Biomedical subjects
Publications and source records attributed to A Brattström.
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Various extracts prepared from the traditional dye and medicinal plant Isatis tinctoria L. were submitted to a broad in vitro screening against 16 anti-inflammatory targets. Dichloromethane (DCM) extracts from dried leaves showed a marked cyclooxygenase (COX) inhibitory activity with a preferential effect on COX-2 catalysed prostaglandin synthesis. A supercritical fluid extraction (SFE) procedure employing CO2-modifier mixtures was developed by which the bioactivity profile and chromatographic fingerprint of the DCM extract could be reproduced. High-resolution activity directed on-line identification of the COX-2 inhibitory principle, using a combination of LC-DAD-MS with a microtitre-based bioassay, led to the identification of tryptanthrin (1) as the constituent responsible for essentially all COX-2 inhibitory activity in the crude extract. Following on-line identification, 1 was isolated at preparative scale and its structure confirmed by comparison with synthetic tryptanthrin. In an assay with lipopolysaccharide stimulated Mono Mac 6 cells, tryptanthrin (1) was of comparable potency (IC50 = 64 nM) than the preferential COX-2 inhibitors nimesulide (IC50 = 39 nM) and NS 398 (IC50 = 2 nM). The SFE extract and 1 showed no cytotoxicity in Mono Mac 6 and RAW 264.7 cells when tested at 100 microg/ml and 10 microM, respectively.
OBJECTIVE: Sleep disorders may critically affect working performance and quality of life. Sleep pillows have been traditionally used to overcome such disorders. Scientifically based clinical trials to demonstrate the efficacy are missing. METHODS: 28 patients with problems falling asleep and/or staying asleep not related to psychiatric or organic diseases were investigated in an accredited sleep laboratory. The diagnosis was confirmed by polysomnography. After 2 and 4 weeks of treatment the polysomnography was repeated to document any influences by the sleep pillows. RESULTS: The polysomnographic records showed a monotonic trend to regain an age-related distribution of the non-REM sleep stages. The REM sleep phase increased nearly twofold; however, the norm values were not reached within the 4-week period of treatment. Sleep pillows of intensity 2 were superior to those of intensity 1; a further increase to intensity 3 did not create any additional effect. CONCLUSION: The results demonstrate an effective treatment of non-complicated sleep disorders with sleep pillows, which has been shown with objective measurements in a sleep laboratory.
The following study was performed to evaluate the effects of chronic 6-month administration of the angiotensin I receptor antagonist valsartan on restenosis rate after stenting of type B2/C lesions in comparison to placebo. Despite encouraging results of the BENESTENT and STRESS trials, stenting of complex coronary lesions leads to an in-stent restenosis rate of up to 40%. Several attempts at systematic medical therapy (e.g., ACE inhibitors) have not improved these results. Because of the important role of angiotensin in endothelial function, the hypothesis that angiotensin I receptor antagonists after stent implantation lead to a reduction of the in-stent restenosis rate should be tested in a single-center trial. Two hundred and fifty patients with type B2/C coronary lesions were randomized in an open-label study with respect to age, gender, lesion type and indication of percutaneous coronary intervention to a chronic administration of 80 mg valsartan or placebo (beta-blocking agents and/or ACE inhibitors). In-stent restenosis rate according to quantitative coronary angiography (QCA) and need for reintervention as primary and secondary endpoints were analyzed after a repeat angiogram at 6 months in 99 patients with 80 mg valsartan and 101 patients with placebo. Chronic administration of 80 mg valsartan reduced the in-stent restenosis rate to 19.2% (n = 19/99) in comparison to placebo with an in-stent restenosis rate of 38.6% (n = 39/101) (p < 0.005). Reintervention rate was 28.7% (n = 29/101) in the placebo group and only 12.1% (n = 12) in the valsartan group (p < 0.005). QCA analysis of stented coronary segments disclosed no differences in reference vessel diameter (2.68 +/- 0.26 mm in the valsartan group versus 2.71 +/- 0.24 mm in the placebo group) but significant differences in stented vessel diameter (2.17 +/- 0.27 mm in the valsartan group and 1.60 +/- 0.20 mm in the placebo group) (p < 0.000001).
A pilot study with a fixed extract combination Ze 91019 of valerian and hop was conducted in 30 patients suffering from mild-moderate, non-organic insomnia. The diagnosis was confirmed by polysomnographic standard examinations. The patients were treated with 2 tablets in the evening. Each tablet contains 250 mg valerian extract and 60 mg hop extract. A polysomnographic re-examination after 2 weeks of treatment revealed declines in the sleep latency and the wake time. As a consequence the sleep efficiency increased. Sleep stage 1 (S1) was reduced and the slow wave sleep increased. In addition, the patients judged their being refreshed in the morning by assigning a rating of 1 to 6. They reported an improvement after 2 weeks of treatment. No adverse events were observed. Based on these findings a pivotal study can be designed.
The aim of this investigation was to objectify the pharmacodynamic effects of different dosages of a commercially available plant extract mixture of valerian and hops by means of the quantitative topographical EEG (qEEG) in healthy young adults in comparison to placebo. Two different dosages were applied in two single-blind, cross-over designed observation trials in 12 healthy volunteers (1st dosage: 500 mg valerian and 120 mg hops, versus placebo, first clinical trial; 2nd dosage: 1500 mg valerian and 360 mg hops, versus placebo, second clinical trial). QEEG was recorded bipolarly from 17 surface electrodes according to the 10:20 system and analysed using the Fast Fourier Transformation prior to, 1, 2 and 4 hours after drug intake in the recording conditions eyes open, eyes closed and under mental demand. The EEG-spectra were cut into six frequency bands. Both resting conditions (eyes open and eyes closed) were analysed together. After application of the low dosage qEEG power changes remained more or less within placebo range following the normal circadian rhythmics, except for a tendentious reduction of alpha- and beta1-power 4 h after drug intake. The high dosage led to power increases in delta, decreases in alpha and a weak decrease in beta-power. Under mental performance only weak differences to placebo were seen which are not discussed here. In the CPT (completion of complicated additions and subtractions) the concentration and performance capability were hardly influenced. However, a minimal increase of mean answer time and mean OK time (time for correct answers) was observed 4 hours after intake of 2 dragees and 1 hour after 6 dragees of valerian and hops mixture with more pronounced changes after the low dosage than the high one. In summary, the quantitative topographical EEG was able to show slight, but clear visible effects on the CNS especially after intake of the high dosage of valerian-hops mixture Ze 91019 indicating reproducible pharmacodynamic responses of the target organ.
In a 61 year old female patient who suffered from atypical chest pain we diagnosed long QT syndrome by QTc duration of 467 ms, macroscopic T wave alternans and notched T waves in three leads and hypertrophic cardiomyopathy with asymmetric thickening of basal parts of the septum (2.0 cm) without relevant outflow tract obstruction by echocardiography. Coronary angiography could exclude coronary artery disease. In a systematic family screening two sons of the patient could also be diagnosed as having long QT syndrome with QTc durations of 472 and 496 ms and asymmetric septal thickening (1.8 and 2.1 cm, respectively). One of these two sons suffered from pre-syncope, the other was asymptomatic despite maximum sports activity. In the third son, LQTS and hypertrophic cardiomyopathy could be excluded.
In a prospective, multicentre trial the efficacy of an Vitex agnus castus L extract Ze 440 was investigated in 50 patients with pre-menstrual syndrome (PMS). The patients were treated daily with one tablet (20 mg native extract) during three menstrual cycles. 43 patients completed the study protocol which encompassed 8 menstrual cycles (2 baseline, 3 treatment and 3 post-treatment). 13/43 patients were receiving concomitant oral contraceptives. 6 patients did not complete the study for reasons not related to study medication, and one patient complained of fatigue possibly related to study medication. All evaluated patients took at least 85% of the prescribed medication. The main effect parameter was the validated Moos' menstrual distress questionnaire (MMDQ), and secondary parameters were a visual analogue scale (VAS; self-assessment) and a global impression scale (GI, self-assessment). The study population was homogenous in age (31.3+/-7.7 years) weight (58.9+/-6.9 kg) and cycle length (28.4+/-0.3 d). The diagnosis was according to DMS-III. At the end of the study, PMS-related symptoms were reduced by treatment. There was a significant score reduction (42.5%) of the MMDQ as the main effect parameter (p<0.001). Symptoms gradually returned after treatment cessation. However, a difference from baseline remained (20%; p<0.001) up to 3 cycles thereafter. 20/43 patients were considered "responders", with a reduction in MMDQ score by at least 50% relative to baseline. At baseline, the VAS score was elevated in the late luteal phase and low at the follicular phase, as expected. During treatment, VAS score decreased in the late luteal phase (47.2%; p<0.01) and remained 21.7% (p<0.001) below baseline after 3 cycles post-cessation of treatment. The low VAS score within the follicular phase remained unchanged over the whole observation period. 38 patients judged the global efficacy moderate to excellent, 5 patients indicated no global efficacy. The number of days patients sustained PMS symptoms was reduced slightly from 7.5 to 6. Resting levels of blood prolactin remained within the physiological range throughout. No differences were seen between patients on or off oral contraceptives. 20 patients reported 37 adverse events (AE). No serious AE were reported. One patint withdrew after four days of treatment due to fatigue and headache. Laboratory safety control parameters were not affected. In conclusion, patients with PMS can be treated successfully with Vitex agnus-castus extract Ze 440, as indicated by clear improvement in the main effect parameter during treatment and the gradual return after cessation of treatment. The main response to treatment seems related to symptomatic relief rather than to the duration of the syndrome.
In the present study the cardiovascular effects of intracerebroventricularly (i.c.v.) applied angiotensin II (AN II) and angiotensin III (AN III) were analysed in conscious Wistar rats. The baroreceptor heart reflex (BHR) was elicited by intravenous bolus injection of both phenylephrine (1 microgram) and sodium nitroprusside (5 micrograms) before and after i.c.v. administration (1.5 and 15 min) of the peptides. Administration of 20 ng and 200 ng AN II produced a short increase in inter-beat interval (IBI) and a long-lasting increase in mean blood pressure (MBP), inclusive of a drinking response. Only after the high dose of 200 ng AN II we found a continuous impairment in the BHR for reflex bradycardia. Inversely, the small doses of both 100 pg AN II and 100 pg AN III were without effects on IBI and MBP; they induced an enhancement in BHR for the reflex bradycardia and after 100 pg AN II it was also found for the reflex tachycardia. Pretreatment with 20 nmol amastatin (AM), a specified aminopeptidase A inhibitor, followed by 100 pg An II suppressed the enhancement in BHR. AM alone was without effects in this respect. These findings suggest that: 1) the influence of central angiotensin on the BHR could be dose-dependent in the opposite way and 2) AN III seems to be the active form and involved in the central blood pressure regulatory mechanism.
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The effects of intracerebroventricularly (i.c.v.) administered Substance P (100 pg, 1 microgram, 10 micrograms) on mean blood pressure (MBP), inter-beat interval (IBI) and the baroreceptor heart reflex (BHR) were studied in conscious Wistar rats. The BHR was induced by intravenous injection of both phenylephrine (1 microgram) and sodium nitroprusside (5 micrograms) before and after SP administration (3 and 15 min). The dose of 100 pg SP was without effect on the resting values of both MBP and IBI but enhanced the BHR sensitivity by about + 0.5 ms/mm Hg in the phenylephrine test 3 min after i.c.v. SP. 1 microgram and 10 micrograms SP caused a long-lasting dose dependent increase in MBP and changed the IBI. In contrast to the results obtained with 100 pg, the BHR sensitivity was impaired-1 microgram SP: -0.2 ms/mm Hg (phenylephrine) and -0.45 ms/mm Hg (nitroprusside), 10 micrograms SP: -0.35 ms/mm Hg (phenylephrine). These changes in BHR sensitivity were only recognised 3 min, but not 15 min, after i.c.v. treatment even hough changes in the resting values of MBP and IBI were still present at 15 min. These data suggest that SP through the cerebrospinal fluid may participate in central cardiovascular control and, moreover, it may influence the baroreflex regulation.
In anaesthetized rats the baroreflex was checked before and 15 min after i.c.v. administration of 10 micrograms SP. The baroreflex was checked indirectly by relating both the reflex prolongation in heart period (inter-beat-interval: IBI) and the reflex inhibition of SNA to a pharmacologically induced BP rise. After i.c.v. administration of SP (n = 10) the resting values of the BP increased significantly from 73 +/- 16 mm Hg to 86 +/- 9 mm Hg (diastolic pressure) and from 98 +/- 20 mm Hg to 113 +/- 14 mm Hg (systolic pressure) whilst in the control group (n = 14) the BP remained constant (63 +/- 9 vs 63 +/- 7 mm Hg diastolic pressure and 106 +/- 12 vs 106 +/- 9 mm Hg systolic pressure). In the experimental group the resting value in IBI was shortened significantly from 218 +/- 40 ms to 167 +/- 28 ms (controls: 218 +/- 22 ms vs 218 +/- 18 ms) and the SNA (estimated in arbitrary units) rose significantly by about 50% in relation to the reference period before i.c.v. SP (3.31 +/- 0.11 vs 6.27 +/- 0.17 arbitrary units per IBI). In contrast, the baroreflex behaved similarly before and after any treatment, i.e. both the reflex prolongation in IBI (1.34 +/- 0.75 vs 1.39 +/- 0.95 ms/mm Hg) and the reflex inhibition of SNA (0.0312 +/- 0.01 vs 0.0555 +/- 0.015 arbitrary units/mm Hg) caused by that pharmacologically induced BP rise were comparable before and after i.c.v. SP.(ABSTRACT TRUNCATED AT 250 WORDS)
Local administration of small amounts of vasopressin, angiotensin or endothelin into the nucleus tractus solitarii elicits similar decreases in blood pressure and heart rate. These central effects oppose the peripheral action of these hormones on the cardiovascular system. The baroreceptor-heart-reflex, however, is influenced differentially: vasopressin and angiotensin II enhances the sensitivity of the reflex but angiotensin III impairs it. In this way the cardiovascular system may be adjusted to different demands including those related to electrolyte and fluid homeostasis.
In conscious and anaesthetized rats the baroreceptor heart reflex (BHR) was checked before and after i.c.v. application of isotonic or hypertonic (0.6 M; 1.0 M) NaCl solution, artificial cerebrospinal fluid (aCSF) and 1.0 M mannitol solution. The BHR was tested by evaluating the alteration of the inter-beat interval (IBI) in response to an artificial BP rise or drop which had been evoked by i.v. bolus injection of either phenylephrine or sodium nitroprusside. The slope of the correlation function was taken to index the reflex sensitivity. In anaesthetized rats the mean sensitivity of the BHR was 0.6 ms/mm Hg (phenylephrine). l.c.v. administration of isotonic NaCl solution did not change BP, IBI or the BHR sensitivity, whilst i.c.v. infusion of hypertonic NaCl solution increased BP and shortened IBI. The BHR sensitivity was impaired only when 1.0 M NaCl solution was i.c.v. infused by 0.23 ms/mm Hg. In conscious rats the mean sensitivity of the BHR was 1.14 ms/mm Hg (phenylephrine) and 1.35 ms/mm Hg (sodium nitroprusside). In the conscious rats i.c.v. bolus injection of hypertonic NaCl solution increased BP as in anaesthetized rats, however, the IBI was prolonged, whilst 1.0 M mannitol solution and aCSF were without any influence on BP, IBI and BHR. l.c.v. administration of hypertonic NaCl solution reduced the BHR sensitivity by approximately 0.6 ms/mm Hg.
Intracerebroventricular (i.c.v.) infusion of hypertonic sodium chloride solution increased blood pressure (BP) and shortened heart period (interbeat-interval: IBI) that is why an impairment in baroreflex regulation is believed to be part of that process. Therefore, in anaesthetized rats (1.35 g urethane/kg BW) the baroreceptor-heart reflex (BHR) was tested before and during i.c.v. infusion (15 min) of isotonic or hypertonic (0.6 M, 1.0 M) sodium chloride solution by inducing an acute BP rise by i.v. pressoric agents (phenylephrine, methoxamine). The evoked reflex prolongation of the IBI was taken to estimate the sensitivity of that BHR (delta ms/mm Hg). Whilst i.c.v. infusion of isotonic sodium chloride solution did not affect BHR sensitivity, hypertonic sodium chloride solution not only elevated BP and shortened IBI but also reset and impaired the BHR. Therefore, an increased central sensitivity to sodium chloride might not only increase BP but also impair the buffering capacity of the BHR against this rise and in this way support development of hypertension.
In conscious, unrestrained rats, the resting values of mean arterial blood pressure (BP) and heart rate (HR) as well as the baroreceptor heart rate reflex (BHR) were measured before and after intracerebroventricular (i.c.v.) application of arginine vasopressin (AVP). The BHR was induced by intravenous (i.v.) injection of different doses of phenylephrine. Basal values of BP and HR were 114 +/- 2.4 mm Hg and 376 +/- 13 beats/min (mean +/- SE). These values were not altered by i.c.v. application of vehicle or 5, 10, 30, 300, 3,000 pg AVP or 1 pg AVP antagonist [(D(CH2)5Tyr(Me)-AVP)]. Ten and 30 pg AVP administered i.c.v. attenuated the phenylephrine-induced decrease in HR. Lower or higher doses of AVP were not effective. Administration of the AVP antagonist i.c.v. sensitized the BHR. When the BHR was rechecked 24 h after treatment, the influence of the i.c.v.-administered peptides had disappeared. We conclude that AVP through the cerebrospinal fluid impairs the baroreflex regulation.
In anesthetized, normotensive Wistar rats, Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), 100 pg [Arg8]-vasopressin was micro-injected bilaterally into the nucleus tractus solitarii (NTS). Blood pressure and the interbeat heart interval were measured. In both Wistar rats and WKY the interbeat interval was prolonged and blood pressure was decreased, while in SHR only the interbeat interval was prolonged. Thus, within a very low dose range, the influence of [Arg8]-vasopressin within the NTS on mechanisms of cardiovascular regulation seems to differ between normotensive rats and SHR.
Arginine-vasopressin (VP), the VP fragments VP-(1-8), [pGlu4,Cyt6]VP-(4-9) and -(4-8), and a fragment of the C-terminal glycopeptide of the VP precursor [CPP-(22-39)] decreased blood pressure and heart rate in anesthetized rats when microinjected bilaterally into the nucleus tractus solitarii (NTS). The magnitude of the effect was similar at doses of 20 pg, except for VP-(1-8) which required about 500 pg. The strongest decrease in blood pressure and heart rate was observed with 100 pg VP. Higher doses of other peptides either were ineffective [CPP-(22-39)] or increased blood pressure [( pGlu4,Cyt6]VP-(4-9) and -(4-8)). VP metabolites thus may participate in the control of cardiovascular functions exerted by VP. The effect of CPP-(22-39) indicates that the C-terminal glycopeptide of the VP precursor contains biological activity, which may support the cardiovascular action of VP in the NTS.