[Effect of Wei's triple nine needling on eye regulation in patients with presbyopia complicated with visual fatigue of liver depression and spleen deficiency].

OBJECTIVE: To compare the clinical efficacy between Wei's triple nine needling combined with esculin and digitalis glycosides eye drops and esculin and digitalis glycosides eye drops alone for presbyopia complicated with visual fatigue of liver depression and spleen deficiency. METHODS: Forty-six cases (92 eyes) with presbyopia complicated with visual fatigue of liver depression and spleen deficiency were randomly divided into an observation group (23 cases) and a control group (23 cases, 2 cases dropped off). The cases in the observation group were treated with Wei's triple nine needling and esculin and digitalis glycosides eye drops. The acupoints included Shangming (Extra), Chengqi (ST 1), Cuanzhu (BL 2) to Jingming (BL 1), Sizhukong (TE 23) to Taiyang (EX-HN 5), etc; the needling was given once every other day, three times a week, and the eye drops were given one drop each time, three times a day. The cases in the control group were only treated with the eye drops. Both groups were treated for 7 days as one course of treatment, and 2 courses of treatment were given. The visual fatigue core symptoms score, adjustment amplitude, adjustment lag and best average corrected visual acuity were observed in the two groups before treatment, 1 week and 2 weeks into treatment, respectively. RESULTS: Compared before treatment, the visual fatigue core symptoms scores in the two groups were decreased after 1-week and 2-week treatment (P<0.05); in the observation group, the adjustment amplitude was increased after 2-week treatment (P<0.05), while in the control group, the adjustment amplitude was increased after 1-week and 2-week treatment (P<0.05); in the observation group, the adjustment lag was decreased after 1-week and 2-week treatment (P<0.05). After 2-week treatment, the visual fatigue core symptoms score in the observation group was lower than that in the control group, and the adjustment amplitude was higher than that in the control group (P<0.05). There were no significant differences in adjustment lag and best average corrected visual acuity between the two groups after 1-week and 2-week treatment (P>0.05). CONCLUSION: Wei's triple nine needling combined with esculin and digitalis glycosides eye drops could improve the visual fatigue and eye regulation ability in patients with presbyopia complicated with visual fatigue of liver depression and spleen deficiency, and the effect is better than esculin and digitalis glycosides eye drops alone.

An investigation into the effects of ocular nebulization combined with meibomian gland massage on ocular surface status and corneal higher-order aberrations for the treatment of meibomian gland dysfunction.

PURPOSE: To evaluate ocular surface status and corneal higher-order aberrations after a new ocular nebulization therapy combined with meibomian gland massage for the treatment of meibomian gland dysfunction (MGD). PATIENTS AND METHODS: This prospective randomized study involved 38 patients diagnosed with MGD. Subjects were classified into two groups: the nebulization and meibomian gland massage group (or NB group, 14 patients, 28 eyes) and the eye drop group (or ED group, 24 patients, 48 eyes). Azithromycin solution and esculin and digitalis glycoside eye drops were tested in the therapy. Best-corrected visual acuity (BCVA) testing; noncontact tonometry; fundoscopy; the Ocular Surface Disease Index (OSDI) questionnaire; tear film assessment encompassing tear meniscus height (TMH) and non-invasive keratograph breakup time (NIKBUT); corneal fluorescein staining; the Schirmer I test (SIT); and anterior, posterior and total corneal aberrations were evaluated at 1 and 3 months after treatment. RESULTS: At 3 months, the NB group showed significantly better improvement than the ED group in terms of TMH (0.23 ± 0.04 versus 0.19 ± 0.05, p = 0.002) and first breakup time (f-BUT; 7.42 ± 2.49 versus 5.53 ± 2.12, p = 0.001). The average breakup time (Av-BUT) of the NB group was significantly longer than that of the ED group at 1 month (9.52 ± 2.70 versus 8.02 ± 2.33, p = 0.013) and 3 months (5.53 ± 2.12 versus 8.35 ± 2.38, p = 0.018). Both groups achieved improvement in corneal fluorescein staining (CFS) and SIT results at 1 and 3 months (p < 0.05). At the 3-month follow-up, anterior corneal trefoil aberrations decreased significantly in the NB group (p = 0.008), and improvements in anterior corneal coma aberrations and posterior corneal higher-order aberrations (HOAs) were observed in the ED group (p < 0.05) over the 4 mm pupil zone. Over a 6 mm zone at 3 months, anterior, posterior and total trefoil aberrations as well as total HOAs were significantly decreased in the NB group (p < 0.05), while posterior HOAs and trefoil aberrations were found to be decreased in the ED group (p < 0.05). For individual Zernike terms, anterior and total corneal Z(3, -3) showed decreases over the 4 and 6 mm zones, while no improvement was detected in the NB group at 3 months. CONCLUSION: In terms of comfort and visual quality, nebulization therapy combined with meibomian gland massage to deliver azithromycin solution and esculin and digitalis glycoside eye drops appears to be more effective in treating clinical symptoms and signs of MGD than simply applying esculin and digitalis glycoside eye drops.

Foxglove poisoning: diagnostic and therapeutic differences with medicinal digitalis glycosides overdose.

We report a case of a 19-year-old woman who ingested Digitalis purpurea leaves as a suicide attempt. She developed gastro-intestinal symptoms, loss of colour vision, cardiac conduction disturbances as well as an elevated serum potassium. Treatment was initiated in analogy to medicinal digoxin poisoning by means of digoxin-specific Fab-fragments with a good effect. However during the further course we faced difficulties of prolonged intestinal absorption and inability to estimate the ingested dose or half-life of the vegetal cardiac glycoside compounds. To prevent further absorption and interrupt enterohepatic recycling, multi-dose activated charcoal was administered. Because of a relapse of cardiac conduction disturbances and hyperkalemia, two supplementary doses of Fab-fragments were given, up to a total dose of nineteen vials (one vial containing 40 mg). The important diagnostic and therapeutic differences of vegetal digitalis intoxication as compared to medicinal intoxication and the applicability of existing guidelines on medicinal digitalis intoxication in the light of these differences will be discussed here.

Effect of Wei's triple nine needling on eye regulation in patients with presbyopia complicated with visual fatigue of liver depression and spleen deficiency / 中国针灸

OBJECTIVE@#To compare the clinical efficacy between Wei's triple nine needling combined with esculin and digitalis glycosides eye drops and esculin and digitalis glycosides eye drops alone for presbyopia complicated with visual fatigue of liver depression and spleen deficiency.@*METHODS@#Forty-six cases (92 eyes) with presbyopia complicated with visual fatigue of liver depression and spleen deficiency were randomly divided into an observation group (23 cases) and a control group (23 cases, 2 cases dropped off). The cases in the observation group were treated with Wei's triple nine needling and esculin and digitalis glycosides eye drops. The acupoints included Shangming (Extra), Chengqi (ST 1), Cuanzhu (BL 2) to Jingming (BL 1), Sizhukong (TE 23) to Taiyang (EX-HN 5), etc; the needling was given once every other day, three times a week, and the eye drops were given one drop each time, three times a day. The cases in the control group were only treated with the eye drops. Both groups were treated for 7 days as one course of treatment, and 2 courses of treatment were given. The visual fatigue core symptoms score, adjustment amplitude, adjustment lag and best average corrected visual acuity were observed in the two groups before treatment, 1 week and 2 weeks into treatment, respectively.@*RESULTS@#Compared before treatment, the visual fatigue core symptoms scores in the two groups were decreased after 1-week and 2-week treatment (P<0.05); in the observation group, the adjustment amplitude was increased after 2-week treatment (P<0.05), while in the control group, the adjustment amplitude was increased after 1-week and 2-week treatment (P<0.05); in the observation group, the adjustment lag was decreased after 1-week and 2-week treatment (P<0.05). After 2-week treatment, the visual fatigue core symptoms score in the observation group was lower than that in the control group, and the adjustment amplitude was higher than that in the control group (P<0.05). There were no significant differences in adjustment lag and best average corrected visual acuity between the two groups after 1-week and 2-week treatment (P>0.05).@*CONCLUSION@#Wei's triple nine needling combined with esculin and digitalis glycosides eye drops could improve the visual fatigue and eye regulation ability in patients with presbyopia complicated with visual fatigue of liver depression and spleen deficiency, and the effect is better than esculin and digitalis glycosides eye drops alone.

Profiling and structural analysis of cardenolides in two species of Digitalis using liquid chromatography coupled with high-resolution mass spectrometry.

Plants of the Digitalis genus contain a cocktail of cardenolides commonly prescribed to treat heart failure. Cardenolides in Digitalis extracts have been conventionally quantified by high-performance liquid chromatography yet the lack of structural information compounded with possible co-eluents renders this method insufficient for analyzing cardenolides in plants. The goal of this work is to structurally characterize cardiac glycosides in fresh-leaf extracts using liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) that provides measured accurate mass. Fragmentation of cardenolides is featured by sequential loss of sugar units while the steroid aglycone moieties undergo stepwise elimination of hydroxyl groups, which distinguishes different aglycones. Using a reverse-phase LC column, the sequence of elution follows: diginatigenin→digoxigenin→gitoxigenin→gitaloxigenin→digitoxigenin for cardenolides with the same sugar units but different aglycones. A linear range of 0.8-500 ng ml-1 has been achieved for digoxigenin, ß-acetyldigoxin, and digitoxigenin with limits of detection ranging from 0.09 to 0.45 ngml-1. A total of seventeen cardenolides have been detected with lanatoside A, C, and E as major cardenolides in Digitalis lanata while seven have been found in Digitalis purpurea including purpurea glycoside A, B, and E. Surprisingly, glucodigifucoside in D. lanata and verodoxin and digitoxigenin fucoside in D. purpurea have also been found as major cardenolides. As the first MS/MS-based method developed for analyzing cardenolides in plant extracts, this method serves as a foundation for complete identification and accurate quantification of cardiac glycosides, a necessary step towards understanding the biosynthesis of cardenolide in plants.

Clinical Use of Digitalis: A State of the Art Review.

The history of digitalis is rich and interesting, with the first use usually attributed to William Withering and his study on the foxglove published in 1785. However, some knowledge of plants with digitalis-like effects used for congestive heart failure (CHF) was in evidence as early as Roman times. The active components of the foxglove (Digitalis purpurea and Digitalis lanata) are classified as cardiac glycosides or cardiotonic steroids and include the well-known digitalis leaf, digitoxin, and digoxin; ouabain is a rapid-acting glycoside usually obtained from Strophanthus gratus. These drugs are potent inhibitors of cellular membrane sodium-potassium adenosine triphosphatase (Na+/K+-ATPase). For most of the twentieth century, digitalis and its derivatives, especially digoxin, were the available standard of care for CHF. However, as the century closed, many doubts, especially regarding safety, were raised about their use as other treatments for CHF, such as decreasing the preload of the left ventricle, were developed. Careful attention is needed to maintain the serum digoxin level at ≤ 1.0 ng/ml because of the very narrow therapeutic window of the medication. Evidence for benefit exists for CHF with reduced ejection fraction (EF), also referred to as heart failure with reduced EF (HFrEF), especially when considering the combination of mortality, morbidity, and decreased hospitalizations. However, the major support for using digoxin is in atrial fibrillation (AF) with a rapid ventricular response when a rate control approach is planned. The strongest support of all for digoxin is for its use in rate control in AF in the presence of a marginal blood pressure, since all other rate control medications contribute to additional hypotension. In summary, these days, digoxin appears to be of most use in HFrEF and in AF with rapid ventricular response for rate control, especially when associated with hypotension. The valuable history of the foxglove continues; it has been modified but not relegated to the garden or the medical history book, as some would advocate.

The problem of misidentification between edible and poisonous wild plants: Reports from the Mediterranean area.

Today, in many European countries, people are looking for wild edible plants to experience new tastes and flavors, by following the new trend of being green and environmentally friendly. Young borage and spinach leaves can be easily confused by inexpert pickers with those of other plants, including poisonous ones, such as Mandragora autumnalis Bertol. (mandrake) or Digitalis purpurea L. (foxglove), common in southern and northern Italy respectively. In the last twenty years, several cases of intoxication by accidental ingestion of mandrake and foxglove have been reported. The purpose of this work was to perform a pharmacognostic characterization of young leaves from borage, mandrake, foxglove and spinach, by micro-morphological, molecular and phytochemical techniques. The results showed that each of the three techniques investigated could be sufficient alone to provide useful information for the identification of poisonous species helping the medical staff to manage quickly the poisoned patients. However, the multi-disciplinary approach proposed could be very useful to asses the presence of poisonous plants in complex matrices, to build a database containing morphological, molecular and phytochemical data for the identification of poisonous species or in forensic toxicology, given their increasingly frequent use due to their low cost and relatively common availability.

[New pharmacologic therapies for chronic heart failure]. / Neue medikamentöse Therapieansätze bei chronischer Herzinsuffizienz.

Heart failure is a disease with a high prevalence and incidence. New therapeutic approaches are needed to prevent the onset of heart failure and to reduce the high morbidity and mortality associated with this disease. An optimized therapy of arterial hypertension in patients with risk factors and the use of the SGLT2 inhibitor empagliflozin in type 2 diabetics are proven strategies to prevent heart failure. The therapeutic options in heart failure with preserved ejection fraction are still insufficient. In heart failure with reduced ejection fraction sacubitril/valsartan, the first approved angiotensin receptor-neprilysin inhibitor, is superior to an angiotensin converting enzyme (ACE) inhibitor. Whether digitalis affects the prognosis in heart failure remains unclear; however, serum concentration should be targeted at the lower therapeutic range. Iron supplementation in heart failure with reduced systolic function and iron deficiency improves symptoms and quality of life.

New cardenolide glycosides from the seeds of Digitalis purpurea and their cytotoxic activity.

A chemical investigation of Digitalis purpurea seeds led to the isolation of three new cardenolide glycosides (1, 8 and 11), together with 12 known cardenolide glycosides (2-7, 9, 10 and 12-15). The structures of 1, 8 and 11 were determined by 1D and 2D NMR spectroscopic analyses and the results of an acid or enzymatic hydrolysis. The cytotoxic activity of the isolated compounds (1-15) against HL-60 leukemia cells was examined. Compounds 2, 9, 11 and 12 showed potent cytotoxicity against HL-60 cells with respective 50% inhibition concentration (IC50) values of 0.060, 0.069, 0.038, and 0.034 µM. Compounds 2, 9 and 11 also exhibited potent cytotoxic activity against HepG2 human liver cancer cells with respective IC50 values of 0.38, 0.79, and 0.71 µM. An investigation of the structure-activity relationship showed that the cytotoxic activity was reduced by the introduction of a hydroxy group at C-16 of the digitoxigenin aglycone, methylation of the C-3' hydroxy group at the fucopyranosyl moiety, and acetylation of the C-3' hydroxy group at the digitoxopyranoyl moiety.

[Drug-induced magnesium deficiency]. / Magnesium-Mangel und Arzneimittel.

A lot of drugs can induce hypomagnesemia as side effect. On the other hand, magnesium deficiency may be a risk factor for digitalis and drugs known to prolong the QT-interval and thus favour the development of torsades-de-pointes tachycardias. Controversely, the indication for most oral magnesium supplements in Germany is: proven magnesium deficiency if this is the cause for muscular troubles (neuromuscular disturbances, calf cramps). Due to this cutback magnesium attracts poor attention in clinical practice and the determination of serum magnesium concentrations is seldom ordered. Moreover, the lower level of the reference range for serum magnesium is often kept too low. As a consequence hypomagnesemia as side effect remains frequently undetected.

Cardiovascular effects, pharmacokinetics and cross-reactivity in digitalis glycoside immunoassays of an antidiarrheal uzara root extract.

Uzara glycosides (UG) extracted from Xysmalobium undulatum are used for treating non-specific diarrhea.Cross-reactivity has been described for UG in digitalis glycoside assays but digitalis-like cardiac effects are controversially discussed. Therefore, we performed a randomized, singleblind cross-over study in 18 healthy volunteers receiving a commercially available Uzara product (Uzara® Lösung N, Stada AG, Bad Vilbel, Germany (ULN)), digoxin (1 mg, i.v., positive control) and placebo in double-dummy technique. Pharmacodynamic effects were quantified by means of ECG and impedance cardiography (ICG). After oral administration of ULN, main metabolites were determined using HPLC-MS/MS and digitalis-like serum levels (DLSL) were measured in two digitoxin and digoxin assays, respectively. In comparison to placebo, ULN did not change significantly any PD parameters whereas digoxin altered significantly area under the effect curve of several ECG and ICG parameters, respectively. Since some serum levels of three ULN ingredients (uzarin, uzarigenin and xysmalorin) were below LLQ, PK analyses could only be performed for allouzarigenin and revealed a marked inter-individual variability. Therefore, median values (min; max) were calculated as follows: Cmax = 0.39 (0.15; 1.81) ng/ml, tmax = 7.0 (3.0; 36.0) h, T1/2 = 5.2 (0.8; 23.6) h, AUC0-36h = 4.2 (0.8; 11.1) ng/ml×h, AUC0-∞ = 5.8 (1.8; 13.1) ng/ml×h. DLSL reached Cmax of 28 ng/ml and 1,980 ng/ml for digoxin and digitoxin, respectively. We could not observe significant cardiovascular pharmacodynamic effects after oral administration of the recommended single dose of Uzara extract to healthy volunteers. However, considerable DLSL could be detected, proving cross-reactivity of uzara components with the conventional digitalis assays used. However, none of the metabolites we had suspected to be the cause for the crossreactivity could be identified in reasonable quantities.

[Considerations about study on mechanisms of acupuncture underlying efficacy-enhancement and toxicity-attenuation of digitalis drugs for heart failure].

Digitalis glycosides, a group of cardiotonic agents for heart failure, have been used for a long time, but may often trigger arrhythmias as a result of digitalis intoxication. It is of great significance in finding a method to reduce their toxicity and improve clinical curative effects simultaneously in the application of digitalis glycosides. It has been well documented that acupuncture has good therapeutic effects in improving cardiac function and inhibiting arrhythmia induced by myocardial ischemia. Acupuncture combined with chemotherapeutics can reduce the adverse effects of chemotherapeutics. Accordingly, acupuncture combined with digitalis is likely to reduce the side effects of digitalis by regulating intracellular Ca2+, improving the function of Ca(2+)-ATPase in the sarcoplasmic reticulum, increasing calcium sensitivity of cardiac troponin, etc. These considerations may provide a novel clue for treatment of heart failure by joint administration of acupuncture and drugs.

A fond farewell to the foxglove? The decline in the use of digitalis.

Since William Withering's report on the foxglove in 1785, digitalis, in 1 form or another, has remained a mainstay in the treatment of congestive heart failure and as a means of rate control in atrial fibrillation. Recently, with the introduction of potent diuretics and other agents for the treatment of these conditions, there has been a deemphasis on the role of digitalis despite its therapeutic value. Continued evidence of the frequent usefulness of digitalis in both conditions suggests that this venerable drug should remain within the therapeutic armamentarium of cardiologists and other physicians.

[The clinical efficacy and safety study of Esculin and Digitalis glycosides Eye Drops in treating ametropic asthenopia].

OBJECTIVE: To study the clinical efficacy and safety of the Esculin and Digitalis glycosides Eye Drops used in the patients of ametropic asthenopia. METHODS: Multicenter clinical trial. Asthenopia patients were chosen from eleven hospitals cross China from July, 2008 to January, 2009. The experiment was conducted asthenopia patients who used the Esculin and Digitalis glycosides Eye Drops for 4 weeks continuously. Symptoms of asthenopia, UCVA (uncorrected vision acuity), refraction, amplitude of accommodation, accommodative lag, accommodative sensitivity and positive/negative relative accommodation were measured at different time points, such as treated before, 1 week and 4 week in treated after. RESULTS: After the 4-week's use of Esculin and Digitalis glycosides Eye Drops, each subjective symptom of the patients was decreased significantly (F=353.30, P<0.05). In addition, most of the objective exams of accommodation ability were significantly improved, such as UCVA (left eye: F=23.39, P<0.05; right eye: F=15.62, P<0.05), refraction (left eye: F=10.34, P<0.05; right eye: F=17.13, P<0.05), amplitude of accommodation (left eye: F=14.46, P<0.05; right eye: F=8.29, P<0.05; eyes: F=13.86, P<0.05), accommodative lag (F=14.89, P<0.05) and accommodative sensitivity (left eye: F=62.67, P<0.05; right eye: F=68.77, P<0.05; eyes: F=82.74, P<0.05). And no patient appeared any adverse reaction in whole experiment. CONCLUSIONS: Esculin and Digitalis glycosides Eye Drops is effective and safety for use in the patients of ametropia asthenopia.

Digitalis, a targeted therapy for cancer?

The clinical benefit of digitalis for patients with heart disease is well established. However, recent studies have also suggested that digitalis has antineoplastic activities at clinically relevant serum concentrations. Much of the early evidence supporting the anticancer activity of digitalis has been circumstantial. Observational studies suggest a protective benefit and improved outcomes in patients who develop cancer while they are taking digitalis. The mechanism by which digitalis selectively affects the growth of malignant cells is complex, involving several important signaling pathways. Experiments to determine its mechanism of action have demonstrated that digitalis inhibits cell growth and angiogenesis and induces apoptosis in multiple cancer cell lines. Most, if not all, of these effects are mediated through its target enzyme, sodium- and potassium-activated adenosine triphosphatase. This article reviews the literature, which supports the use of digitalis in patients with malignancies with a discussion of the potential mechanisms of action. We hypothesize that sodium- and potassium-activated adenosine triphosphatase is an important new target for cancer therapy. It is reasonable to expect that the addition of digitalis to current cancer treatments will improve the clinical outcomes.

Digitalis: a dangerous drug in atrial fibrillation? An analysis of the SPORTIF III and V data.

OBJECTIVE: In heart failure, digitalis increases exercise capacity and reduces morbidity, but has no effect on survival. This raises the suspicion that the inotropic benefits of digitalis may be counteracted by serious adverse effects. Patients with atrial fibrillation (AF) were studied to clarify this. DESIGN: In the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF) III and V studies, 7329 patients with AF at moderate-to-high risk were randomised to preventive treatment of thromboembolism, either with warfarin or the oral direct thrombin inhibitor ximelagatran. The survival of users and non-users of digitalis was investigated. RESULTS: At baseline, 53.4% of the study population used digitalis, and these patients had a higher mortality than non-users (255/3911 (6.5%) vs 141/3418 (4.1%), p<0.001; hazard ratio (HR) = 1.58 (95% CI 1.29 to 1.94)). Digitalis users also had more baseline risk factors. After multivariate risk factor adjustment, the increased mortality persisted (p<0.001; HR = 1.53 (95% CI 1.22 to 1.92 vs 1.23 to 1.92)). CONCLUSIONS: The results suggest that digitalis, like other inotropic drugs, may increase mortality. This may be concealed in heart failure, but be revealed in patients with AF, who need the rate-reducing effect of digitalis, but do not benefit much from an increased inotropy. Cautious interpretation of the data is mandatory since the patients were not randomised with respect to digitalis use.