A randomized trial of Korodin Herz-Kreislauf-Tropfen as add-on treatment in older patients with orthostatic hypotension.

In a randomized, double-blind, placebo-controlled, parallel group, phase III clinical trial efficacy and safety of Korodin, a combination of natural D-camphor and an extract from fresh crataegus berries, was investigated in patients 50 years and older with orthostatic hypotension. At visit 1 eligibility of patients was checked and a placebo medication was given to all patients. At visit 2 orthostatic hypotension had to be reconfirmed, then the patient was randomized either to Korodin or placebo, study medication (25 drops) was applied once and then outcome was measured. After 7 days of home treatment with daily 3 x 25 drops outcome was measured at visit 3. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were documented 10, 5, 2 and 0 min before as well as 1, 3, 5, 8, and 10 min after getting in the upright position at visit 1, at visit 2 before and after application of study medication and at visit 3. Primary outcome was the change of mean arterial blood pressure (MAP) from just before standing up to the nadir within the first 3 min after standing up. Secondary outcome variables were SBP, DBP, HR, quality of life (SF-12) and seven typical signs and symptoms of orthostatic hypotension. The study was performed in a rehabilitation clinic and in two doctor's practices in Germany from November 2002 to May 2003. During this time, 57 patients were admitted to the study, 39 patients were eligible and randomized, 38 patients were treated according to protocol and evaluated, 21 patients with Korodin and 17 patients with placebo. After a single application the median decrease of MAP was 11.4 mmHg for Korodin and 14.0 mmHg for placebo. Compared to baseline, the median MAP improved 4.3 mmHg for Korodin and 0.3 mmHg for placebo. After 1 week of treatment the decrease of median MAP after standing up was 9.3 mmHg for Korodin and 13.3 mmHg for placebo. Compared to baseline, the improvement was 5.9 mmHg for Korodin and 1.6 mmHg for placebo. Efficacy of 1 week treatment was significant. For the single application a superiority of Korodin over placebo was seen; however, it was not significant. All secondary outcome variables confirmed these findings, except for the physical summary score in the quality of life evaluation (SF-12 questionnaire). Only one adverse event occurred, but this was not serious and without relationship to the study medication. The other safety variables (SBP, DBP, HR, ECG, physical examination) did not show any problems. This study demonstrates that Korodin is efficacious for orthostatic hypotension in patients over 50 years.

Phase solubility studies of pure (-)-alpha-bisabolol and camomile essential oil with beta-cyclodextrin.

(-)-Alpha-bisabolol was found to form an inclusion complex with beta-cyclodextrin (beta-CD) in solution as well as in the solid state. To investigate molecular associations of beta-CD with pure (-)-alpha-bisabolol or (-)-alpha-bisabolol as a component of camomile essential oil, phase solubility studies were undertaken. A B(s) type solubility with an apparent complex constant of 273 M(-1) for the pure (-)-alpha-bisabolol and 304 M(-1) for (-)-alpha-bisabolol as a constituent of the essential oil were obtained. The two curves in the phase solubility diagram reach their plateau at different concentrations of (-)-alpha-bisabolol, 7.04 x 10(-4) M for the pure substance and 2.88 x 10(-4) M for the substance as a component of the essential oil. Although the shapes of the curves are almost similar, the intrinsic solubility's of pure (-)-alpha-bisabolol (4.85 x 10(-4) M) and (-)-alpha-bisabolol as a component of the essential oil (1.82 x 10(-4) M) differ significantly. An inclusion complex having a stoichiometric composition of 2:1 (beta-CD: drug) was obtained. A mechanism of complexation has been proposed on the basis of the stability constant calculated from phase solubility data and the stoichiometric ratio of the solid state complexation.

[Actions of standardized extracts of Crataegus berries on exercise tolerance and quality of life in patients with congestive heart failure]. / Wirksamkeit eines standardisierten Extraktes aus frischen Crataegus-Beeren auf Belastungstoleranz und Lebensqualität bei Patienten mit Herzinsuffizienz (NYHA II).

Standardized extracts of Crataegus leaves and blossoms are said to have positive inotropic, positive dromotropic and negative bathmotropic effects. Clinical trials produce evidence for an improvement of symptoms in patients with congestive heart failure (NYHA II). In this trial the efficacy of a standardized extract of fresh Crataegus berries (Rob 10) on exercise tolerance and quality of life was studied in 88 patients. In a three-month placebo-controlled, randomized, double-blind trial these patients were treated with Rob 10 (3 x 25 drops daily). Total exercise time in bicycle ergometry was defined as primary efficacy variable, while quality of life (Minnesota Questionnaire), Dyspnea-Fatigue Index and the assessment of dyspnea by the patient on a visual analogous scale were chosen as secondary parameters. Investigations were performed after a two week placebo run-in period as well as 6 and 12 weeks after the onset of the study. Treatment with Rob 10 led to a increase of exercise time of 38.9 s vs placebo (95% confidence interval 5.7-72.1 s). Quality of life improved accordingly in favour of Rob 10. In the Minnesota Questionnaire, the total score fell by 31% (30.6 vs 44.1) under Rob 10 vs 18% (34.6 vs 42.4) under placebo. The Dyspnea-Fatigue Index demonstrated an increase of the total score of 12% (9.41 vs 8.37) vs 8% (8.92 vs 8.26) under administration of placebo. According to findings of the assessment of dyspnea by the patient, dyspnea decreased by 11% (50.5 vs 56.6 mm) vs 4% (54.8 vs 57.3 mm) under placebo. The present study proves the efficacy and safety of a standardized extract of fresh Crataegus berries (Rob 10) in patients with congestive heart failure (NYHA II) regarding the parameters evaluated.

Absolute stereochemistry of guaianolides, of matricin and its epimers, of yarrow proazulenes, and of chamazulene carboxylic acid.

Known determinations of the absolute configuration of guaianolides were collected and found to be few. The absolute configurations of guaianolides rest on the assumption that 7-H always has alpha-orientation. For matricin, only the relative configuration was determined. On the basis of a detailed study of the NMR spectra of matricin and its epimers, and of synthetic, NMR, and CD studies with its decomposition product, chamazulene carboxylic acid, we were able to reconfirm the accepted 3S,3aR,4S,9R,9aS,9bS configuration of matricin.

On the absolute configuration of matricin.

The assignment of the absolute configuration of matricin rests on indirect evidence. On the basis of synthetic, NMR and CD studies with its decomposition product, chamazulene carboxylic acid, we were able to firmly establish the accepted 3S,3aR,4S,9R,9aS,9bS configuration of matricin.

Use of a serum-free medium for long-term storage of human corneas. Influence on endothelial cell density and corneal metabolism.

BACKGROUND: The success of long-term corneal organ culture is limited by the progressive loss of endothelial cells during culture and the use of culture medium supplemented with fetal calf serum as a possible source of contamination with infectious agents. In this study, we investigated the suitability of a serum-free medium (Endothelial-SFM) to improve preservation conditions for human donor corneas. METHODS: Six pairs of corneas were stored in Minimum Essential Medium (MEM) supplemented with 2% fetal calf serum (FCS) for 8-14 days. One cornea of each pair was then further cultivated in Endothelial-SFM supplemented with 2% FCS or in MEM with 2% FCS, respectively. In a second series of experiments, the endothelial cell density of seven pairs of freshly isolated donor corneas was determined during cultivation in Endothelial-SFM with 2% FCS or serum-free Endothelial-SFM. RESULTS: After precultivation in conventional medium, the endothelial cell density of corneas allocated to cultivation in Endothelial-SFM was 1000-1950 cells/mm2 and that of those subsequently cultured in MEM 1200-2000 cells/mm2. At 9 weeks, cell densities of 900-1500 cells/mm2 were found after cultivation in Endothelial-SFM compared with a total cell loss in MEM. Freshly isolated corneas cultured in Endothelial-SFM with or without FCS supplementation showed a decrease of endothelial cell density of about 20% within the first 2 weeks of storage. During further cultivation cell density remained constant without statistically significant differences between the groups. Glucose consumption of the corneas was higher in Endothelial-SFM than in MEM. Corneas stored in Endothelial-SFM with 2% FCS showed a higher glucose consumption than those preserved in serum-free Endothelial-SFM. CONCLUSION: Organ culture of human donor corneas using the serum-free basal medium Endothelial-SFM is superior to conventional culture conditions because the decrease in endothelial cell density can be ameliorated, the culture period can be prolonged and the risk of transmitting infectious agents via serum can be minimised.

[Clinical double-blind trial of topical zinc sulfate for herpes labialis recidivans]. / Klinische Doppelblindprüfung mit Zinksulfat topisch bei Herpes labialis recidivans.

In a placebo controlled, double-blind clinical trial in patients with herpes labialis recidivans, zinc sulfate (CAS 7733-02-0) as gel (Virudermin Gel) proved to be significantly more effective than the gel alone. With zinc sulfate as gel, the symptoms were less marked and healing was faster. This simple preparation can be applied in cases of herpes labialis recidivans without any risk of side effects. Due to the antiseptic properties of zinc sulfate superinfections can be prevented.

Coronary artery bypass grafting and heart transplantation in end-stage coronary artery disease: a comparison of hemodynamic improvement and ventricular function.

Heart transplantation has now become an accepted treatment for end-stage coronary heart disease (CAD). However, the limited supply of suitable donor organs imposes constraints upon the decision of whether patients are selected for transplantation or for coronary artery bypass grafting (CABG). From April 1986 until the end of March 1992, 265 patients with end-stage CAD involving left ventricular ejection fraction (LVEF) 10% to 30% and predominant angina pectoris underwent CABG. All patients received an average of 2.9 +/- 0.3 venous grafts. Intraaortic balloon pumps were implanted in 30 patients (11.3%) who began to develop low cardiac output syndrome intraoperatively. The actuarial survival rate was 87.8% after 2 years and 86.9% after 3 years. LVEF was measured in 35 patients via left heart catheterization 12 months after their operations and was found to have increased from a mean of 23.8% to 38.1%. Left ventricular end-diastolic pressure had decreased from 16.2 mmHg to an average of 12.1 mmHg. Swan-Ganz catheterization was performed on 120 patients 6 months postoperatively. The pulmonary wedge pressure had reduced significantly from 18.1 mmHg to a mean of 12.7 mmHg (p < 0.01). From 1990 until the end of March 1992, 55 patients with CAD and predominant heart failure received transplants. Their 2-year survival rate was 66.3%. Mean LVEF was 55.6% postoperatively. We conclude that CABG is adequate for patients who have end-stage CAD and angina pectoris symptoms, and that it significantly improves hemodynamic functions. Patients suffering predominantly from heart failure (NYHA Class IV) can be transplanted and subsequently regain normal heart function.

Survival predictors in patients with a left ventricular ejection fraction of 10-30% receiving a coronary bypass: analysis of preoperative variables.

A total of 224 patients with angina pectoris and a left ventricular ejection fraction in the range of 10-30% (mean 24.2%) underwent coronary artery bypass grafting between April 1986 and August 1991. These patients received a mean (s.d.) of 2.9 (0.3) aortocoronary vein grafts. The overall operative mortality rate was 8.9%. The 1-, 2- and 3-year survival rates were 87.7%, 86.7% and 85.2%, respectively. Analysis of operative risk factors showed that patients with an end-diastolic left ventricular pressure > 24 mmHg were significantly more at risk (mortality rate 20.0%, P < 0.05) than those with an end-diastolic left ventricular pressure < or = 24 mmHg (mortality rate 6.2%). Patients with a perioperative cardiac index < 2.5 l min-1m-2 had higher mortality (25.4%) than those with a cardiac index > or = 2.5 l min-1m-2 (mortality 1.9%, P < 0.001). The operative mortality rate of patients with a cardiac index < 2.5 l min-1m-2 and an end-diastolic left ventricular pressure > 24 mmHg was 40.5%. Patients with a left ventricular ejection fraction of 10-20% were not significantly more at risk (P > 0.05) than those with a left ventricular ejection fraction of 21-30%.

[Coronary revascularization in end-stage coronary heart disease in relation to assessment of myocardial vitality]. / Koronarrevaskularisation im Endstadium der KHK in Abhängigkeit von Myokardvitalitätsprüfung.

From 4/1986-12/1990, 177 pts. with endstage coronary artery disease (CAD) and left ventricular ejection fraction 10-30% received coronary artery bypass grafting (CABG). Preoperatively myocardial infarction rate was 1.5 (mean). Presupposition for CABGs was myocardial ischaemia at present demonstrated in myocardial viability test. 66.1% of the pts. had signs of ischaemia at e.c.g. after work. Additionally 97.6% of the pts. had myocardial ischaemia defined as redistribution in myocardial scintigraphy. Angina pectoris was present in 93.8% of the pts. preoperatively. 1-5 (mean 2.9) CABG per pt. were performed. 35 pts. received an internal mammaria bypass to the left coronary artery also. Operative mortality was 11.3% (1986-1990) and in 1990 alone 7.3%. Actuarial survival rate was calculated after one year to 87.4% after two years to 86.1% and after three years to 84.8%. Postoperatively all pts. were free from angina pectoris. 5 months after the operation e.c.g. after work was performed. The physical stress bearing area was increased to 82.7 Watt (mean) compared to 51.7 Watt (mean) preoperatively (p less than 0.001 s.). In conclusion pts. with endstage CAD and left ventricular ejection fraction 10-30% appeared to be good candidates for CABG with good prognosis and significant symptomatic improvement when signs of myocardial ischaemia are present preoperatively.

[Therapy of terminal heart failure using heart transplantation]. / Therapie der terminalen Herzinsuffizienz durch Herztransplantation.

Heart transplantation (HTx) has now become an accepted treatment modality for end-stage heart disease. The limited supply of suitable donor organs imposes constraints upon the decision of who should be selected for transplantation. Usually patients are candidates for HTx, who remain NYHA functional class III or IV despite maximal medical therapy. Further criteria are low left ventricular ejection fraction (less than 20%) with heart rhythm disturbances class IIIA-V (LOWN), which are associated with poor prognosis. Additionally, the suffering of the patient and also the course of heart failure are essential for judging the urgency of HTx. Contraindications are absolute in patients with untreated infections, fixed pulmonary vascular resistance (PVR) above 8 WOOD-degrees, severe irreversible kidney and liver disease, active ventricular or duodenal ulcers and acute, psychiatric illness. HTx is relatively contraindicated in patients with diabetes mellitus, age over 60 years, PVR above 6 WOOD-degrees and an unstable psychosocial situation. To prevent rejection of the transplant heart, live-long immunosuppressive therapy is needed. Most immunosuppressive regimes consist of Cyclosporine A and Azathioprine (double drug therapy) or in combination (tripple drug therapy) with Prednisolone. For monitoring of this therapy, control of hole blood cyclosporine A level and white blood count is needed. Rejection episodes can be suspected if there is a greater than 20 mmHg decrease of systolic blood pressure, elevated body temperature, malaise, tachycardia or heart rhythm disturbance. The diagnosis of cardiac rejection can be established by endomyocardial biopsy. Measurement of the voltage of either the surface or intramyocardial ECG, echocardiography with special consideration to early left ventricular filling time as well as immunological methods are additionally used tools. Graft sclerosis as the main risk factor of the late transplant period remains an unsolved problem.

[Surgical ligation of patent ductus arteriosus on the intensive care unit in small premature infants]. / Ductusligatur auf der Intensivstation bei kleinen Frühgeborenen.

This paper summarizes the experience with ligation of persistent ductus arteriosus in prematures performed in the intensive care unit during the years 1986 to 1988. Records of 35 operated prematures on artificial ventilation were analyzed retrospectively. Management and organization of the operation are described. For comparison, records were analysed of 47 prematures, also artificially ventilated, who during the years 1978 to 1986 had to be transported to an operating theatre over a distance of 3 or 10 km for the ligation.

[Penetration and action of edoxudine in vitro and in vivo]. / Penetration und Wirksamkeit von Edoxudin in vitro und in vivo.

The penetration of 5-ethyl-2'-deoxyuridine (edoxudine, Aedurid) from gel base with and without the addition of urea and other adjuvant has been studied in an in vitro model using guinea pig skin. The formulation of 3% edoxudine gel with 5% urea showed the best results. In vivo experiments on hairless mice infected intracutaneously with herpes simplex virus type 1 also showed this formulation's good efficacy as compared to other formulations.

Heart transplantation in Berlin.

Since July 1983, our group experience with heart transplantation as a routine procedure now includes 346 patients. Predominant diagnosis was dilated cardiomyopathy (64%). The age range was 3 months to 68 years (mean 44.3 years). Immunosuppression has followed several evolving protocols and now emphasizes preoperative administration of cyclosporine A and quadruple immunosuppression with additional azathioprine, cortisone medication, and early postoperative cytolytic prophylaxis with rabbit ATG. We have accepted donor organs up to 55 years without coronary angiography and with very satisfying functional and late results. The diagnosis of rejection by endomyocardial biopsy has been supplemented by routine use of telemetric intramyocardial electrogram monitoring and M-mode echocardiography. Routine use of these methods has distinctly increased diagnostic safety. Eleven children between the ages of 3 months and 18 years have been transplanted with a 72% overall survival rate. Four children younger than age 8 have been followed with noninvasive methods for rejection diagnosis exclusively. A bridge to transplantation program was initiated in July 1987; 31 patients were bridged, 18 of whom could be transplanted. Thirteen patients were discharged after a mean posttransplant period of 31 days. Future development issues will include extension of donor heart criteria, noninvasive diagnosis of rejection, and increasing experience with mechanical bridging.

[Effectiveness of various forms of therapy in chronic cardiovascular diseases--a vector analysis of the transition probabilities of degrees of severity]. / Effektivität differenter Therapieformen bei chronischen Herz-Kreislauf-Krankheiten--eine Vektorenanalyse der Ubergangswahrscheinlichkeiten von Schweregraden.

The present findings result from a check of probationers representative for approx. 280,000 inhabitants of defined territories, who had been designated as suspects of heart and vessel disease on grounds of X-ray-morphological criterions (classification by Richter). Those about 3,000 suspects, subdivided into 3 comparable patient groups A, B and C, underwent different regimes of treatment of outpatient medical practice after standardized and noninvasive diagnostics in a follow-up during 5 years and had been valued by means of a problem-specific grading. The comparative analysis about the distribution of severe degrees concerning hypertension and coronary heart disease after the conclusion of the intervention showed significant differences concerning the results of treatment to the credit of the patient group A (treated by specialists) contrary to the patient group B (treated by family doctors) and patient group C (principle of announcing the patients themselves). Also the patient group B showed significantly better results of therapy compared with the patient group C. In addition to the concluding rating the estimation of yearly transition of severe degrees gave an insight into the therapeutical decision of the person who looks after as well as the different distribution of severe degrees of special heart diseases in dependence on the starting severe degree in the special period of intervention conditioned on the therapy. The results gain exceptional importance for practice on the grounds of methodics of the study-automatable classification of dv-thorax-X-ray pictures, problem-specific grading of noninvasive, simple parameters, variants of therapy in dependence on the graduated system of medical care.

[Assessment of prognosis with Markov chains in chronic cardiovascular diseases in relation to various therapies]. / Prognoseabschätzung mit Markoff-Ketten bei chronischen Herz-Kreislauf-Krankheiten in Abhängigkeit von Therapievarianten.

On the basis of 5-years intervention results concerning chronic heart and vessel diseases of a check, which is representative for approx. 280.000 inhabitants of defined territories (EBMO-Cor Berlin), the prognose for the time of 5 and 10 years were estimated. It refers to ambulantories with the diagnosis hypertension and coronary heart disease, who were treated in a different way. The fundamental idea was to extract a prognostic index to make possible a choice of the treatment, adequate to the specific disease and its severe degrees, free of chance. The basic requirement of the application of the "Markoff-model" was the evidence of homogeneity concerning transition of severe degrees, used as reference, which was proved by means of the 2-k-chi 2-Felder-test. By using a starting vector of 1000 patients in each case inquiries about the distribution to the severe degrees had been made. The so achieved results illustrate a therapy-dependent susceptibility of these (morphologically defined) population suffering from a heart disease and allow a forecast, estimated also for a longer period, about the extent of the transition of a respecting and with the possibilities of the outpatient practice defined severe degrees of a heart and circulation disease and with that about chance and risk of a patient. By means of the epidemiological reference of the study the result gains special importance for outpatient practice.

[Problem-specific grading in disease course assessment and calculation of the likelihood of transition of chronic cardiovascular diseases]. / Problemspezifisches Grading zur Verlaufsbeurteilung sowie zur Berechnung von Ubergangswahrscheinlichkeiten chronischer Herz-Kreislauf-Krankheiten.

For the course rating of cardiovascular caused drop in efficiency a problem-specific grading is introduced, the characterization of which is composed of simple, non-invasive parameters. The grading is specified for 4 clinical diagnostic classes (hypertension, coronary heart diseases, pulmonary heart, "other heart and vessel diseases") and takes into consideration the frequent coincidence or connection of several diagnoses of heart and vessel diseases with each other. The choice of parameter and connection have to fulfil the demand, which is essential for the course rating of heart and vessel diseases, like practicability proportionate with the frequency of heart and vessel diseases, adequate registration of changes in severe degrees, statement about the patient and not about several parameters. Furthermore it has to make it possible to calculate provisional probabilities under variable conditions as well as to make possible a valuation of prognosis. For that purpose the construction of suitable matrixes is shown and an integral projection is represented, which is used for the interpretation of courses dependent on severe degrees. The conception of grading has the function to modify necessary parameters for inclusion in the hierarchy according to medical starting position (for instance primary mode of registration). The model which is applicable to level of population makes possible an electronic data - processing - based evaluation including algorithmic classification.

[Isolation and identification of metabolites of 5-ethyl-2'-deoxyuridine from rat urine]. / Isolierung und Identifizierung der Metaboliten von 5-Ethyl-2'-desoxyuridin aus Rattenurin.

The metabolites of 5-ethyl-2'-deoxyuridine (Aedurid) have been isolated and purified from rat urine by preparative thin-layer and column chromatography. With the aid of 1H-NMR and mass spectroscopy and by comparison with an authentic sample, the major metabolite could be identified as 5-(1-hydroxyethyl)uracil. The minor metabolite was identified as 5-ethyluracil.

[Pharmacokinetics of 5-ethyl-2'-desoxyuridine in the rat]. / Pharmakokinetische Untersuchungen mit 5-Ethyl-2'-desoxyuridin an Ratten.

The pharmacokinetic behaviour of the virostatic drug 5-ethyl-2'-deoxyuridine (EtUdR, Aedurid) and its metabolite 5-ethyluracil was determined after intravenous and oral application in a nonindividual study using inbred rats. EtUdR is metabolized and eliminated rapidly. The saturation of the metabolic pathway could not be achieved. Higher initial blood levels resulted from a pretreatment of rats with probenecid or the application of the better water-soluble compound 5-ethyl-2'-deoxyuridine-5'-monophosphate; the elimination characteristic of EtUdR could not be altered by these methods.

2-14C-1-Allyl-3,5-diethyl-6-chlorouracil I: Synthesis, absorption in human skin, excretion, distribution, and metabolism in rats and rabbits.

With 14C-potassium cyanate as the starting material, 2-14C-1-allyl-3,5-diethyl-6-chlorouracil was synthesized for in vitro and in vivo absorption studies in human skin and for metabolic studies in rats and rabbits. The radioactivity in the horny layer, epidermis, and dermis of the human skin was determined after different intervals of time, and the radioactivity excreted in the urine was measured by collecting samples for 5 days from a patient and also under occlusion conditions. Almost 90% of the radioactivity remained on the surface and approximately 6.28% penetrated and was systemically absorbed. Over a 5-day period, a total of 3.25% was excreted. Almost 3% was systemically absorbed and cumulated in the system. After intraperitoneal application in male and female rats, most of the radioactivity was excreted in the feces and urine, with female rats excreting more in the urine than male rats. The radioactivity rose in the organs in the first 3 hr and then decreased. At the end of 144 hr, no appreciable radioactivity could be found in the organs and tissues, except in the carcass where the cumulation was maximum (1%). After intravenous injection in rabbits, most of the radioactivity (80%) was excreted in the urine and only 4% in the feces. At the end of 96 hr, approximately 3% was cumulated in the body. The drug was quantitatively metabolized in both rats and rabbits: Metabolite 1 (70-85%), Metabolite 2 (10-15%), Metabolite 3 (5-10%), and Metabolite 4 (0.3%).