Skin tolerance of a new bath oil containing St. John's wort extract.

BACKGROUND: Dry and atopic skin requires skin care with lipid-rich emollients and moisturizing bath or shower oils. However, it has been shown recently that some bath oils may even impair the skin barrier. OBJECTIVE: To investigate the skin-irritating potential of a new bath oil containing a lipophilic St. John's wort (Hypericum perforatum) extract. METHODS: In this single-center, randomized, double-blind, prospective study, 3 bath oils together with positive and negative controls were applied under occlusion on test areas on the volar forearms of 18 volunteers (visit 1). After 24 h, the tapes were removed, and the test areas were evaluated by a visual score and the instrumental measurement of skin erythema and transepidermal water loss (TEWL) using a Mexameter and a Tewameter (visit 2). The test substances were applied a second time, and the measurements were performed after another 24 h (visit 3). RESULTS: The positive control, 1% vol/vol sodium lauryl sulfate (SLS), caused a significant increase in skin erythema and TEWL. In contrast, distilled water as a negative control did not influence these parameters. The new bath oil containing St. John's wort extract and 1 of the other 2 commercial products were not different from the water control. The third bath oil displayed a skin-irritating effect similar to SLS. CONCLUSION: The results of this study confirm the different skin-irritating potential of bath oils and demonstrate good skin tolerance of the new bath oil containing St. John's wort extract.

Use of metoprolol CR/XL to maintain sinus rhythm after conversion from persistent atrial fibrillation: a randomized, double-blind, placebo-controlled study.

OBJECTIVES: The primary objective of the present study was to assess the efficacy of metoprolol CR/XL to reduce the risk of relapse after cardioversion of persistent atrial fibrillation to sinus rhythm. BACKGROUND: Indirect data from studies with d,l sotalol provide evidence that the beta-blocking effects of the compound are important in maintaining sinus rhythm after cardioversion of atrial fibrillation. METHODS: After successful conversion to sinus rhythm, 394 patients with a history of persistent atrial fibrillation were randomly assigned to treatment with metoprolol CR/XL or placebo. The two treatment groups were similar with respect to all pretreatment characteristics. Patients were seen on an outpatient basis for recording of resting electrocardiogram (ECG) after one week, one, three and six months of follow-up or whenever they felt that they had a relapse into atrial fibrillation or experienced an adverse event. RESULTS: In the metoprolol CR/XL group, 96 patients (48.7%) had a relapse into atrial fibrillation compared with 118 patients (59.9%) in the placebo group (p = 0.005). Heart rate in patients after a relapse into atrial fibrillation was significantly lower in the metoprolol group (98 +/- 23 beats/min) than in the placebo group (107 +/- 27 beats/min). The rate of adverse events reported was similar in both groups when the difference in follow-up time was taken into account. CONCLUSIONS: The results of this double-blind, placebo-controlled study in patients after cardioversion of persistent atrial fibrillation showed that metoprolol CR/XL was effective in preventing relapse into atrial fibrillation or flutter.

Endotheliitis in hepatic allografts.

Endotheliitis (EN) is a feature of hepatic allograft rejection, characterized by the adherence of immunocytes to the endothelium of veins, often leading to endothelial damage, endophlebitis, and, sometimes, panphlebitis. We found EN at least once in 28 of 41 allografts (68%) that had survived 6 months or longer. In approximately half the affected cases, the condition recurred. The EN was mild in most instances; moderate or severe manifestations were found in only 13% of the cases. The histologic changes were present for about 1 week in approximately half the cases; a duration of more than 2 weeks was noted in 17%, and then EN usually persisted. After retransplantation, recurrence of EN was observed in all of nine cases. We were unable to establish specific clinicopathologic and laboratory correlations for EN. The immunocytes in EN consisted mainly of helper and suppressor/cytotoxic T cells as well as natural killer cells. Sometimes, the immunocytes assumed a blastlike appearance; in these instances, the condition was severe. Such blastlike changes may be specific for EN. The immunocytes were attached to the endothelium by pseudopodia, broad bases, or both; some also were interconnected by cytoplasmic bridges. Underlying endothelial cells often showed evidence of cytoplasmic damage. The pathogenesis of EN is not completely understood; the immunocytes probably attach themselves to antigenic epitopes. Their nature, however, has not been clearly identified; HLA-A, B, and C and HLA-DR were displayed in areas of EN, but the antigens also were found in vessels without EN.

Modulation of cytokine expression by hypericum extract.

The effect of hypericum extract LI 160 on the stimulated cytokine expression was investigated in vitro in a whole blood culture system. Blood samples were taken from five healthy volunteers and four depressive patients. The release of interleukin-6 (IL-6), interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) was measured quantitatively after an incubation time of 24 hours on microtiter plates. A massive suppression of the interleukin-6 release was found for PHA-stimulated hypericum extract. Possible relations to the antidepressive effects of hypericum extract are discussed.

Multicenter double-blind study examining the antidepressant effectiveness of the hypericum extract LI 160.

Seventy-two depressive patients of 11 physicians' practices were treated in a double-blind study for a period of 6 weeks either with hypericum extract LI 160 or with placebo. Inclusion criterion was a major depression in accordance with DSM-III-R. The changes were assessed using four psychometric scales (HAMD, D-S, BEB, CGI). After 4 weeks of therapy, the statistical evaluation revealed a significant improvement in all four psychometric tests in the active group as compared to the placebo group. After switching the placebo group to active treatment (5th to 6th week of therapy), significant improvements were found in the original placebo group. No serious side effects were observed.

Pharmacokinetics of hypericin and pseudohypericin after oral intake of the hypericum perforatum extract LI 160 in healthy volunteers.

The single- and multiple-dose pharmacokinetics of the naphthodianthrones hypericin and pseudohypericin derived from St. John's wort (Hypericum perforatum, LI 160, Lichtwer Pharma GmbH, Berlin) were studied in 12 healthy male subjects. After a single oral dose of 300, 900, or 1800 mg of dried hypericum extract (250, 750, or 1500 micrograms hypericin and 526, 1578, or 3156 micrograms pseudohypericin), plasma levels were measured with a modified highly sensitive high-pressure liquid chromatography (HPLC) method (lower detection limit 0.1 ng/mL) up to 3 days. The median maximal plasma levels were 1.5, 4.1, and 14.2 ng/mL for hypericin and 2.7, 11.7, and 30.6 ng/mL for pseudohypericin, respectively, for the three doses given above (interim evaluation of four volunteers). The median elimination half-life times of hypericin were 24.8 to 26.5 hours, and varied for pseudohypericin from 16.3 to 36.0 hours. Ranging between 2.0 to 2.6 hours, the median lag-time of absorption was remarkably prolonged for hypericin when compared to pseudohypericin (0.3 to 1.1 hours). The areas under the curves (AUC) showed a nonlinear increase with raising dose; this effect was statistically significant for hypericin. During long-term dosing (3 x 300 mg/day), a steady-state was reached after 4 days. Mean maximal plasma level during the steady-state treatment was 8.5 ng/mL for hypericin and 5.8 ng/mL for pseudohypericin, while mean trough levels were 5.3 ng/mL for hypericin and 3.7 ng/mL for pseudohypericin. In spite of their structural similarities there are substantial pharmacokinetic differences between hypericin and pseudohypericin.

Efficacy and tolerability of valerian extract LI 156 compared with oxazepam in the treatment of non-organic insomnia--a randomized, double-blind, comparative clinical study.

Patients aged 18 to 73 years and diagnosed with non-organic insomnia according to ICD-10 (F 51.0) were treated in a multicentre, double-blind, randomised parallel group comparison with either 600 mg/die valerian extract LI 156 (Sedonium) or 10 mg/die oxazepam taken for 6 weeks. A total of 202 outpatients with a mean duration of insomnia of 3.5 months at baseline were included at 24 study centres (general practices) in Germany. - Sleep quality (SQ) after 6 weeks measured by the Sleep Questionnaire B (SF-B; CIPS 1996) showed that 600 mg/die valerian extract LI 156 was at least as efficacious as a treatment with 10 mg/die oxazepam. Both treatments markedly increased sleep quality compared with baseline (p <0.01). The other SF-B subscales, i.e. feeling of refreshment after sleep (GES), psychic stability in the evening (PSYA), psychic exhaustion in the evening (PSYE), psychosomatic symptoms in the sleep phase (PSS), dream recall (TRME), and duration of sleep confirmed similar effects of both treatments. Clinical Global Impressions scale (CGI) and Global Assessment of Efficacy by investigator and patient, again, showed similar effects of both treatments. Adverse events occurred in 29 patients (28.4%) receiving valerian extract LI 156 and 36 patients (36.0%) under oxazepam, and were all rated mild to moderate. No serious adverse drug reactions were reported in either group. Most patients assessed their respective treatment as very good (82.8% in the valerian group, 73.4% in the oxazepam group). During the 6 week treatment phase Valerian extract LI 156 (Sedonium) 600 mg/die showed a comparable efficacy to 10 mg/die oxazepam in the therapy of non-organic insomnia.

Effect of two artichoke extracts (36_U and 36_EB) on rat ileum (with respect to bowel syndrome) and the peristaltic threshold.

The diagnosis and treatment of irritable bowel syndrome (IBS) are complicated. Artichoke extracts are well known to be helpful in various gastrointestinal disorders. A hydrophilic extract 36_U mainly containing luteolin-7-glycoside, luteolin-7-O-glucoside, small amounts of cynarin and luteolin increased contraction of rat ileum. This is mainly mediated by 5-HT(3) - and 5-HT(2) receptors but not 5-HT(4) receptors as can be derived by using specific antagonists such as tropisetrone, GR113806 and ketanserine. Additional mechanisms (receptors) are involved since the combination of these three antagonists was not able to fully prevent the contractive effect of extract 36_U. The lipophilic extract 36_EB mainly containing cynarin, luteolin including its glycosides, and cholorogenic acid in contrast to extract 36_U had a relaxing effect which could hardly be washed out. It was diminishing a serotonin effect and was not modified by ACh or substance P. The peristaltic threshold, i.e. the distension necessary for inducing a pathophysiologically relevant propulsion activity, is one of the important features being correlated with IBS. The peristaltic threshold was decreased by both serotonin and extract U_36. From the data it can be derived that the extract 36_U may be useful in IBS combined with obstipation when gastrointestinal contraction is necessary, whereas 36_EB may be useful in IBS combined with diarrhea when gastrointestinal relaxation is desired. Especially interesting are the influence on the threshold. It would be interesting to know which effects are mediated via cynarin and luteolin or its glycosides.

5-HT3 receptor blocking activity of arylalkanes isolated from the rhizome of Zingiber officinale.

Different extracts (ethanolic, hexane, aqueous) of ginger (rhizomes of Zingiber officinale) and the essential oil were tested using [14C]guanidinium influx into N1E-115 cells and the isolated rat ileum in order to identify their activity in inhibiting 5-HT3 receptor function. The hexane extract proved to be the most active and yielded upon bioassay-guided fractionation nine constituents: [6]-, [8]-, [10]-gingerols, [6]- and [8]-shogaols which were previously shown as active in vivo against cytotoxic drug-induced emesis; [4]-gingerol, [6]-gingerdiol, diacetyl-[6]-gingerdiol and [6]-dehydrogingerdione have not been previously tested for anti-emetic or 5-HT3 receptor antagonistic effects. Even though the latter four compounds are only minor constituents, their identification contributed towards the characterisation of a structure-activity relationship of this class of compounds. The order of potency for the nine constituents in the N1E-115 cell system was [6]-gingerdiol approximately diacetyl-[6]-gingerdiol approximately [6]-dehydrogingerdione approximately [6]-shogaol > or = [8]-shogaol approximately [8]-gingerol > [10]-gingerol > or = [6]-gingerol > [4]-gingerol.

Bioavailability and pharmacokinetics of caffeoylquinic acids and flavonoids after oral administration of Artichoke leaf extracts in humans.

Extracts from artichoke leaves are traditionally used in the treatment of dyspeptic and hepatic disorders. Various potential pharmacodynamic effects have been observed in vitro for mono- and dicaffeoylquinic acids (e.g. chlorogenic acid, cynarin), caffeic acid and flavonoids (e.g. luteolin-7-O-glucoside) which are the main phenolic constituents of artichoke leaf extract (ALE). However, in vivo not only the genuine extract constituents but also their metabolites may contribute to efficacy. Therefore, the evaluation of systemic availability of potential bioactive plant constituents is a major prerequisite for the interpretation of in vitro pharmacological testing. In order to get more detailed information about absorption, metabolism and disposition of ALE, two different extracts were administered to 14 healthy volunteers in a crossover study. Each subject received doses of both extracts. Extract A administered dose: caffeoylquinic acids equivalent to 107.0 mg caffeic acid and luteolin glycosides equivalent to 14.4 mg luteolin. Extract B administered dose: caffeoylquinic acids equivalent to 153.8 mg caffeic acid and luteolin glycosides equivalent to 35.2 mg luteolin. Urine and plasma analysis were performed by a validated HPLC method using 12-channel coulometric array detection. In human plasma or urine none of the genuine target extract constituents could be detected. However, caffeic acid (CA), its methylated derivates ferulic acid (FA) and isoferulic acid (IFA) and the hydrogenation products dihydrocaffeic acid (DHCA) and dihydroferulic acid (DHFA) were identified as metabolites derived from caffeoylquinic acids. Except of DHFA all of these compounds were present as sulfates or glucuronides. Peak plasma concentrations of total CA, FA and IFA were reached within 1 h and declined over 24 h showing almost biphasic profiles. In contrast maximum concentrations for total DHCA and DHFA were observed only after 6-7 h, indicating two different metabolic pathways for caffeoylquinic acids. Luteolin administered as glucoside was recovered from plasma and urine only as sulfate or glucuronide but neither in form of genuine glucosides nor as free luteolin. Peak plasma concentrations were reached rapidly within 0.5 h. The elimination showed a biphasic profile.

Efficacy of the Hawthorn (Crataegus) preparation LI 132 in 78 patients with chronic congestive heart failure defined as NYHA functional class II.

Seventy-eight male and female patients between the ages of 45 and 73, who were affected by chronic heart failure defined as NYHA functional class II, were treated either with Crataegus extract or with a placebo preparation. The extract LI 132 was administered to the patients in the form of 3 dragées a day (verum preparation) corresponding to a daily dose of 600 mg. Treatment was continued over a period of 8 weeks, with a wash-out phase of one week. The confirmatory parameter used to asses the efficacy of the preparation was the patients' working capacity which was measured using an ergometer bicycle. Before the start of the study, an increase in the patients' working capacity of at least half an exercise step on the ergometer bicycle (12.5 watt) was determined to be clinically relevant. Apart from the compatibility of the preparation, a score system was used to assess the severity level of the typical symptoms. From day 0 to day 56 of the trial, the median values obtained for the working capacity of the patients treated with the verum preparation were found to have increased by 28 watt, while the increase in the working capacity of the placebo patients was as little as 5 watt. The difference was statistically significant (p < 0.001). Apart from that, a significant reduction of the systolic blood pressure, of the heart rate and of the pressure/rate product was observed for the patients treated with the verum preparation, compared to the patients treated with the placebo preparation. Also, the clinical symptoms (score system) were found to have improved significantly. There were no severe side effects observed.

Clinical trials with Phyto-Psychopharmacological agents.

Phyto-psychopharmacological agents are extracts of plants with stimulating or calming effects on the central nervous system. Phyto-psycho-pharmacological agents are among the most commonly prescribed herbal medicines in Germany. The efficacy and harmlessness of some of the preparations have been established by high quality clinical trials. Between 1975 and 1992, a total of 34 clinical studies involving some 2326 patients were published on the effects of Ginkgo special extract EGb 761 and LI 1370; to date, 28 clinical trials in 2120 patients have been under-taken with alcoholic extracts of St. John's Wort. The therapeutic efficacy of kava and valerian extracts has been investigated in six and four controlled studies, respectively. In general, a high placebo effect is likely, which is why it is essential to include control groups in these studies. A considerable advantage over synthetic psychopharmacological agents is the low incidence of side effects, which in safety assessment studies is below 3%. The sharp increase in quality standards for clinical trials has meant that only a few preparations have undergone large scale testing programs in accordance with international guidelines. For other phyto-psychopharmacological agents, there is the danger that no further clinical trials will be undertaken due to the excessively high standards now demanded.

Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericin.

Single-dose and steady-state pharmacokinetics of antivirally acting hypericin (H) and pseudohypericin (PH) were studied in 13 healthy volunteers by administration of St. John's Wort extract LI 160, a plantal antidepressant. Oral administration of 250, 750, and 1,500 micrograms of H and 526, 1,578, and 3,156 micrograms of PH resulted in median peak levels in plasma (Cmax) of 1.3, 7.2, and 16.6 micrograms/liter for H and 3.4, 12.1, and 29.7 micrograms/liter for PH, respectively. The Cmax and the area under the curve values for the lowest dose were disproportionally lower than those for the higher doses. A lag time of 1.9 h for H was remarkably longer than the 0.4-h lag time for PH. Median half-lives for absorption, distribution, and elimination were 0.6, 6.0, and 43.1 h after 750 micrograms of H and 1.3, 1.4, and 24.8 h after 1,578 micrograms of PH, respectively. Fourteen-day treatment with 250 micrograms of H and 526 micrograms of PH three times a day resulted in median steady-state trough levels of 7.9 micrograms/liter for H and 4.8 micrograms/liter for PH after 7 and 4 days, respectively; the corresponding Cssmax levels were 8.8 and 8.5 micrograms/liter, respectively. Kinetic parameters after intravenous administration of Hypericum extract (115 and 38 micrograms for H and PH, respectively) in two subjects corresponded to those estimated after an oral dosage. Both H and PH were initially distributed into a central volume of 4.2 and 5.0 liter, respectively. The mean distribution volumes at steady state were 19.7 liters for H and 39.3 liters for PH, and the mean total clearance rates were 9.2 ml/min for H and 43.3 ml/min for PH. The systemic availability of H and PH from LI 160 was roughly estimated to be 14 and 21%, respectively. Treatment with Hypericum extract, even in high doses, was well tolerated.

Debrisoquine hydroxylation phenotype, acetylation phenotype, and ABO blood groups as genetic host factors of lung cancer risk.

Bronchogenic carcinoma is closely associated with cigarette smoking although additional environmental or individual factors might regulate a person's susceptibility to that disease. To further define such risk factors, the prevalence of the genetic debrisoquine 4-hydroxylation deficiency was determined before therapeutic intervention in 270 lung cancer patients. Nineteen homozygous carriers of this defect (poor metabolizers) were found (7.0%, 95% confidence limits 4.3%-10.8%), a number being lower than 30 out of 270 reference patients (11.1%, 95% confidence limits 7.6%-15.5%). The odds ratio of 0.61 was of marginal statistical significance (P = 0.067). Subdividing the collective according to histology revealed a trend towards underrepresentation of poor metabolizers especially among patients with adenocarcinoma (1 out of 37, P = 0.086) and among young patients not older than 50 years (none out of 32, P = 0.028). All poor metabolizers (PMs) in the cancer group were smokers. In 18 patients the phenotype assignment was confirmed by a second test several weeks after surgical or other treatment. In 220 of the lung cancer patients the N-acetyltransferase polymorphism was evaluated by means of the molar ratio of 5-acetylamino-6-formylamino-3-methyluracil and 1-methylxanthine in urine after ingestion of caffeine (coffee). There were 111 (50.5%) slow acetylators and 109 (49.5%) fast acetylators. A statistically significant clustering of either phenotype after stratification according to histology, or debrisoquine hydroxilator status was lacking. Moreover, there was no difference in the ratio of both phenotypes as compared to the reference collective of 245 patients (53.5% slow and 46.5% fast acetylators). As a third genetic host factor the AB0 blood group frequencies were evaluated in 263 lung cancer patients. The frequency ratio of A/O was significantly higher as compared to 41,423 blood donors (odds ratio 1.37, 95% confidence limits 1.02-1.84, P less than 0.05). A/O tended to be especially high in young patients not older than 50 years. The ratio B/O in bronchial cancer was significantly higher than expected. The results suggest that the debrisoquine hydroxilator status might have an impact on an individual's susceptibility to lung cancer. This association is either a weak one and/or is restricted to certain histological cancer types or to patients with certain characteristics. The acetylator phenotype could not be established as a risk factor, whereas AB0 blood groups seem to influence lung cancer susceptibility.

The effect of garlic on arteriosclerotic nanoplaque formation and size.

OBJECTIVE: In an in vitro biosensor model (PCT/EP 97/05212), the interplay between different lipoproteins in arteriosclerotic nanoplaque formation, as well as aqueous garlic extract (0.2-5.0 g/l from LI 111 powder) as a possible candidate drug against arterio/atherosclerosis were tested within the frame of a high throughput screening. METHODS: The processes described below were studied by ellipsometric techniques quantifying the adsorbed amount (nanoplaque formation) and layer thickness (nanoplaque size). A thorough description of the experimental setup has been given previously. RESULTS: Proteoheparan sulfate (HS-PG) adsorption to hydrophobic silica was monoexponential and after approximately 30 min constant. The addition of 2.52 mmol/l Ca2+ led to a further increase in HS-PG adsorption because Ca2+ was bound to the polyanionic glycosaminoglycan (GAG) chains thus screening their negative fixed charges and turning the whole molecule more hydrophobic. Incubation with 0.2 g/l aqueous garlic extract (GE) for 30 min did not change the adsorption of HS-PG. However, the following addition of Ca2+ ions reduced the increase in adsorption by 50.8% within 40 min. The adsorption of a second Ca2+ step to 10.08 mmol/l was reduced by even 82.1% within the next 40 min. Having detected this inhibition of receptor calcification, it could be expected that the build-up of the ternary nanoplaque complex is also affected by garlic. The LDL plasma fraction (100 mg/dl) from a healthy probationer showed beginning arteriosclerotic nanoplaque formation already at a normal blood Ca2+ concentration, with a strong increase at higher Ca2+ concentrations. GE, preferably in a concentration of 1 g/l, applied acutely in the experiment, markedly slowed down this process of ternary aggregational nanoplaque complexation at all Ca2+ concentrations used. In a normal blood Ca2+ concentration of 2.52 mmol/l, the garlic induced reduction of nanoplaque formation and molecular size amounted to 14.8% and 3.9%, respectively, as compared to the controls. Furthermore, after ternary complex build-up, GE similar to HDL, was able to reduce nanoplaque formation and size. The incubation time for HDL and garlic was only 30 min each in these experiments. Nevertheless, after this short time the deposition of the ternary complex decreased by 6.2% resp. 16.5%, i.e. the complex aggregates were basically resolvable. CONCLUSIONS: These experiments clearly proved that garlic extract strongly inhibits Ca2+ binding to HS-PG. In consequence, the formation of the ternary HS-PG/LDL/Ca2+ complex, initially responsible for the 'nanoplaque' composition and ultimately for the arteriosclerotic plaque generation, is decisively blunted.