Bernhard Uehleke

Pharmacokinetics and bioavailability of quercetin glycosides in humans

Due to its potentially beneficial impact on human health, the polyphenol quercetin has come into the focus of medicinal interest. However, data on the bioavailability of quercetin after oral intake are scarce and contradictory. Previous investigations indicate that the disposition of quercetin may depend on the sugar moiety of the glycoside or the plant matrix. To determine the influence of the sugar moiety or matrix on the absorption of quercetin, two isolated quercetin glycosides and two plant extracts were administered to 12 healthy volunteers in a four‐way crossover study. Each subject received an onion supplement or quercetin‐4′‐O‐glucoside (both equivalent to 100 mg quercetin), as well as quercetin‐3‐O‐rutinoside and buckwheat tea (both equivalent to 200 mg quercetin). Samples were analyzed by HPLC with a 12‐channel coulometric array detector. In human plasma, only quercetin glucuronides, but no free quercetin, could be detected. There was no significant difference in the bioavailabilityand pharmacokinetic parameters between the onion supplement and quercetin‐4′‐O‐glucoside. Peak plasma concentrations were 2.3 ± 1.5 μg•mL−1 and 2.1 ± 1.6 μg•mL−1 (mean ± SDJ and were reached after 0.7 ± 0.2 hours and 0.7 ± 0.3 hours, respectively. After administration of buckwheat tea and rutin, however, peak plasma levels were—despite the higher dose—only 0.6 ± 0.7 μg•mL−1 and 0.3 ± 0.3 μg•mL−1, respectively. Peak concentrations were reached 4.3 ± 1.8 hours after administration of buckwheat tea and 7.0 ± 2.9 hours after ingestion of rutin. The terminal elimination half‐life was about 11 hours for all treatments. Thus, the disposition of quercetin in humans primarily depends on the sugar moiety. To a minor extent, the plant matrix influences both the rate and extent of absorption in the case of buckwheat tea administration compared with the isolated compound. The site of absorption seems to be different for quercetin‐4′‐O‐glucoside and quercetin‐3‐O‐rutinoside. The significance of specific carriers on the absorption of quercetin glycosides, as well as specific intestinal b‐glucosidases, needs to be further evaluated.

Hyperforin content determines the magnitude of the St John's wort-cyclosporine drug interaction.

Hyperforin (HYF) has been discussed as a potential cause of the reduction in the bioavailability of numerous drugs seen with St Johns wort (SJW) comedication. This study compared the effects of 2 SJW preparations with high and low HYF content on the pharmacokinetics of cyclosporine (INN, ciclosporin) (CSA).

Effect of St John's Wort Dose and Preparations on the Pharmacokinetics of Digoxin

St Johns wort preparations vary in composition, main constituents, formulation, and daily dose administered. The aim of the study was to evaluate the possible pharmacokinetic interaction of marketed St Johns wort formulations and doses with digoxin.

Phase II trial on the effects of Silexan in patients with neurasthenia, post-traumatic stress disorder or somatization disorder.

Silexan, a novel lavender oil preparation for oral use, has been authorized in Germany for the treatment of states of restlessness during anxious mood. An open-label, exploratory trial was performed to assess the potential of the medicinal product in the treatment of restlessness caused by anxiety as related to several disorders. Outcome measures included the Symptom Checklist-90-Revised (SCL-90-R), von Zerssens Depression Scale (D-S), the 36-item Short Form Health Survey Questionnaire (SF-36), and a sleep diary. 50 male and female patients with neurasthenia (ICD-10 F48.0), post-traumatic stress disorder (PSD; F43.1), or somatization disorder (F45.0, F45.1) were included to receive 1 × 80 mg/day Silexan over 6 weeks; 47 could be analyzed for efficacy as full analysis set. At baseline, patients suffered from restlessness (96%), depressed mood (98%), sleep disturbances (92%), or anxiety (72%). Of those, resp. 62%, resp. 57%, resp.51%, resp. 62% showed improvements during treatment (p < 0.001). For all patients, mean D-S score decreased by 32.7% and SCL-90-R Global Severity Index by 36.4% as compared to baseline, (p < 0.001), while the SF-36 Mental Health Score increased by 48.2% (p < 0.001). Waking-up frequency (p = 0.002), Waking-up duration (p < 0.001) and morning tiredness (p = 0.005) were reduced, while efficiency of sleep (p = 0.018) and mood (p = 0.03) improved. Patients suffering from neurasthenia or PSD showed comparable improvements with most outcomes. The results in this trial justify to further investigate Silexan in disorders with accompanying restlessness caused by sub-threshold anxiety. Adverse reactions, predominantly gastrointestinal complaints, were judged as mild or moderate.

Randomised controlled trial with medical leeches for osteoarthritis of the knee

OBJECTIVES To evaluate the possible efficacy of medical leeches (Hirudo medicinalis) in the treatment of patients with active osteoarthritis of the knee. DESIGN Unblinded, randomised controlled trial with outpatients in a crossover design with single interventions of either leeches or transcutaneous electrical nerve stimulation (TENS) as comparator. MAIN OUTCOME MEASURES Change in Lequesnes combined index for pain and function and change (L.I.) and overall assessment of complaints by visual analog scale (VAS). Cross-over at day 42, with further observation period of 21 days. RESULTS 52 out of 72 screened patients were randomised (intent to treat) to initial treatment with either eight leeches (group 1: 27 patients) or TENS (group 2: 25 patients). Due to phase effects, confirmatory evaluation had to be restricted to the first period. Between days 0 and 21, we observed highly significant (p<0.001) improvements for means of Lequesnes index from 12.07 to 9.37 and for VAS from 5.89 to 4.16 cm for leeches, but no significant differences for TENS. Effect size as group difference was -2.50 for L.I. (95% confidence interval -3.88 to -1.11), resp. -1.86 cm for VAS (95% confidence interval -2.85 to -0.87 cm). 12 patients (5 group 1, 7 group 2) did not finish the trial, mostly due to non-compliance (6). No serious adverse effects were observed. CONCLUSIONS Single leech therapy showed significant, relevant and sustaining effects, comparable to other trials with leeches. The method deserves further research, esp. into mechanisms of possible specific effects and optimization of dosing by number of leeches and possible repeats.

Cholesterol reduction using psyllium husks – Do gastrointestinal adverse effects limit compliance? Results of a specific observational study

PURPOSE Despite known cholesterol lowering effects the use of psyllium husk (Plantaginis ovatae testa) in Germany for hypercholesterolemia is limited compared to their use as a laxative. To investigate whether use in hypercholesterolemia is limited due to adverse effects on the gastrointestinal system, a prospective observational study was conducted. METHODS Sixty-two outpatients with documented hypercholesterolemia and complaints of constipation were identified from an academic clinical center. Treatment with 3.5g psyllium husk preparation administered three times daily was initiated and patients were monitored at weekly intervals. Gastrointestinal symptoms were quantified using a validated Nepean Dyspepsia Index modified to identify both upper and lower abdominal symptoms. Diaries and study medication records were used to evaluate compliance. RESULTS Fifty-four of 62 patients enrolled in the study completed the study protocol with 4 subjects discontinuing due to adverse reactions associated with psyllium husks. Total cholesterol was significantly decreased from 252+/-39mg/dl before treatment to 239+/-37mg/dl after 3 weeks of treatment. Similarly, low density lipoprotein (LDL)-cholesterol decreased from 174+/-34 to 162+/-31mg/dl during the study. Triglycerides and high density lipoprotein (HDL) were unchanged. Gastrointestinal symptoms were rated lower at the end than at the beginning of the study. In week 1 most of the patients reported gastrointestinal symptoms and also gastrointestinal adverse reactions, which however, showed a decrease from week 1 to weeks 2 and 3 in the diaries. Patient response to study medication was positive for patients completing the study. CONCLUSIONS Psyllium husk preparations may be a therapeutic option for patients with mild to moderately elevated cholesterol levels. Adverse gastrointestinal symptoms associated with the preparation appear to be transient in some of the patients. Compliance may be optimized with adequate patient counseling.

Therapeutic Fasting in Patients with Metabolic Syndrome and Impaired Insulin Resistance

Background: In this study, we evaluated whether a short- to mid-term fasting therapy (7-18 days) might improve insulin resistance according to the homeostasis model assessment for insulin resistance (HOMA-IR), measured during mid-term (80 days) follow-up observation in patients with metabolic syndrome. Methods: In this open label observational study in inpatients, criteria of metabolic syndrome were defined. Before medically controlled Buchinger fasting, a wash-out period for hypoglycemic agents was conducted. Further evaluation was carried out on day 80. Results: 25 patients (13 males, 12 females, mean age 61.3 years) were included in this study (mean fasting duration 11.5 days). Out of 16 inpatients with type 2 diabetes, 4 had been treated with metformin, 3 with insulin, and 1 with glimepiride before the intervention. After therapy, body mass index (BMI), fasting insulin, fasting glucose, and HOMA-IR were all significantly reduced. Compared to baseline, HOMA-IR decreased by 33% in all patients, by 38% in patients with type 2 diabetes, and by 23% in patients without diabetes. At day 80, BMI further improved, while other parameters showed complete (insulin) or partial (glucose, HOMA-IR) rebound. At this time, HOMA-IR values showed an only insignificant improvement in 15% of all patients, in 20% of patients with type 2 diabetes, and in 6% of patients without diabetes. There was no correlation between change in BMI and change in HOMA-IR (r2 = 0.008, baseline minus day 80). No serious side effects were observed. Conclusions: Fasting as a safe and acceptable procedure may cause short- and mid-term improvement of increased insulin resistance (HOMA-IR). Patients with type 2 diabetes benefit more than those without diabetes. A possible clinical significance of this effect should be explored in larger and controlled clinical trials.

Assoziationen zwischen chronischer Tonsillenreizung, Verquellungen von Bindegewebszonen und einer Brachialgia paraesthetica nocturna

Projective and reflex zones of inner organs to the body’s surface are well described but there are only few clinical studies about abnormal zones. Objective: The aim of our study was to investigate associations between chronic irritation of tonsils, abnormalities of the connective tissue areas over the musculus trapezius and the severity of brachialgia paresthetica nocturna. Methods: Cross sectional study in 100 adult pain patients from an outpatient pain department. Patients with tonsillectomy were excluded. Examinations of tonsils and the connective tissue area were done separately by two mutually blinded physicians. Both were also blinded to the patients’ evaluation of his/her brachialgia. Results: Regardless of the lateralization, the severity of the tonsil irritations was correlated with the abnormalities of the connective tissue areas (Spearman’s ρ = 0.82; 95% confidence interval (CI): 0.74-0.87; p < 0.001) and the severity of the brachialgia (ρ = 0.64, CI: 0.50-0.74; p < 0.001), furthermore indurations of connective tissue areas correlated with the severity of brachialgia homolaterally (ρ = 0.57; CI: 0.42-0.69; p < 0.001). These correlations are considerably higher than those of other connective tissue areas. Conclusions: The results support the existence of easy to diagnose reflex zones, at least in a highly selected population of pain patients. They can give plausible hints for naturopathic treatments of brachialgia paresthetica nocturna, i.e. treatment of the relevant connective tissue zone above the M. trapezius.

Naturheilverfahren und «Traditionelle Europäische Medizin» TEM: Ergebnisse einer Experten-Umfrage (Delphi-Methode)

Hintergrund: Der Begriff ‘Traditionelle EuropÄische Medizin TEM’ wird in Fachkreisen immer hÄufiger verwendet, ohne dass eine klare Begriffs-Definition vorliegt. Zielsetzung: Einordnung derjenigen Naturheilverfahren bzw. Alternativer Heilverfahren, welche als Teil der “Traditionellen EuropÄischen Medizin (TEM)” betrachtet werden. Design: Zwei-stufiger Fragebogen mit zweimaliger Auswertung (Delphi-Methode), anonym mit Ausnahme des Auswerters. Teilnehmer: Ein Expertenpanel mit 19 akademischen Fachleuten der Naturheilkunde und 5 Fachleuten der Medizingeschichte/Naturheilkunde erhielt den ersten Fragebogen. 15 Experten der Naturheilkunde and 4 Experten der Medizingeschichte beantworteten den Fragebogen und erhielten die Auswertung zusammen mit dem 2. Fragebogen. Intervention: Der erste Fragebogen enthielt 20 Fragen einschliesslich Kontrollfragen zu Charakteristika und Beziehungen von alternativen Heilmethoden zur Naturheilkunde bzw. TEM. Diese konnten mit ‘Ja’ oder ‘Nein’ oder ‘je nachdem’ beantwortet werden; bei letzterem wurde um freitextliche ErklÄrung gebeten. In der 2. Stufe wurde ein Vorschlag zur Definition, Inhalt und Argumentation der TEM vorgestellt zur Beurteilung und Kommentierung. Zielparameter: Meinung der Experten zu Charakterisierung und Klassifikation von Naturheilverfahren und Alternativverfahren in Bezug auf Naturheilkunde und TEM. Ergebnisse und Schlussfolgerungen: Eine klare Mehrheit empfiehlt TEM als definiertes medizinisches System mit eigener geschichts-basierter Philosophie zu entwickeln und zu definieren. Mehrere Experten betonten, dass TEM einen besseren Bezug zur Geschichte bekommen sollte. Eine Mehrheit sieht Balneotherapie, Hydrotherapie, ErnÄhrungstherapie, Bewegung, Massage und Phytotherapie als Inhalte der TEM, hingegen HomÖopathie und Elektrotherapie nicht. Im zweiten Teil sind viele individuelle VerbesserungsvorschlÄge zur vorgeschlagenen Definition und Charakteristik von TEM ein Grund, mit dem Konsensusprozess fortzufahren, wobei ein persÖnliches Treffen intensive Diskussionen erlauben wird.

Beeinflusst Knoblauch die Blutfliesseigenschaften und die Durchblutung bei progressiver systemischer Sklerose

According to traditional European naturopathy garlic is an agent that increases perfusion. In studies with healthy subjects and in-vitro research garlic has shown influences on erythrocyte and thrombocyte aggregation as well as on vasoregulation. However, data on its effects in clinical populations are still lacking. Garlic may be useful for systemic sclerosis which is characterised by impaired perfusion that often cannot sufficiently be influenced by standard treatment. We investigated if dried garlic powder can influence rheologic properties and vasomotor function in systemic sclerosis. Subjects and Methods: During a randomised, double blind pilot study, 20 female inpatients with systemic sclerosis received a 7 day add-on therapy with either 900 mg dried garlic powder or placebo. Rheologic properties (erythrocyte aggregation, ADP-induced thromboycyte aggregation, plasma viscosity, fibrinogenous plasma level, blood sedimentation rate) were assessed initially as well as after 1 and 7 days of treatment. Vasomotor function was evaluated using near-infrared red photoplethysmography, a new diagnostic tool to assess microcirculation. Furthermore, acral skin temperature was measured. Results: After 7 days, only the verum treatment had induced a significant reduction of ADP-induced thrombocyte aggregation and a decrease in erythrocyte aggregation. Results showed no significant effects on vasomotor function, but an immediate effect of garlic on acral skin temperature. Discussion: According to the ‘Qualitätenlehre’ of traditional European naturopathy, garlic is classified as a ‘heating agent’. Our results suggest that the improvement of rheologic properties could be a possible biological correlate for this. Although further research is required, we conclude garlic could be a rational add-on therapy in the ‘Kältekrankheit’ (‘cold disease’) of systemic sclerosis.