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  • 1
    Publication Date: 2024-03-30
    Description: Gilles de la Tourette Syndrome (TS) is a common, albeit severely under-diagnosed, neuropsychiatric disorder that is caused by a complex genetic basis, interacting with environmental factors. High comorbidity rates with other neurodevelopmental disorders such as attention deficit/hyperactivity disorder and obsessive compulsive disorder raise the intriguing hypothesis of a shared etiological background. Abnormalities of corticostriatal-thalamic-cortical circuits (CSTC) and dysfunction of both dopamine and serotonin neurotransmitter systems are assumed to be associated with TS. Recently, multiple lines of evidence also point towards an important role of additional neurotransmitters such as histamine and glutamate. For a very long time, efforts to elucidate the etiology and pathophysiology of TS have been fragmented and hampered by low statistical power. Finally, after more than two decades of active research aiming to identify the etiology and pathophysiology of TS, we are on the verge of a new era, promising exciting and rapid discoveries in the field. Investigators from around the world, representing multiple disciplines and scientific approaches, are joining their efforts in large-scale initiatives supported both by European Union and US National funding agencies, such as the European-funded EMTICS, TACTICS, and TSGeneSEE consortia, the Marie Curie Initial Training Network TS-EUROTRAIN and the European Society for the Study of TS joining forces with the NIH-funded TSAICG, GGRI, and Tic Genetics consortia. Importantly, all these initiatives are supported by TS patient support and advocacy groups. Multiple resources are being consolidated and coming together to serve the study of TS, including large well-characterized patient cohorts, and specialized epidemiological databases, such as the unique resource of the Netherlands Twin Register. This research topic showcases current large-scale collaborative efforts aiming to elucidate the genetic and neurobiological background of TS, through diverse approaches; from genomewide association studies aiming to identify common variants associated to the disorder to neuroimaging studies and animal models. Furthermore, current approaches on the clinical assessment and management of the disorder are presented. Propelled by the gradual availability of large scale TS cohorts, novel methodologies, and importantly, sheer enthusiasm by multiple researchers working together across different countries, the new era of the neurobiology of TS holds the promise to identify novel targets for improved therapies.
    Keywords: R5-920 ; RC321-571 ; RC435-571 ; RJ1-570 ; Q1-390 ; Treatment ; clinical research ; Neurobiology ; Collaborative studies ; Gilles de la Tourette syndrome ; Genetics
    Language: English
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  • 2
    ISSN: 1432-1041
    Keywords: hyperlipidaemia ; magnesium pyridoxal 5-phosphate glutamate ; renal insufficiency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Chronic renal insufficiency is often accompanied by hyperlipidaemia and subsequent coronary heart disease. Two groups of 15 patients with serum creatinine 〉2 mg/100 ml and serum cholesterol 〉250 mg/100 ml were given 3×50 mg magnesium pyridoxal 5-phosphate glutamate (MPPG) or placebo for 12 weeks in a double-blind, randomised study. Total cholesterol in the MPPG group (282.4 mg·100 ml−1) was lower than in the placebo group (354.3 mg·100 ml−1) after 12 weeks of treatment. Triglycerides in the MPPG group were 265.1 mg·100 ml−1 compared to 361.9 mg·100 ml−1. After 12 weeks on MPPG the LDL/HDL ratio of 3.56 was lower than in the placebo group — 6.83. Side effects in the MPPG group were similar to those in the placebo group. Thus, MPPG was an effective antihyperlipidaemic agent in patients with renal insufficiency.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 39 (1990), S. 435-439 
    ISSN: 1432-1041
    Keywords: co-dergocrine mesylate ; hypertension ; aldosterone ; catecholamines ; nifedipine ; renin side effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Co-dergocrine mesylate (Cod), which inhibits norepinephrine secretion by stimulating presynaptic dopamine receptors, and has no known metabolic side effect, has an additive antihypertensive effect to that of Nifedipine (Nif). Plasma norepinephrine, epinephrine, renin activity and aldosterone have been measured after acute administration of Nif and Cod alone and in combination to 18 patients with a diastolic blood pressure 〉 105 mm Hg in a cross-over, randomized, double-blind study. Every patient received 4 mg Cod then 20 mg Nif, placebo then 20 mg Nif and 4 mg Cod then placebo. The second treatment was always given 1 h after the first medication. Blood pressure was measured before and every 15 min during the study period. Blood for measurement of catecholamines, aldosterone and renin activity was collected before medication, 1 h after the first dose and 90 min after the second treatment. Blood pressure was significantly lower (P 〈 0.05) where Cod preceded Nif. Cod caused a significant decrease in plasma norepinephrine from 293 to 202 pg · ml−1 and in epinephrine from 67 to 55 pg · ml−1. The Nif-induced increase in norepinephrine from a pre-treatment value of 293 pg · ml−1 with preceding Cod to 331 pg · ml−1 was much less than the increase with placebo as premedication, from 284 to 440 pg · ml−1. Nif caused an increase in renin activity but no increase in aldosterone. Nif-related side effects, such as flushing and headache, occurred in 6 patients of whom 5 had no received Cod as premedication. Due to the stabilizing action of Cod on catecholamines and on the side effects of Nif, Cod may be preferable to other antihypertensives in augmenting the antihypertensive action of Nif.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-1041
    Keywords: Naftopidil ; Serotonin ; 5-Hydroxytryptamine ; platelets ; aggregation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Naftopidil exerts its antihypertensive action via α1-adrenoceptor blockage and Ca2+ antagonism in vascular smooth muscle. Since the chemically similar 1-(1-naphthyl) piperazine is known to be a 5-hydroxytryptamine2 receptor antagonist, the 5-hydroxytryptamine (5-HT) antagonistic properties of naftopidil were tested by examining 5-HT-induced aggregation and 5-HT uptake in platelets from 12 healthy volunteers after oral administration of 60 mg naftopidil or placebo. Platelet aggregation in vitro was inhibited by naftopidil with a Ki value of 1.1 μM, the pIC50 was 5.09 with induction of aggregation by 1 μM 5-HT. After oral administration of naftopidil, 5-HT-induced aggregation was significantly inhibited by 36%. 4 h after naftopidil administration, 5-HT uptake velocity was reduced by 33%. Naftopidil not only cancelled the circadian increase in 5-HT-induced aggregation velocity observed during placebo application, but also caused a decrease in aggregation velocity directly after peak plasma naftopidil levels. 5-HT uptake in platelets was also reduced following peak naftopidil plasma concentrations. The 5-HT inhibitory action of naftopidil adds a third possible antihypertensive property to naftopidil's α1-adrenoceptor blocking and Ca2+ antagonistic properties.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-1041
    Keywords: urapidil ; pharmacodynamics ; pharmacokinetics ; hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The study was designed to follow the haemodynamic effects and pharmacokinetics under steady-state conditions of three different doses of urapidil infused continuously. Nine male hypertensive patients received three randomly assigned intravenous infusions of 32.5, 65 and 130 mg urapidil, over 14 h during 6 consecutive days, in a change-over fashion. Blood pressure and heart rate were measured over a period of 28 h after the infusion began and were compared with a reference profile obtained prior to the treatment periods. Urapidil and its main metabolite, parahydroxylated urapidil, were also determined for 28 h after the infusion began using HPLC. The 32.5 mg dose of urapidil caused a maximum decrease in systolic blood pressure of 33±8 mmHg, the 65 mg dose a maximum decrease of 39±12 mmHg and the 130 mg dose a maximum decrease of 50±12 mmHg. The 32.5 and 65 mg doses resulted in similar serum urapidil concentrations, with maximum levels in the 100 to 200 ng/ml range, and the 130 mg dose caused a maximum level approximately four times that achieved with the 32.5 mg dose. The serum concentration of parahydroxy urapidil was proportional to the corresponding dose of urapidil. Four patients reported mild headache, fatigue, weakness, pressure in the head, perspiration and orthostatic dysregulation. The side-effects were probably drug related but required no specific therapy. In summary, the 32.5 mg dose of urapidil resulted in a pronounced decrease in blood pressure. The average pressure reduction over the 14-h infusion period showed further dose-dependent increases after the 65 and 130 mg doses. In severe hypertension, the 130 mg dose can be employed, since it does result in a further, significantly larger decrease in blood pressure.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-1041
    Keywords: urapidil ; hypertension ; alpha-adrenoceptor blocker ; antihypertensive agent ; pharmacodynamics ; pharmacokinetics ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and haemodynamic effects of infused urapidil and an infusion-capsule combination were followed to study the correlation between the serum urapidil level and the blood pressure. Prior to urapidil administration, basal blood pressure and heart rate were measured for 16 h in 12 male hypertensive patients. Six patients received infusions lasting for 4 h of urapidil 10, 2.5 and 5 mg/h. Six patients were infused with urapidil 10 mg/h for 4 h and 2 h after the end of the infusion each took a 60-mg capsule. After a 5 day washout period the procedures were crossed over. A maximum serum urapidil level of 625±232 ng/ml was achieved at the end of the 10 mg/h infusion, when the fall in blood pressure was 37/21 mmHg. During the 2.5 and 5 mg/h infusions the serum urapidil level was 330 and 420 ng/ml, respectively, and the corresponding decreases in blood pressure were 28/16 mmHg and 31/8 mmHg. Although the urapidil concentration 1 hour after beginning the infusion was only 184±89 ng/ml a near maximal blood pressure decrease had already occurred 33±9/20±8 mmHg, whereas, 1 h after the end of the infusion the reduction in blood pressure was only 10±12/3±8 mm, with a urapidil concentration of 358±120 ng/ml. During the plateau phases of both the infusion and infusion-capsule treatments the falls in blood pressure followed the serum urapidil levels. Only in the initial rising and final falling phases of the treatments were the pharmacodynamics and pharmacokinetics of urapidil not correlated.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 24 (1983), S. 21-30 
    ISSN: 1432-1041
    Keywords: clonidine ; bioavailability ; blood pressure ; elimination half-life ; pharmacokinetics ; plasma catecholamines ; rebound phenomenon
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Using considerably improved analytical methods, the kinetics and effects of clonidine were observed in healthy volunteers over periods of time more than 3 times longer than those previously reported. The high sensitivity and small work load of the newly developed method permitted the performance of low-dose and multipledose trials. 1. The complete bioavailability of clonidine and its elimination half-life (20 to 25.5 h) remained constant after single and multiple doses. 2. Approximately 62% of a given dose was excreted unchanged in the urine, independent of the quantity administered (0.075, 0.15, 0.2, 0.25 or 0.3 mg), the drug formulation (solution, tablet, Perlonget) or of the mode of administration (i.v., p.o.; single or multiple doses). 3. As the pharmacokinetics of the drug were affected by entero-hepatic circulation, it cannot be described by a conventional, open one or two compartment model. 4. The time courses of the plasma clonidine concentration and its drug effects ran asynchronously. 5. On cessation of chronic clonidine administration, blood pressure and plasma catecholamine levels increased to pretreatment levels without exhibiting any “overshoot” reaction.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-1041
    Keywords: mental stress ; blood pressure ; nifedipine ; hydrochlorothiazide ; plasma catecholamines ; heart rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a model of mental stress the influence of nifedipine and hydrochlorothiazide on stress-induced changes in blood pressure, heart rate, and plasma catecholamines was studied in normal persons. The drugs were used to investigate whether substances with antihypertensive but no particular sympatholytic properties were capable of suppressing emotionally induced stress reactions. In all subjects blood pressure and heart rate increased significantly during mental stress, and this effect was not inhibited either by nifedipine or hydrochlorothiazide. In the hydrochlorothiazide group plasma noradrenaline levels were significantly higher than in controls in the resting state and during the stress reaction, whereas in the nifedipine group no difference was observed. It is concluded that nifedipine or hydrochlorothiazide do not inhibit emotional stress reactions in normotensive persons.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 30 (1986), S. 289-294 
    ISSN: 1432-1041
    Keywords: platelet aggregation ; epinephrine ; simultaneous measurement ; propranolol ; phentolamine ; α2-receptor sensitivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A method is described for the simultaneous measurement of epinephrine-induced platelet aggregation in 14 different plasma samples in 15 min. It is based upon discontinuous registration of platelet aggregation and computer evaluation of the data. The samples are placed in holders mounted over magnetic stirring bars in a 37 °C water bath and the extinction is measured by removing the samples one after the other, placing them in a Braun Universal Aggregometer and returning them to their holders in the water bath. The time required to reach 37% of maximal aggregation was chosen as the evaluation criterion. It sufficed for the determination of aggregation sensitivity. This method for the first time permits measurement of a complete titration curve rapidly and under identical conditions and can be used to show the influence of a wide range of aggregation inducers and the concurrent effects of inducers plus various blocking agents. A correlation between aggregation sensitivity and α2-receptor binding capacity in platelets, measured by competitive radioactive binding, was established in samples from 10 healthy volunteers. One group exhibited high aggregation sensitivity coupled with high α2-binding capacity and the other showed low sensitivity with low binding capacity.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 37 (1989), S. 117-120 
    ISSN: 1432-1041
    Keywords: cholesterol ; guar ; hyperlipidaemia ; HDL-/LDL-cholesterol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The antihyperlipidaemic effect of a guar preparation which absorbs a particularly large amount of water has been examined in 13 patients with Type II hyperlipidaemia. A 30-day pre-treatment phase was followed by 60 days of treatment with 4 g guar dissolved in 200-ml liquid at each meal-time (total guar 12 g/day), and a 60-day post-treatment observation period. Routine other clinical blood tests were performed 30, 15 or 0 days before treatment, 15, 30 and 60 days after the start of treatment, and 30 and 60 days after its end. Total cholesterol fell by 0.85 mmol·l−1, from a pre-treatment concentration of 7.4 mmol·l−1 to a treatment value of 6.5 mmol·l−1, and LDL-cholesterol fell by 0.64 mmol·l−1, from 5.5 mmol·l−1 to a treatment value of 4.8 mmol·l−1. There was no significant change in triglyceride and VLDL concentrations during the study. A slight but significant fall in HDL-cholesterol was seen. The sole adverse effect was occasional intestinal discomfort.
    Type of Medium: Electronic Resource
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