to slow down the onset and progression of the paralysis in transgenic mice expressing a mutation in the superoxide dismutase gene found in certain forms of familial ALS. The current study, a double blind, placebo-controlled, randomised, stratified, parallel-group clinical trial, was designed to determine whether vitamin E (5000 mg per day) may be efficacious in slowing down disease progression when added to riluzole. METHODS: 160 patients in 6 German centres with either probable or definite ALS (according to the El Escorial Criteria) and a disease duration of less than 5 years, treated with riluzole, were included in this study and were randomly assigned to receive either alpha-tocopherol (5000 mg per day) or placebo for 18 months. The Primary outcome measure was survival, calculating time to death, tracheostomy or permanent assisted ventilation, according to the WFN-Criteria of clinical trials. Secondary outcome measures were the rate of deterioration of function assessed by the modified Norris limb and bulbar scales, manual muscle testing (BMRC), spasticity scale, ventilatory function and the Sickness Impact Profile (SIP ALS/19). Patients were assessed at entry and every 4 months thereafter during the study period until month 16 and at a final visit at month 18. Vitamin E samples were taken for compliance check and Quality Control of the trial. For Safety, a physical examination was performed at baseline and then every visit until the treatment discontinuation at month 18. Height and weight were recorded at baseline and weight alone at the follow-up visits. A neurological examination as well as vital signs (heart rate and blood pressure), an ECG and VEP's were recorded at each visit. Furthermore, spontaneously reported adverse experiences and serious adverse events were documented and standard laboratory tests including liver function tests performed. For Statistical Analysis, the population to be considered for the primary outcome measure was an "intent-to-treat" (ITT) population which included all randomised patients who had received at least one treatment dose (n = 160 patients). For the secondary outcome measures, a two way analysis of variance was performed on a patient population that included all randomised patients who had at least one assessment after inclusion. RESULTS: Concerning the primary endpoint, no significant difference between placebo and treatment group could be detected either with the stratified Logrank or the Wilcoxon test. The functional assessments showed a marginal trend in favour of vitamin E, without reaching significance. CONCLUSION: Neither the primary nor the secondary outcome measures could determine whether a megadose of vitamin E is efficacious in slowing disease progression in ALS as an add-on therapy to riluzol. Larger or longer studies might be needed. However, administration of this megadose does not seem to have any significant side effects in this patient population.

Amyotrophic Lateral Sclerosis↗
PubMed2004

Transdermal lisuride delivery in the treatment of Parkinson's disease.

Transdermal delivery of dopamine agonists (DA) is a promising therapeutic concept, which aims to ameliorate frequency and intensity of motor fluctuations in patients with Parkinson's disease (PD). We treated 8 PD patients with unpredictable on-off phenomena with lisuride patches (release: 2-5 microg lisuride base/cm2/hour in mice) in addition to their preexisting antiparkinsonian drug regime up to a period of 8 days. In order to quantify the intensity and frequency of motor fluctuations, we determined the motor changing rate (MCR), which corresponds to the patient's self rating of motor function, performed every thirty minutes, divided through the number of scored intervals minus 1. Additional lisuride patch application significantly (p = 0.023) improved the MCR compared to baseline. Relevant side effects were transient skin irritations in four patients. Our observational study demonstrates the safety, tolerability and efficacy of transdermal lisuride delivery in the treatment of motor complications.

Administration, Cutaneous↗
PubMed2004

Striatal plasticity and motor learning-importance of circadian rhythms, sleep stages and dreaming....

In this brief comment, we emphasize the importance of circadian rhythms, sleep stages and especially REM sleep for motor and procedural learning which needs to be taken into account when studying striatal plasticity. Mode and timing of application could also play a crucial role for long-term dopaminergic therapies and behavioural and other changes. We further propose a model where the brain, during REM sleep/dreaming, by random recombinations of small pieces of past experiences, tries to anticipate situations not yet experienced and to prepare it-self, in an 'off' situation, for adequate new motor procedural responses.

Animals↗
PubMed2001

[A short history of beta-interferon therapy of multiple sclerosis].

Basic sciences including biotechnology and diagnostic imaging as well as dedicated and substantial clinical research have contributed to the progress in the therapy of multiple sclerosis (MS) which is no longer an orphan disease. Pivotal studies using interferon beta-1b for early and later phases of MS are described in their historical context. In addition, possible mechanisms of action of interferon beta-1b and new directions for future research are discussed. Interferon beta-1b already now has become a global standard for the expected further therapeutic progress.

Adjuvants, Immunologic↗
PubMed2000

From Wilhelm von Humboldt to Hitler-are prominent people more prone to have Parkinson's disease?

We describe Parkinsonism in prominent people, where Wilhelm von Humboldt and Adolf Hitler provide just two spectacular, opposing examples. In both of them, there is little if any evidence that the disease did influence their life ambitions, methods of achieving them or cognitive function in general. Thus, Hitler's Parkinsonism should remain a 'footnote' to history, and historians should acknowledge that in his last years, his trembling, his curbed posture, his slow walking, mask-like face and low voice did not indicate remorse, fear or depression as a consequence of his crimes, but were mere expressions of his disease which, until the end, had no impact on his intellectual skills and methods. The apparently higher incidence of Parkinsonism in prominent people may be just due to their higher visibility, or a consequence of disease-related personality traits (e.g. ambition, perfectionism, rigidity) which may contribute to becoming, e.g., a prominent authoritarian person. Perhaps even some early behaviour pattern (such as repressed emotions or acting in public-which could even increase the risk of some infection) contributes to a greater vulnerability for developing Parkinsonism. Further studying other prominent cases might lead us to better understanding of risk factors and the expression of early Parkinsonism.

Journal Article↗
PubMed1996

Effects of terguride on anterior pituitary function in parkinsonian patients treated with L-dopa: a double-blind study versus placebo.

In a randomized double-blind study, 20 parkinsonian patients (suffering from the disease for 2-18 years), chronically treated with levodopa (500-750 mg/day for 0.5-12 years), received terguride (1 mg b.i.d.) or placebo for 4 weeks. Growth hormone (GH), prolactin (PRL), thyroid-stimulating hormone (TSH), and insulin-like growth factor (IGF-I) secretions were studied before and after the morning dose of levodopa (250 mg p.o.), both before and at the end of study period. At the beginning of the study, basal hormonal levels were within normal limits, and levodopa administration induced a significant suppression in PRL and TSH levels (both p < 0.01)) and a significant increase in GH (p < 0.01). The same results were observed at the end of the study period in the placebo group. Addition of terguride induced a significant suppression in basal PRL levels (p < 0.01), whereas levodopa-induced hormonal changes were unaffected. These data suggest that the hypothalamic dopaminergic function that controls anterior pituitary hormones is preserved in parkinsonian patients, regardless of both the duration of the disease and the long-term treatment with levodopa. The strong additional prolactin-lowering effect of terguride indicates long-lasting dopaminergic effects, as is already known from hyperprolactinemic conditions. The dopaminergic effects of levodopa on TSH, GH, and IGF-I secretion were unchanged by terguride treatment. The anti-dopaminergic effects of terguride observed in the motor system in animal studies, as well as in levodopa-induced dyskinesias in parkinsonian patients, could not be observed in the case of the dopaminergic control of anterior pituitary hormones under the conditions of this study.

Aged↗
PubMed1995

An essay on Wilhelm von Humboldt and the shaking palsy: first comprehensive description of Parkinson's disease by a patient.

James Parkinson first described what is now known as Parkinson's disease in his essay in 1817 on the shaking palsy, but the disease became well-known to neurologists only in the second half of the 19th century. In his letters from 1828 until his death in 1835, Wilhelm von Humboldt, a well-known German academic reformer, humanist scholar, and statesman, precisely described the manifestations of this disease. These included resting tremor and especially problems in writing, called by him "a special clumsiness" that he attributed to a disturbance in executing rapid complex movements. In addition to lucidly describing akinesia, he was also the first to describe micrographia. He furthermore noticed his typical parkinsonian posture and, in all probability, his rigidity as "internal tremor not visible by others which causes a distortion of the continuity of my movements." He insisted, however, that he was suffering not from a disease but just from accelerated aging related to the death of his wife. His description of the disease is more complete than the observations and definition by James Parkinson; his attitude toward his disease illustrates why it was not readily accepted as a disease in itself but might have been considered an extreme variant of aging instead.

Famous Persons↗
PubMed1995

Schaltenbrand.

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Ethics, Medical↗
PubMed1994

The role of pulsatile versus continuous dopamine receptor stimulation for functional recovery in Parkinson's disease.

More effective measures to control and replace the dopaminergic deficit of Parkinson's disease are being actively sought. One basic problem is how the striatal dopamine loss should be replaced in order to mimic most accurately the physiological state. Animal electrophysiology indicates that the dopaminergic nigrostriatal pathway has a dual tonic and phasic action. Intermittent dopaminergic stimulation is associated with behavioural hyposensitivity both in animal models and in patients with Parkinson's disease. Continuous dopaminergic stimulation provides a tonic background and improves some clinical problems but is also associated with tolerance. None of the available pharmacological approaches can restore the dopamine deficiency of Parkinson's disease to physiological levels. Continuous dopaminergic stimulation for < 24 h, associated with small doses of levodopa or a short-acting dopamine agonist, appears to be the best, albeit imperfect, therapeutic approach until other, more efficacious remedies are developed.

Animals↗
PubMed1993

The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates.

Degeneration of nigrostriatal dopaminergic neurons is the primary histopathological feature of Parkinson's disease. The neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces a neurological syndrome in man and non-human primates very similar to idiopathic Parkinson's disease by selectively destroying dopaminergic nigrostriatal neurons. This gives rise to the hypothesis that Parkinson's disease may be caused by endogenous or environmental toxins. Endogenous excitatory amino acids (EAAs) such as L-glutamate could be involved in neurodegenerative disorders including Parkinson's disease. We report in this study that the competitive NMDA antagonist CPP (3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) protects nigral tyrosine hydroxylase (TH) positive neurons from degeneration induced by systemic treatment with MPTP in common marmosets. This indicates that EAAs are involved in the pathophysiological cascade of MPTP-induced neuronal cell death and that EAA antagonists may offer a neuroprotective therapy for Parkinson's disease.

Animals↗
PubMed1993

[The differential diagnosis of Parkinson diseases--123I-IBZM-SPECT vs. the apomorphine test].

The aim of our study was to compare the striatal dopamine D2-receptor density as measured by 123I-IBZM-SPECT with the results of the apomorphine-test. 30 patients were studied; 21 with idiopathic Parkinson's disease (IPD), 9 with Parkinson plus syndromes (PPS). Patients with IPD showed a significantly higher striatal IBZM binding as compared to patients with PPS (p = 0.006). A good correlation between IBZM binding and outcome of the apomorphine-test was found (p = 0.006). Low striatal IBZM binding indicates reduced dopamine D2-receptor density. This compromises successful dopaminergic medical therapy and is indicative of non-IPD disease. 123I-IBZM-SPECT could be diagnostic aid in the work-up of patients with extrapyramidal movement disorders. The response to dopaminergic drug treatment might be precluded by IBZM-SPECT in patients with Parkinsonian syndromes.

Adult↗
PubMed1992

Terguride stimulates locomotor activity at 2 months but not 10 months after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment of common marmosets.

The mixed dopamine (DA) agonist/antagonist terguride acts as a DA antagonist on normosensitive receptors but shows DA agonistic properties at supersensitive DA receptors. Such a compound could offer an alternative to the treatment of Parkinson's disease with indirect or direct DA agonists. The present study compares the actions of terguride, 4-12 mg/kg i.p., in naive common marmosets with its effects in animals rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 2 months or 10 months previously, in order to test its antiparkinsonian efficacy. Terguride reduced locomotor activity in naive common marmosets, similar to its effects in rodents and in line with the DA antagonistic activity of the compound. In marmosets treated with MPTP 2 months previously and exhibiting pronounced behavioural motor deficits, terguride stimulated locomotor activity, showing DA agonistic properties under these conditions. In contrast, the locomotor activity of animals that had recovered from MPTP treatment 10 months previously was not altered by terguride. It is concluded that terguride has anti-akinetic efficacy in this primate model of Parkinson's disease. In addition, terguride offers a unique opportunity to differentiate, pharmacologically, the extent of dopaminergic recovery from MPTP treatment in this primate species.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗