Interaction with St. John's wort due to exposure with blackcurrant aroma? How not to present a case report of an adverse event.

Background: Adverse events case reports are important for signal generation in pharmacovigilance. They require a thorough collation of the facts, otherwise they may lead to erroneous conclusions which may conceal other treatment-related causes of the observation. Methods: We describe a case report from the literature that arrives at an erroneous conclusion merely from taking insufficient care when collating and interpreting the facts: The authors of the case report confused blackcurrant (Ribes nigrum) with St. John's wort preparation (Hypericum perforatum) and erroneously assumed that the intake of a herbal preparation was responsible for a drop in serum levels of everolimus. Results: The clinical observations in this case report may actually reflect a potentially lethal situation emerging from the prescribed medication everolimus. St. John's wort preparations rich in hyperforin do in fact reproducibly lead to the decrease of blood levels of medications metabolized through cytochrome P450 subtype 3A4. However, a case report requires more care than just ascribing the blame to something seemingly well-known. Conclusion: The readers of this report might have profited more from the description of the risks of treating graft-versus-host disease with everolimus, and the action to be taken in case of potentially severe adverse reactions to everolimus.

Celastrol, an active constituent of the TCM plant Tripterygium wilfordii Hook.f., inhibits prostate cancer bone metastasis.

BACKGROUND: Treatment failure of prostate cancer (PCa) is often due to bone metastasis. Celastrol, an active constituent of Tripterygium wilfordii roots, has shown anti-tumor effects in previous studies in accordance with its indication in traditional Chinese medicine. METHODS: Using a PC-3 cell model, in vitro assays were performed to evaluate the effects of celastrol on proliferation, migration (wound healing assay), tissues invasion (Transwell-Matrigel penetration assay) and vascular endothelial growth factor (VEGF) secretion (enzyme-linked immunosorbent assay). An intra-tibia injection mouse model was used to assess the effect of celastrol on PCa bone metastasis in vivo. RESULTS: Pretreatment with celastrol significantly reduced proliferation of PC-3 cells in a dose-dependent manner and cell migration was much slower than in controls. Significantly fewer cells penetrated the gel-membrane after celastrol administration and their skeletal invasive ability was significantly reduced in a dose-dependent manner. Correspondingly, a significant, dose-dependent decrease in VEGF secretion was observed. In the in vivo mouse model, pretreatment with celastrol (8 µmol l-1) inhibited the tumorigenicity of PC-3 cells so that almost no bone invasion occurred as compared with control injections. Histological examinations using hematoxylin and eosin staining showed that tibiae injected with celastrol pretreated PC-3 cells retained their natural bone structure. CONCLUSIONS: Celastrol may have preventive potential against PCa bone metastasis.

Atomically precise (catalytic) particles synthesized by a novel cluster deposition instrument.

We report a new high vacuum instrument which is dedicated to the preparation of well-defined clusters supported on model and technologically relevant supports for catalytic and materials investigations. The instrument is based on deposition of size selected metallic cluster ions that are produced by a high flux magnetron cluster source. The throughput of the apparatus is maximized by collecting and focusing ions utilizing a conical octupole ion guide and a linear ion guide. The size selection is achieved by a quadrupole mass filter. The new design of the sample holder provides for the preparation of multiple samples on supports of various sizes and shapes in one session. After cluster deposition onto the support of interest, samples will be taken out of the chamber for a variety of testing and characterization.

Stachydrine in Leonurus cardiaca, Leonurus japonicus, Leonotis leonurus: detection and quantification by instrumental HPTLC and 1H-qNMR analyses.

Stachydrine ((2S)-1,1-dimethylpyrrolidinium-2-carboxylic acid) may be regarded as an essential active principle of the aerial parts of Leonurus japonicus Houtt. (Leonuri herba, yimucao; Chin.Ph., DAB) which are used in TCM and Kampo for the treatment of various gynaecological and cardiovascular disorders. Medically and botanically closely related Lamioideae drugs are the fruits of L. japonicus (Leonuri fructus, chongweizi; Chin.Ph.), the aerial parts of European Leonurus cardiaca L. (Leonuri cardiacae herba; Ph.Eur.) as well as the aerial parts of their South African relative Leonotis leonurus (L.) R.Br. (Leonotis leonuri herba). Regarding L. cardiaca, stachydrine might be an exceptionally interesting constituent as Dragendorff-positive substances like stachydrine were found to be enriched in an antiarrhythmic L. cardiaca refined extract, which was most recently developed via bioassay guided fractionation. The few pharmacological publications on this betaine do indeed describe cardiovascular, hypotensive, and tissue protective effects. However, its pharmacopeial analytics poses a severe difficulty, as it does not contain any chromophoric group suitable for customary HPLC-UV detection. For quality control of yimucao according to Chin.Ph. the entirety of its N-containing compounds is photometrically quantified after Reinecke's complexation. Unfortunately, this method suffers from a relatively low reproducibility. Since no reliable quantification method for stachydrine is available up to now, a highly reproducible instrumental HPTLC method was newly developed, using postchromatographic derivatization by Vágújfalvi reagent, thus changing non absorbing stachydrine into a detectable derivative at 517 nm, and an automatic HPTLC system with scanner and analysis software (winCATS). This method was shown to be precise with respect to concentration and yielded highly reproducible data over numerous inter-day repetitions. Not only did the independent evaluation of the scanned HPTLC sheets for stachydrine peak area and height result in almost identical values for all samples, but also the results of a parallel-developed direct quantitative 1H-NMR procedure using its N-CH3 singlet delta 3.03 ppm in comparison with the singlet of the two vinylic protons of the internal standard maleic acid at delta 6.18 ppm were always within the standard deviation of the HPTLC data. These measurements of 12 drug samples revealed stachydrine contents (w/w) of 0.2 to 1.0% for the L. japonicus aerial parts, 0.6 to 1.5 % for the L. cardiaca aerial parts, 6.7% for the antiarrhythmic refined extract of L. cardiaca, and 0.3% for the aerial parts of Leonotis leonurus, while both L. japonicus and L. cardiaca fruits contained, on average, 0.2 %. Furthermore, stachydrine was found for the first time as a constituent of L. japonicus and L. cardiaca fruits as well as Leonotis leonurus. Methodically, instrumental HPTLC may be a powerful tool for quality assurance for stachydrine containing plants and herbal drugs, especially for industrial routine protocols.

Leonurus japonicus, Leonurus cardiaca, Leonotis leonurus: a novel HPLC study on the occurrence and content of the pharmacologically active guanidino derivative leonurine.

Leonurine is a prominent pharmacologically active guanidine alkaloid (4-{[amino(imino)methyl]amino} butyl-4-hydroxy-3,5-dimethoxybenzoate), mainly exerting cardiovascular, hypotensive, uterotonic, and neuroprotective effects. It is commonly regarded as the predominant active principle of Leonurus and Leonotis drugs (subfamily Lamioideae), though its presence has only been unambiguously proven for the aerial parts of Leonurus japonicus Houtt. (yimucao/Chin.Ph.,DAB), used in TCM/Kampo for the treatment of various gynaecological and cardiovascular disorders. Although a series of claims concerning the occurrence of leonurine in European Leonurus cardiaca L. (Ph.Eur.) can be found describing it as an important active principle, this has never been conclusively demonstrated. The same holds true for the officinal Leonurus japonicus fruits (chongweizi/Chin.Ph.) and the closely related South African herb Leonotis leonurus (L.) R.Br. Since no reliable HPLC determination and quantification method for leonurine has been published up to now, in the present study, a highly reproducible RP-HPLC method was newly developed using a special octadecyl-bonded stationary phase and an acetonitrile/water gradient (adjusted to pH 2.5 by phosphoric acid) as mobile phase (DAD/277nm). In particular, this use of reversed phase packing with hydrophilic endcapping clearly contributes to an improved peak shape for leonurine, to our knowledge the first application of this technique on a natural zwitterionic analyte, and clearly enhances the selectivity of separation compared to classical RP-phases. The method was shown to be precise with respect to concentration, exhibiting a linear response in the range of 2.5-12.5 microg/ml leonurine, detection limit well below 0.5 microg/ml, and correlation coefficients constantly higher than 0.99 (5 levels, n = 3) over numerous inter day repetitions, demonstrating the robustness of the newly developed HPLC protocol. Thus, nine samples of L. japonicus aerial parts, two of L. japonicus fruits, four of L. cardiaca aerial parts, as well as one sample each of L. cardiaca fruits, and Leonotis leonurus aerial parts were examined. No leonurine could be detected in any sample of L. cardiaca in contrast to newly published official drug assessments, which consequently have to be revised. Leonotis leonurus and surprisingly, seeds of L. japonicus did not contain leonurine, either. However, in aerial parts of L. japonicus drug samples, obtained from China and Japan, leonurine contents between 0.001 and 0.049% were determined, while L. japonicus from domestic cultivation displayed significantly higher amounts of at least 0.1%. Thus, the HPLC method described above could be used for quality control of leonurine contained in TCM/Kampo medicines and in pharmacopeial analytics for the differentiation of L. japonicus and L. cardiaca samples.

Olea europaea leaf (Ph.Eur.) extract as well as several of its isolated phenolics inhibit the gout-related enzyme xanthine oxidase.

In Mediterranean folk medicine Olea europaea L. leaf (Ph.Eur.) preparations are used as a common remedy for gout. In this in vitro study kinetic measurements were performed on both an 80% ethanolic (v/v) Olea europaea leaf dry extract (OLE) as well as on nine of its typical phenolic constituents in order to investigate its possible inhibitory effects on xanthine oxidase (XO), an enzyme well known to contribute significantly to this pathological process. Dixon and Lineweaver-Burk plot analysis were used to determine K(i) values and the inhibition mode for the isolated phenolics, which were analysed by RP-HPLC for standardisation of OLE. The standardised OLE as well as some of the tested phenolics significantly inhibited the activity of XO. Among these, the flavone aglycone apigenin exhibited by far the strongest effect on XO with a K(i) value of 0.52 µM. In comparison, the known synthetic XO inhibitor allopurinol, used as a reference standard, showed a K(i) of 7.3 µM. Although the phenolic secoiridoid oleuropein, the main ingredient of the extract (24.8%), had a considerable higher K(i) value of 53.0 µM, it still displayed a significant inhibition of XO. Furthermore, caffeic acid (K(i) of 11.5 µM; 1.89% of the extract), luteolin-7-O-ß-D-glucoside (K(i) of 15.0 µM; 0.86%) and luteolin (K(i) of 2.9 µM; 0.086%) also contributed significantly to the XO inhibiting effect of OLE. For oleuropein, a competitive mode of inhibition was found, while all other active substances displayed a mixed mode of inhibition. Tyrosol, hydroxytyrosol, verbascoside, and apigenin-7-O-ß-D-glucoside, which makes up for 0.3% of the extract, were inactive in all tested concentrations. Regarding the pharmacological in vitro effect of apigenin-7-O-ß-D-glucoside, it has to be considered that it is transformed into the active apigenin aglycone in the mammalian body, thus also contributing substantially to the anti-gout activity of olive leaves. For the first time, this study provides a rational basis for the traditional use of olive leaves against gout in Mediterranean folk medicine.

Intraoperative evaluation of tissue perfusion in high-risk patients by invasive and noninvasive hemodynamic monitoring.

OBJECTIVE: Although invasive monitoring has not been effective in late stages after organ failure has occurred, early postoperative monitoring revealed differences in survivor and nonsurvivor patterns and provided goals for improving outcome. We searched for the earliest divergence of survivor and nonsurvivor circulatory changes as an approach to earlier preventive therapy. The aim was to describe the intraoperative time course of circulatory dysfunction in survivors and nonsurvivors among high-risk elective surgery patients using both the thermodilution pulmonary artery catheter (PAC) and multicomponent noninvasive monitoring. DESIGN: Prospective intraoperative description of circulatory dysfunction. SETTING: University-run county hospital. PATIENTS: Two hundred nine consecutively monitored high-risk elective surgery patients. MEASUREMENTS AND MAIN RESULTS: We evaluated the data of high-risk elective surgery patients using both PAC and multicomponent noninvasive monitoring. The latter consisted of the following: a) an improved bioimpedance method for estimating cardiac output; b) the standard pulse oximetry to screen for pulmonary problems; c) transcutaneous oxygen and carbon dioxide tension sensors to evaluate tissue perfusion; and d) routine noninvasive blood pressure and heart rate. The current noninvasive impedance cardiac output estimations closely approximated those of the thermodilution method; r2 = .74, p < .001; the precision and bias was -0.124 +/- 0.75 L/min/m2. Outcome measures included intraoperative description of circulatory patterns of high-risk surgical patients who survived compared with nonsurvivors. Hypotension, low cardiac index, arterial hemoglobin desaturation, low transcutaneous oxygen, high transcutaneous carbon dioxide tensions, low oxygen delivery, and low oxygen consumption developed intraoperatively gradually over time; the abnormalities were more pronounced in the nonsurvivors than in the survivors. CONCLUSIONS: The survivors had slightly higher mean arterial pressure, cardiac index, and mixed venous oxygen saturation, as well as significantly higher oxygen delivery, oxygen consumption, transcutaneous oxygen tension, and transcutaneous oxygen tension/FIO2 ratios, than did the nonsurvivors. The data suggest that blood flow, oxygen delivery, and tissue oxygenation of the nonsurvivors became inadequate toward the end of the operation. Noninvasive monitoring provides similar information to that of the PAC; both approaches revealed low-flow and poor tissue perfusion that were worse in the nonsurvivors. The continuous on-line real-time displays of hemodynamic trends facilitate early recognition of acute circulatory dysfunction.

General anesthesia via tracheosubmental intubation from our own experience.

In our department from 1995 to 1998, 30 patients were operated on under general anesthesia via tracheosubmental intubation (TSI). No local or general complications were observed. Operating in the field free from the intubation tube is very comfortable for a surgeon, while for an anesthesiologist the safety of the tube and efficiency of ventilation are very important. TSI, as a technically simple, safe, and efficient procedure, is extremely helpful in the surgical treatment of patients with simultaneous multifragmentaric and comminuted fractures of the maxilla and mandible, and in orthognathic and aesthetic plastic surgery of the face, where assessment of facial symmetry and occlusion is especially important.

Intraoperative maintenance of tissue perfusion prevents ARDS. Adult Respiratory Distress Syndrome.

Patients undergoing prolonged, complex oncological surgery are at increased risk of developing the adult respiratory distress syndrome (ARDS) and other organ failures. Our hypothesis is that maintaining adequate tissue perfusion and oxygenation may prevent tissue hypoxia and acidosis in pulmonary, peripheral, and splanchnic microcirculations. Experimental evidence suggests that the hypoxic, acidotic endothelium stimulates the release of cytokines, kinins, and other mediators. We developed and tested an intraoperative protocol for surgical patients likely to develop ARDS and organ dysfunction; the protocol focuses on the intraoperative period but is not limited to this time. Nitroglycerin and fluids were used to maintain tissue perfusion and prevent tissue hypoxia as reflected by transcutaneous oxygen tension values. In 155 high-risk patients, none developed ARDS. We conclude that maintenance of tissue perfusion and oxygenation in high-risk surgical patients decreases the incidence of ARDS.

A prospective randomized comparison of the metabolic and stress hormonal responses of laparoscopic and open cholecystectomy.

BACKGROUND: In a relatively short period of time, therapeutic laparoscopy has become an everyday part of the general surgeon's life. Although laparoscopy provides distinct clinical advantages, it is not yet clear that it lessens the stress response typical of elective surgical procedures, and as such, the morbidity of surgery. The hypothesis that laparoscopic cholecystectomy produces less of a metabolic and stress hormonal response than open cholecystectomy was tested in a prospective randomized trial. STUDY DESIGN: Twenty otherwise healthy women between 18 and 45 years of age with a history of uncomplicated symptomatic cholelithiasis undergoing either laparoscopic (n = 10) or open cholecystectomy (n = 10) were studied. The hormonal response of the adrenocortical (serum adrenocorticotropic hormone, cortisol, and urinary free cortisol), adrenomedullary (plasma and urinary epinephrine and norepinephrine), thyroid (thyroid-stimulating hormone, thyroxine, and triiodothyronine), pituitary (antidiuretic hormone and growth hormone), and glucose (serum glucose, glucagon, and insulin) homeostatic axes were measured serially over a 24-hour period. RESULTS: No difference was seen between the laparoscopic and open groups in operative time (mean plus or minus standard error of the mean, 70 +/- 6 minutes compared with 77 +/- 6.3 minutes) or hospital stay 1.3 +/- 0.2 compared with 1.1 +/- 0.1 days). Assessment of postoperative pain using an analog pain score was less in the laparoscopic group (4.9 +/- 1.3 compared with 12.3 +/- 2.5, p = 0.01). The response of the adrenocortical, adrenomedullary, thyroid, and glucose axes were similar or identical in both groups. Antidiuretic hormone levels were greater in the laparoscopic group at one hour intraoperatively (281 +/- 79 pg/mL compared with 54 +/- 18 pg/mL, p < 0.01), and at extubation (122 +/- 18 pg/mL compared with 36 +/- 7 pg/mL, p < 0.01). Serum glucose levels were greater immediately following laparoscopic cholecystectomy. Glucose and insulin levels were greater at four, 12, and 24 hours after open cholecystectomy. CONCLUSIONS: Elective laparoscopic and open cholecystectomy for uncomplicated cholelithiasis result in similar degrees of perioperative hormonal stimulation. The different hormonal responses in the immediate and later postoperative periods after laparoscopic and open cholecystectomy suggest differential stressful stimuli between the two procedures.