The reality of routine practice: a pooled data analysis on chronic wounds treated with TLC-NOSF wound dressings.

OBJECTIVE: A number of randomised controlled trials (RCT) have compared control groups with TLC-NOSF dressings (UrgoStart) on chronic wounds. Our aim was to determine whether the clinical trials' results translate into routine management of such wounds, by pooling the data from real-life observational studies. METHOD: Observational studies, conducted in France and Germany, evaluating current practices in patients suffering from non-selected chronic wounds treated with a TLC-NOSF dressing were identified. Demographic data, baseline description of wounds and description of their evolution during treatment were extracted and combined. We used two main indicators of clinical outcomes to measure the impact of the TLC-NOSF dressing on this population: time to wound closure and time to 50% reduction of the Pressure Ulcer Scale for Healing (PUSH) score. RESULTS: In total, data from 10,220 patients were included, with 7903 leg ulcers (LUs), 1306 diabetic foot ulcers (DFUs) and 1011 pressure ulcers (PUs). The overall closure rate was 30.8 % [95 % confidence interval (CI): 29.9-31.7 %]. While the country, patient age, and number of wounds were identified as independent prognosis factors of healing, the most significant were wound duration and baseline area. The delay in initiating TLC-NOSF dressings treatment was also found to be significant. Overall the average time to complete closure was 112.5 days [95%CI: 105.8-119.3] for LUs, 98.1 days [95 %CI: 88.8-107.5] for DFUs and 119.5 days [95%CI: 94.6-144.3] for PUs. Based on a subgroup analysis of the French cohort, time to closure is substantially shorter for wounds treated with the TLC-NOSF dressing as a first-line intervention compared with those where it has been prescribed as a second-line intervention. CONCLUSION: Compared with available data on time to complete closure of chronic wounds managed by 'standard' care, the data from this pooled data analysis showed healing time is reduced, which is consistent with the results of RCTs on TLC-NOSF. That these data are in agreement with those from the RCTs is testimony to their generalisability and important for routine practice. This indicates that using TLC-NOSF dressings in routine wound management can reduce the healing time of LUs, DFUs and PUs. These data also suggest that the earlier the decision to use this dressing, the shorter the time to closure, whatever the severity and the nature of these chronic wounds.

Quality of care of patients with chronic lymphoedema in Germany.

BACKGROUND: The management of lymphoedema is complex and should be based on guidelines. To date, no data assessing quality of care in lymphoedema in Germany are available. OBJECTIVE: We aimed at evaluating the quality of care of lymphoedema in the metropolitan area of Hamburg using guideline-based indicators. METHODS: Cross-sectional, community-based study including patients with lymphoedema. Assessment included a structured interview, clinical examination and patient-reported outcomes. Quality indicators derived from guidelines by a Delphi consensus were applied. RESULTS: 348 patients (median age 60.5 years) with lymphoedema (66.4%), lipoedema (9.5%) or combined oedema (24.1%) were included. 86.4% performed compression therapy, 85.6% received lymphatic drainage. On average 55.0% of the quality of care criteria were met; 64.8% were satisfied with care. The distribution curve of the health care index was almost normal. Treatment by specialists led to a higher quality of care index. CONCLUSION: Although overall quality of care in lymphoedema is fair, many patients are not treated properly according to guidelines.

Quality-of-care for leg ulcers in the metropolitan area of Hamburg--a community-based study.

BACKGROUND: Diagnosis and therapy of chronic wounds constitute an interdisciplinary challenge and should be oriented on the guideline standards. Although no data on the quality-of-care are available for Germany, it can be concluded from qualitative estimates and expert reports that the majority of patients are not receiving adequate treatment. OBJECTIVES: Evaluation of the quality-of-care for leg ulcers in the metropolitan area of Hamburg by means of newly developed guideline-based indicators. METHODS: Leg ulcer patients of any aetiology were consecutively included. The spectrum of 220 health-care providers ranged from wound clinics, office-based practices, nursing homes to home-care services and doss houses. The survey included a clinical examination and the completion of questionnaires covering quality of life, experiences with treatment and quality of health care. RESULTS: A total of 520 patients with leg ulcers were included. Among these patients, 63% were of venous, 23% of mixed, 2% of vasculitic and 12% of other origin; 78.6% of the patients were treated with moist wound dressings. Pain therapy was performed in 54.1%, compression therapy in 53.5%. Shortcomings were noted in the diagnostic work-up and in concomitant wound care such as physiotherapy. Around 70% displayed marked to profound impairment in quality of life. The quality-of-care index showed that 64% of the indicators were met by the actual care; 61.8% of the patients exhibiting a sufficient quality-of-care, regardless of age, social status, place of abode or insurance status. CONCLUSIONS: Although the majority of patients received adequate therapy, many patients are not being treated properly in accordance with the guidelines.

Cardiovascular effects of a novel potent and highly selective azaindole-based inhibitor of Rho-kinase.

BACKGROUND AND PURPOSE: Rho-kinase (ROCK) has been implicated in the pathophysiology of altered vasoregulation leading to hypertension. Here we describe the pharmacological characterization of a potent, highly selective and orally active ROCK inhibitor, the derivative of a class of azaindoles, azaindole 1 (6-chloro-N4-{3,5-difluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-phenyl}pyrimidine-2,4-diamine). EXPERIMENTAL APPROACH: Pharmacological characterization of azaindole 1 was performed with human recombinant ROCK in vitro. Vasodilator activity was determined using isolated vessels in vitro and different animal models in vivo. KEY RESULTS: This compound inhibited the ROCK-1 and ROCK-2 isoenzymes with IC50 s of 0.6 and 1.1 nM in an ATP-competitive manner. Although ATP-competitive, azaindole 1 was inactive against 89 kinases (IC50>10 microM) and showed only weak activity against an additional 21 different kinases (IC50=1-10 microM). Only the kinases TRK und FLT3 were inhibited by azaindole 1 in the sub-micromolar range, albeit with IC50 values of 252 and 303 nM, respectively. In vivo, azaindole 1 lowered blood pressure dose-dependently after i.v. administration in anaesthetized normotensive rats. In conscious normotensive and spontaneously hypertensive rats azaindole 1 induced a dose-dependent decrease in blood pressure after oral administration without inducing a significant reflex increase in heart rate. In anaesthetized dogs, azaindole 1 induced vasodilatation with a moderately elevated heart rate. CONCLUSIONS AND IMPLICATIONS: Azaindole 1 is representative of a new class of selective and potent ROCK inhibitors and is a valuable tool for the elucidation of the role of ROCK in the cardiovascular system.

A prospective study on the use of a non-adhesive gelling foam dressing on exuding leg ulcers.

OBJECTIVE: This non-comparative phase II study aimed to evaluate the safety and performance of a non-adhesive gelling foam dressing (GFD-N) in leg ulcer management. METHOD: Forty-six subjects with moderately to heavily exuding leg ulcers were treated with a regimen including GFD-N. Dressings were changed at least every seven days for four weeks or until healing. RESULTS: Mean GFD-N wear time was 3.2 days per subject. Mean wound area decreased from 10.1 cm2 at baseline to 5.1 cm2 at four weeks (p<0.001) and healed in five subjects (11%). The surrounding skin improved or remained stable in all but one subject. When compared with pre-study dressings, ulcer pain decreased for GFD-N, both with the dressing in place (p<0.001) and on dressing removal (p<0.001). Of final investigator ratings for 45 subjects, most were 'excellent' for ease of application (89%), ease of removal (96%), conformability (67%) and overall performance (58%). Five subjects experienced adverse events; none were serious or dressing-related. CONCLUSION: This small study demonstrates that GFD-N was safe, effective and convenient for wound healing, exudate management, pain/comfort and ease of use.

Effect of a sustained silver-releasing dressing on ulcers with delayed healing: the CONTOP study.

OBJECTIVE: To compare the effect of the sustained silver-releasing foam dressing Contreet Foam (ColoplastA/S) with local best practice (LBP) on delayed healing ulcers using a real-life setting. METHOD: A total of 619 patients with ulcers of varying aetiologies were treated for four weeks with either the silver foam dressing or LBP. RESULTS: Wound area was reduced by 50% with the silver foam and 34% with LBP Less slough and maceration, a faster reduction in exudate level and more positive wound progress was achieved with the silver foam. In addition, exudate handling, ease of use, odour and pain improved. Less time was spent on dressing changes, and mean wear time was longer for the silver foam (3.1 days) than for LBP (2.1 days). All differences were statistically significant (p < 0.05). The silver foam dressing outperformed all of the other dressing categories including moist wound healing products and other silver dressings. CONCLUSION: This large-scale comparative real-life study shows that the silver foam dressing supports faster healing of delayed healing wounds.

[Ulcus cruris venosum--therapeutic principles]. / Druck oder Drainage, Maden oder Skalpell?

An essential element in the management of ulcus cruris venosum is the treatment of the cause applying compression. For this purposes, various systems are currently available, the application of which, however, must always be undertaken with consideration being given to the individual situation and possible contraindications. Topical treatment of chronic wounds, including ulcus cruris venosum, is performed stage-oriented, in accordance with the principles of moist wound care. The critical selection of the most appropriate dressing materials for the case presenting is essential for a treatment that is both medically and economically justifiable. An aim of the treatment continues to be the curtailment of the still too long treatment times, and to reduce the number of recurrences.

ACE-inhibition is superior to endothelin A receptor blockade in preventing abnormal capillary supply and fibrosis of the heart in experimental diabetes.

AIMS/HYPOTHESIS: There is little information whether cardiac capillary supply is deranged in diabetes. Hyperglycaemia is a potent stimulus for endothelin-1 (ET-1) production. We therefore hypothesised that increased ET-1 production in Streptozotocin-induced Type 1 diabetes causes abnormalities of cardiac capillaries and the aorta. To this end we compared the effects of an ET receptor A blocker (ETA-RB) with that of an ACE-inhibitor (ACE-i) or their combination in rats with Streptozotocin (STZ) diabetes. METHODS: Sprague Dawley rats were injected with 65 mg STZ i.v. and subsequently developed diabetes. Rats were left untreated or received daily either the ACE-i Trandolapril, the ETA-RB Darusentan or a combination of both. After 6 months the experiment was terminated and the heart and the aorta were investigated using quantitative morphological techniques. RESULTS: ACE-i but not ETA-RB lowered blood pressure in STZ Type 1 diabetic rats. Capillary length density was lower in untreated STZ diabetic rats (2932+/-128 mm/mm3) compared to non-diabetic control rats (3410+/-252 mm/mm3). Treatment with ACE-i (3568+/-431 mm/mm3), but not with ETA-RB (2893+/-192 mm/mm3), prevented the decrease in capillary supply. Volume density of the myocardial interstitium was higher in untreated STZ diabetic rats (0.86+/-0.04%) compared to non-diabetic control rats (0.36+/-0.06%). In all three intervention groups the values were lower (ACE-i: 0.53+/-0.05%, ETA-RB: 0.7+/-0.08% and combination: 0.69+/-0.1). CONCLUSION/INTERPRETATION: Our study identifies a capillary defect of the heart in STZ diabetes, i.e. decreased capillary supply. This abnormality was reversed by ACE-i, but not by ETA-R blockade. A similar trend, although not complete normalisation, was seen in cardiac fibrosis.

ACE-inhibitors but not endothelin receptor blockers prevent podocyte loss in early diabetic nephropathy.

AIMS/HYPOTHESIS: It was the aim of our study to investigate the influence of a selective ET-A receptor antagonist LU 135252 alone and in combination with the ACE-inhibitor, trandolapril on podocyte number and morphology in streptozotocin diabetic rats. METHODS: Male Sprague-Dawley rats were injected with 65 mg streptozotocin i.v. and subsequently developed diabetes. Animals were left untreated or received daily either trandolapril (0.3 mg/kg body weight), LU 135252 (50 mg/kg body weight) or a combination of both. After 6 months the experiment was terminated. Glomerular geometry and cellularity were assessed by stereological techniques. Protein expression of TGF-beta, ET-1, PDGF-AB, fibronectin, desmin and alpha-smooth muscle cell actin was investigated by immunohistochemistry. RESULTS: The mean number of podocytes per glomerulus was lower (86+/-17 vs. 138+/-25; p<0.05) and mean podocyte volume was higher in untreated diabetic animals than in non-diabetic controls. Only ACE-i alone and in combination, but not ET(A)-RB alone prevented loss of podocytes and podocyte hypertrophy. In diabetic rats, increased numbers of PCNA positive and p27(kip1) positive cells (mainly podocytes) were reduced by all treatments, but only ACE-i decreased numbers of desmin positive podocytes and tubulointerstitial expression of TGF-beta. Albuminuria was increased in untreated diabetes and was prevented only by ACE-i and combination treatment. CONCLUSION/INTERPRETATION: Podocyte hypertrophy and degeneration is an early event in diabetic nephropathy leading to a loss of podocytes. Treatment with an ACE-i, but not with an ET(A)-RB, prevented the development of albuminuria as well as damage and loss of podocytes. The well known anti-proteinuric effect of ACE-i is presumably due at least in part to conservation of podocyte structure. Increased plasma endothelin-1 (ET-1) concentrations and urine excretion of ET-1 have been documented in patients with diabetes and proteinuria [1]. It has been shown that experimental diabetes mellitus increases renal ET-1 gene transcription [2]. To assess the relevance of the ET-system in the pathogenesis of renal structural changes in the model of the STZ-induced diabetic rat we compared the effect of an ET(A)-receptor specific antagonist with the well known beneficial effect of an ACE-i, especially on podocyte cell number and morphology.

Short-stretch versus multilayer compression for venous leg ulcers: a comparison of healing rates.

OBJECTIVE: To compare the performance of two compression systems, (multilayer elastic [Profore], Smith and Nephew) and (short stretch [Comprilan], Beiersdorf), in the treatment of venous leg ulcers in a randomised controlled trial. METHOD: Eighty-nine patients with venous leg ulcers were randomised to receive treatment with Profore (44 patients) or short-stretch (45 patients) compression bandages. Allevyn (Smith and Nephew) was used as the wound contact layer under both systems. RESULTS: Patients treated with Profore healed significantly faster than those treated with short stretch (p = 0.03) and were 2.9 times more likely to heal at any given time during the study period. Younger wounds healed significantly faster than older wounds (p = 0.01). CONCLUSION: Patients treated with Profore healed faster than those treated with short-stretch bandages. In addition, treatment costs are lower with Profore. In this trial the average cost per patient was [symbol: see text] 1345 (short stretch) and [symbol: see text] 587 (Profore).

Physicians' knowledge and attitudes regarding the spontaneous reporting system for adverse drug reactions.

The spontaneous reporting system (srs) is the most important early warning system of adverse drug reactions. As there is serious under-reporting we studied the respective knowledge and attitudes of two samples of physicians in Germany. Five hundred randomly sampled physicians and 815 physicians who had actually reported an ADR were included; the response rate to the mail questionnaire was 51.4 and 43.9%, respectively; 61.3% said to have reported at least one case in their life. As many as 75-85% of physicians said never to have sent an ADR report to the governmental or professional reporting systems. Reporting to pharmaceutical companies, on the other hand, has been substantially better. Sixty-eight and two-tenths percent indicated to have suspected an ADR without reporting it. Major reasons for not reporting were: ADR well known (75.6%), too trivial (71.1%), causality uncertain (66.3%). The ADR with the highest probability of being reported were serious unknown adverse reactions of a new drug (81.1%) or an established drug (72.9%) and serious known reactions to a new drug (65.2%). Almost 20% of the physicians admitted to not know the spontaneous reporting system and 30% to not know how to report; 54% would rather report an ADR if therapeutic advice was offered. The results indicate that the traditional ways of advertising the srs and communicating with physicians could be improved. Proactive services and professional marketing of srs are needed to reduce underreporting.

Increased expression of endothelin-1 and inducible nitric oxide synthase isoform II in aging arteries in vivo: implications for atherosclerosis.

We here report that aging increases expression of endothelin-1 and NO synthases in the vasculature and kidney of normotensive rats in vivo. Expression of preproendothelin-1 mRNA was quantified by RT-PCR and in situ hybridization, and endothelin-1 protein was determined by radioimmunoassay/HPLC. Vascular mRNA expression of NO synthase isoforms II and III was analyzed by RT-PCR. In young animals, vascular endothelin-1 protein was differentially expressed (aorta < renal artery < carotid artery) and increased with aging in all vascular beds (P < 0.05). In the intact aorta of aged rats, mRNA expression of preproendothelin-1, "inducible" NO synthase II, and endothelial cell NO synthase III gene was up-regulated (P < 0.05). Moreover, preproendothelin-1 mRNA expression increased in glomeruli and tubulointerstitial cells (P < 0.05). To our knowledge this is the first study demonstrating local vascular up-regulation of the trophic factor endothelin under physiological conditions. Activation of vascular endothelin and NO synthases may be important, pressure-independent factors contributing to structural and functional abnormalities of age-dependent diseases, including atherosclerosis.

The role of endothelin receptor antagonists in cardiovascular pharmacotherapy.

Endothelin (ET) is a hormone produced predominantly by endothelial cells which has been recognised to play a significant role in the development of several cardiovascular disease states. In order to combat the deleterious effects of ET, several ET-receptor antagonists (ETRA) are currently in clinical development. The agents developed thus far inhibit the actions of ET through either selective inhibition of the ET(A) receptors or non-selective inhibition of both ET(A) and ET(B) receptors. However, due to the differing proportions of the two receptor subtypes in various tissues, animal models and pathologies, it remains a matter of debate whether receptor selective agents impart significant clinical benefits over non-selective agents. This paper seeks to briefly summarise the important preclinical and clinical effects that have been reported in the literature and will attempt to provide a rationale for the use of both types of ETRAs in the treatment of both systemic and pulmonary hypertension as well as chronic heart failure (CHF).

Obesity is associated with tissue-specific activation of renal angiotensin-converting enzyme in vivo: evidence for a regulatory role of endothelin.

In the C57BL/6J mice model, we investigated whether obesity affects the function or expression of components of the tissue renin-angiotensin system and whether endothelin (ET)-1 contributes to these changes. ACE activity (nmol. L His-Leu. mg protein(-1)) was measured in lung, kidney, and liver in control (receiving standard chow) and obese animals treated for 30 weeks with a high-fat, low cholesterol diet alone or in combination with LU135252, an orally active ET(A) receptor antagonist. ACE mRNA expression was measured in the kidney, and the effects of LU135252 on purified human ACE were determined. Aortic and renal tissue ET-1 protein content was measured, and the vascular contractility to angiotensin II was assessed. Obesity was associated with a tissue-specific increase in ACE activity in the kidney (55+/-4 versus 33+/-3 nmol/L) but not in the lung (34+/-2 versus 32+/-2 nmol/L). Long-term LU135252 treatment completely prevented this activation (13.3+/-0.3 versus 55+/-4 nmol/L, P<0.05) independent of ACE mRNA expression, body weight, or renal ET-1 protein but did not affect pulmonary or hepatic ACE activity. Obesity potentiated contractions in response to angiotensin II in the aorta (from 6+/-2% to 33+/-5% KCl) but not in the carotid artery (4+/-1% to 3.6+/-1% KCl), an effect that was completely prevented with LU135252 treatment (6+/-0.4% versus 33+/-5% KCl). No effect of LU135252 on purified ACE was observed. Thus, obesity is associated with the activation of renal ACE in vivo independent of its mRNA expression and enhanced vascular contractility to angiotensin II. These effects are regulated by ET in an organ-specific manner, providing novel mechanisms by which ET antagonists may exert organ protection.

Altered endothelin-1 binding following balloon angioplasty of pig coronary arteries: effect of the ETA receptor antagonist, LU 135252.

OBJECTIVE: Since raised levels of endothelin-1 (ET-1) have been detected in the human coronary sinus following percutaneous transluminal angioplasty (PTCA) we investigated the role of ET-1 in the etiology of vascular restenosis. METHODS: Balloon angioplasty of coronary arteries was performed in pigs and the animals were treated with placebo or the endothelin (ETA) receptor antagonist LU 135252 (30 mg/kg/day). After 4 weeks vascular stenosis and the distribution of endothelin and its receptors was evaluated. RESULTS: The pronounced neointima formation in the control group (neointima:media ratio = 0.87 +/- 0.36) was significantly reduced by LU 135252 (0.43 +/- 0.30, P < 0.001). Angioplasty caused a significant increase in medial ETA (approximately 275%, P < 0.026) and ETB (approximately 250%, P < 0.001) binding to injured, compared with non-injured segments, an effect that was also reduced by LU 135252 (ETA = 11.5% increase; ETB = 14% increase). The neointima of control animals exhibited ET-1 like immunoreactivity as well as ETA and ETB binding sites. CONCLUSION: These data indicate that endothelin is locally-released from endothelial and vascular smooth muscle cells following angioplasty which binds to ETA and ETB receptor sites in the neointima and media. Since administration of the ETA antagonist LU 135252 markedly reduces neointima formation and medial ET binding, we conclude that vascular smooth muscle cell proliferation and subsequent neointima formation is mediated predominantly via ETA receptors. These data underscore the therapeutic potential of ETA antagonists in reducing the degree of restenosis following vascular injury.

Treatment of cardiovascular changes in renal failure--ACE inhibition, endothelin receptor blockade or a combination of both strategies?

ACE-I and specific ETA receptor blockade comparably prevented the development of structural cardiovascular alterations such as LVH, myocardial interstitial expansion and wall thickening of intramyocardial and extracardiac arteries in experimental renal failure. However, the decrease in myocardial capillary supply and the concomitant increase in intercapillary distance could only be prevented by ETA receptor antagonism. These capillary changes which have been shown to occur in experimental renal failure as well as in uraemic patients play an important role in the pathogenesis of reduced cardiac ischaemia tolerance in renal failure. The data argue for a potential role of the local renin-angiotensin system as well as of the ET system in the pathogenesis of cardiovascular changes in renal failure and for ET receptor blockade as a new therapeutic option in the treatment of these alterations. In particular, myocardial capillary supply, which is particularly important for ischaemia tolerance in renal failure, seems to be modulated and regulated predominantly by ET-1. In contrast to what was found with respect to structural and functional changes of the kidney in various experimental models of renal damage, a combination therapy--at least in the doses used--does not seem to provide additional benefit in the prevention of cardiovascular changes compared with the respective monotherapies.

Endothelin-1 and endothelin receptor antagonists in cardiovascular remodeling.

Endothelins build a peptide family composed of three isoforms, each of them containing 21 amino acids. Endothelin-1 is the isoform mainly responsible for any cardiovascular action and therefore the sole scope of this review. Endothelin-1 is the most potent endogenous vasoconstrictor known; in addition it acts as a potent (co)mitogen. There is a substantial body of experimental evidence that endothelin-1 may contribute not only to sustained vasoconstriction, but also to remodeling within the cardiovascular system. Thus, with the help of endothelin receptor antagonists (available for a few years) the involvement of mainly ETA receptors in structural diseases such as heart failure, pulmonary hypertension, atherosclerosis, restenosis, systemic hypertension, and chronic renal failure has been shown. These data make endothelin receptor antagonists, and especially those selective for the ETA receptor, promising agents for the treatment of chronic cardiovascular diseases associated with remodeling. Currently several chemically distinct, orally available members of this novel class of therapeutic agents are under clinical investigation.

Stimulation of the renin-angiotensin system by endothelin subtype A receptor blockade in conscious dogs.

Previous studies in dogs have shown additive or even synergistic effects of combined angiotensin-converting enzyme inhibition and either nonselective endothelin subtype A/B (ETA/B) or selective endothelin subtype A (ETA) receptor blockade on renal vascular resistance and mean arterial blood pressure. A possible mechanism underlying this interaction may be a stimulation of the renin-angiotensin system during endothelin (ET) receptor blockade. We therefore investigated whether plasma renin activity and renin release are regulated by the ETA receptor. Experiments were made in conscious, chronically instrumented dogs receiving either saline or the selective ETA receptor antagonist LU 135252 (10 mg/kg IV). Eighty to 100 minutes after the administration of LU 135252 (n=5), heart rate (99+/-7 versus 81+/-6 bpm; P<0.05) and renal blood flow (327+/-40 versus 278+/-36 mL/min; P<0.05) were increased significantly, whereas mean arterial blood pressure tended to be lower (93+/-5 versus 105+/-7 mm Hg). These changes were associated with a 2-fold increase in plasma renin activity (0.74+/-0.12 versus 0.37+/-0.10 ng angiotensin I per milliliter per hour; P<0.05). Measurements of renin release at various renal perfusion pressures (n=5) with the use of a vascular occluder implanted around the left renal artery revealed that ETA receptor blockade did not alter renin release at resting renal perfusion pressure (78+/-25 versus 71+/-39 U/min) but strongly enhanced the sensitivity of pressure-dependent renin release <80 mm Hg approximately 2.2-fold. In conclusion, selective ETA receptor blockade is associated with a stimulation of the circulating renin-angiotensin system, which results from both a sensitization of pressure-dependent renin release and a larger proportion of blood pressure values falling into the low pressure range, where renin release is stimulated. These find-ings strengthen the view that ET and the renin-angiotensin system closely interact to regulate vascular resistance and provide a physiological basis for synergistic hypotensive effects of a combined blockade of both pressor systems.

The "Phoenix" ADR database of the Drug Commission of the German Medical Profession--a clinically useful approach to optimize evidence-based medicine in Germany.

The innovative "Phoenix" database system of the Drug Commission of the German Medical Profession (AkdA) permits rapid access to data on adverse drug reactions. It enables the user to conduct searches covering a wide variety of questions within a short period of time. No one needs to be an "expert" to extract scientific knowledge from a database that currently already contains some 106,000 reports on adverse drug reactions. While our traditional apprenticeship model of physician training has served us well, an adaptation will be required for the new millennium. New tools are needed to allocate the available resources. Clinical proposals of experts or opinion leaders, guidelines, and highly graded clinical studies, like the use of clinical databases may help to improve safety and efficacy of drug administration. Evidence-based critical care medicine is therefore a potential tool for improving the effectiveness of drug therapy and for the patient's outcome. Over and above, the Phoenix database might be interpreted as an initiative instrument, which is easy to use and contributes to highlight the determinants of clinical decisions.

Analysis and occurrence of adverse events with oral anticoagulant therapy.

The antithrombotic potential of oral anticoagulants is undisputed as the frequency of recurrent thrombosis is high unless anticoagulant therapy is continued after hospital discharge. However, the relationship between potency and/or changes in anticoagulant therapy and frequency of complications remains unclear. Optimizing the clinical management of oral anticoagulation information obtained by databases may be advantageous in addition to meeting safety criteria, as described in the "Saarland Model." The Phoenix-database implicates an association between bleeding complications and the hypertensive elderly. From 1968 to 1993 most reports about cerebral/intraspinal bleedings occurred at prothrombin (PT)-values below 20% in the elder patients (>60 years of age) (12%; 367 reports). In the Saarland Model, 60 patients were followed from our department during a 3-year period. Our findings suggest neither a correlation of the range of PT values and the bleeding events nor an association with age or hypertension. It became obvious that "stable phases" of International Normalized Ratio (INR) [+/-15% change of 4 serial controls using nearly constant weekly oral anticoagulant dosages (+/-15%)] might be considered as a valid criterion of safety. At least the individual risk profile determines the patient's fate.