Anticoagulative effects of the inhaled low molecular weight heparin certoparin in healthy subjects.

Inhalation of heparin results in local antiinflammatory and antifibrotic effects and an inhibition of blood coagulation. A number of experimental and clinical studies demonstrated that inhalant administration of heparin or low molecular weight heparin (LMWH) is a feasible and save tool for anticoagulative treatment. However, heparin and LMWH differ in respect to their molecular weight, pulmonary absorption, and principle of their anticoagulative pattern. In our study we investigated the anticoagulative effect of different doses of the LMWH certoparin after inhalation (3000 IU-9000 IU) and subcutaneous injection (3000 IU) in healthy individuals in a cross-over design. Inhalations were performed using a new device allowing inhalations with optimized and standardized breathing patterns. The anticoagulative effect was determined by measurement of the anti-factor-Xa (anti-FXa) activity. Lung function parameters were measured before and after drug inhalation. Analysis of the anti-FXa activity as a function of the time after administration revealed values of the area under the curve (AUC) of 5.70+/-1.58 U.hour/ml and 8.43+/-1.31 U.hour/ml (mean+/-SD) with interindividual coefficients of variation of 28% and 13% after injection of 3000 IU and inhalation of 9000 IU, respectively. The AUC after inhalation of 9000 IU was significantly higher (P=0.0007) compared with subcutaneous injection of 3000 IU. In consequence, in order to obtain plasma anti-FXa activities of above 0.2 U/ml, which is considered sufficient for prophylaxis of venous thrombosis, 9000 IU LMWH have to be inhaled. Compared with the subcutaneous administration, the action of certoparin is longer after inhalation than after injection. Apparently, the drug is released rapidly according to a two-compartment kinetics, and its anticoagulant activity lasts over a long time without a marked plasma peak after administration. In detail, an elevation of plasma anti-FXa activity is achieved for 12 hours to 24 hours without a distinct peak shortly after inhalation. Inhalation of LMWH does not result in any changes in lung function or other side effects. The administration of LMWH by inhalation bears the following: the non-invasive route of drug application, the low interindividual variability of the anticoagulative effect, and a long-time pharmacological effect. These properties suggest that controlled inhalation of heparin is an attractive alternative to subcutaneous administration.

The effect of oral glucose loads on tissue metabolism during angiotensin II receptor and beta-receptor blockade in obese hypertensive subjects.

AT1 receptor blockers and ACE inhibitors decrease the risk for new onset diabetes mellitus. The phenomenon could be related to a direct angiotensin II effect on tissue metabolism. To address the issue, we recruited eighteen obese hypertensive patients. Patients were randomized to double-blind treatment with either valsartan (n = 8) or atenolol (n = 10) for thirteen weeks. They underwent an oral glucose tolerance test before and during active treatment, while metabolism was monitored through subcutaneous and intramuscular microdialysis and indirect calorimetry. After glucose ingestion, venous glucose and insulin concentrations increased rapidly while systemic free fatty acid concentrations were suppressed. Dialysate glucose and lactate concentrations increased briskly in adipose tissue and in skeletal muscle. Dialysate glycerol decreased profoundly in both tissues. Respiratory quotient increased markedly after glucose ingestion. These responses were identical at baseline and during active treatment either drug. We conclude that AT1 receptor blockade in obese hypertensive patients has no effect on interstitial glucose supply, lipolysis, and substrate oxidation. One possible explanation is that angiotensin II levels in obese hypertensives are not sufficient to elicit the metabolic changes that have been observed after direct angiotensin II application. The exact mechanism by which inhibition of the renin-angiotensin-aldosterone system decreases the diabetes risk remains unresolved and requires further study.

Efficacy and safety of combination therapy using high- or low-dose hydrochlorothiazide with valsartan or other Angiotensin-receptor blockers.

Only a minority of patients treated for hypertension achieve controlled blood pressure (BP) levels. Therapy with fixed-dose combinations of an angiotensinreceptor blocker (ARB) and low-dose hydrochlorothiazide (HCTZ) is commonly prescribed but not always sufficient to achieve the target BP. The efficacy and safety of the fixed-dose combination of valsartan 160 mg and HCTZ 25 mg was evaluated in patients in whom BP had not been controlled with a fixed-dose combination of another ARB and low-dose HCTZ (12.5 mg) in a multicenter trial. After a wash-out period for antihypertensive drugs, patients with a mean sitting diastolic BP (DBP) at trough (3)100 mm Hg but <110 mm Hg were treated with candesartan cilexetil 16 mg plus HCTZ 12.5 mg or telmisartan 80 mg plus HCTZ 12.5 mg for 4 weeks (phase 1). Patients whose BP was still uncontrolled (DBP (3)90 mm Hg) after 4 weeks of therapy were then given valsartan 160 mg plus HCTZ 25 mg for an additional 4 weeks (phase 2). The primary efficacy parameter was the reduction in DBP between week 4 and week 8 in the intention-to-treat (ITT) population. BP reduction during phase 1 was -14.3+/-11.3/-7.5+/-3.9 mm Hg. DBP was controlled in 26% of the patients after phase 1. In patients treated with valsartan 160 mg plus HCTZ 25 mg during phase 2, DBP decreased by an additional 10.3+/-6.5 mm Hg and the mean sitting systolic BP (SBP) by an additional 11.0+/-11.7 mm Hg. The additional decrease was significant (P<.0001) for both parameters and independent of the fixed-dose combination used during phase 1. Among patients whose BP remained uncontrolled during phase 1, 74% achieved a controlled DBP after phase 2. The incidence of adverse events during both phases was comparably low and the results of laboratory tests were unremarkable. Treatment with valsartan 160 mg/HCTZ 25 mg offered a substantial benefit for patients with hypertension not controlled with the combination of candesartan cilexetil 16 mg or telmisartan 80 mg and low dose HCTZ, while maintaining a comparable safety and tolerability profile.

Tegaserod is effective in the initial and retreatment of irritable bowel syndrome with constipation.

BACKGROUND: Symptoms of irritable bowel syndrome are often cyclical and thus may require repeated rather than continuous therapy. Tegaserod is effective and well-tolerated for irritable bowel syndrome with constipation but data on retreatment are lacking. AIM: To assess whether tegaserod retreatment is as efficacious and well-tolerated as initial treatment in a primary care setting. METHODS: This open-label trial was designed to evaluate the effectiveness of tegaserod under real-life conditions. Irritable bowel syndrome with constipation patients received tegaserod 6 mg b.d. for 12 weeks; response was assessed at weeks 4 and 12. Responders (those achieving satisfactory relief for at least 2 of the previous 4 weeks) at weeks 4 and/or 12 entered an 8-week withdrawal period where symptom recurrence was assessed. Patients experiencing recurrence could receive tegaserod 6 mg b.d. for another 4 weeks (retreatment phase) and on completion, could choose to continue tegaserod in a 6-month extension study. RESULTS: A total of 513 patients received initial treatment with tegaserod; 85.0% (436 of 513) responded. 403 responders entered the withdrawal period; symptoms recurred in 83.9% (338 of 403) after a mean of 38 days. Of the 307 patients who subsequently entered retreatment 89.3% (274 of 307) responded. Among patients entering the retreatment period, 269 (87.6%) had responded within the first 4 weeks of initial treatment. Of these, 243 (90.3%) responded to tegaserod retreatment. Adverse events were infrequent and similar during 4 weeks of the initial treatment period (11.1%) and on retreatment (10.4%). The extension study, completed by 188 of 232 (81.0%) patients, demonstrated good long-term tolerability of tegaserod. CONCLUSIONS: Irritable bowel syndrome with constipation patients can be successfully treated, and retreated, with tegaserod 6 mg b.d. Tegaserod was well-tolerated during initial and retreatment periods.

Monitoring of peripheral blood cytotoxic T-cells under fluvastatin treatment in renal transplant recipients.

Flow cytometric T-cell analysis is capable of adding valuable information for balancing immunosuppression in transplant recipients as it can take into account individual effects of immunosuppressive drugs on each patient as well as effects of other drugs which may modify the overall immunosuppression. Studies suggest that HMG-CoA-reductase-inhibitors (statins) reduce the frequency of organ rejection, although the precise mechanism of this effect is unknown. We therefore evaluated the effect of fluvastatin on size and activation of T-cell subpopulations and NK-cell activity in renal transplant recipients. At baseline, the population size of activated (HLA-DR+) T-cells was negatively correlated to serum HDL cholesterol suggesting an increased T-cell activation at low HDL levels. Fluvastatin treatment of a hypercholesterolemic group of patients for two months significantly decreased the LDL cholesterol. A longitudinal analysis revealed a relative increase in non-MHC restricted cytotoxic T-cells (CD3+/CD16+ or CD56+) over time which was significantly attenuated in fluvastatin treated patients but not in normocholesterolemic controls. Moreover, a relative decrease of activated MHC class I-restricted cytotoxic CD8+ T-cells was only observed upon fluvastatin treatment. NK-cell number and activity did not differ between groups. In summary, fluvastatin treatment of hypercholesterolemic renal transplant recipients is associated with a specific modulation of T-cells exerting cytotoxic effector functions.

The co-seasonal application of anti-IgE after preseasonal specific immunotherapy decreases ocular and nasal symptom scores and rescue medication use in grass pollen allergic children.

BACKGROUND: Specific immunotherapy (SIT) and treatment with anti-immunoglobulin (Ig)E antibody are complementary approaches to treat allergic rhinoconjunctivitis, which may be used for single or combined treatment. OBJECTIVE: A randomized, double-blind, placebo-controlled trial was conducted to compare the efficacy of single and combined treatment with SIT and anti-IgE (Omalizumab) in reducing symptom severity and rescue medication use. METHODS: A total of 221 subjects with birch and grass pollen allergic rhinoconjunctivitis aged 6-17 years were analysed during the grass pollen season. Group A (SITbirch + placebo) served as a reference group obtaining no effective treatment for grass pollen allergy. Group B received anti-IgE monotherapy during grass pollen season, group C SIT grass pollen monotherapy, and group D the combined treatment of SIT and Omalizumab. RESULTS: Preseasonal treatment with grass pollen SIT alone compared with SIT with the nonrelated allergen did not reduce symptoms or rescue medication use. Anti-IgE monotherapy significantly diminished rescue medication use and number of symptomatic days. The combined treatment with SIT and anti-IgE showed superior efficacy on symptom severity compared with anti-IgE alone. CONCLUSIONS: Co-seasonal Omalizumab therapy showed considerable effects in children with seasonal allergic rhinitis. The combination of SIT plus Omalizumab was clinically superior to each treatment alone during the first year of observation.

Body-weight-independent dosing of cyclosporine micro-emulsion and three times weekly maintenance regimen in severe psoriasis. A randomised study.

BACKGROUND: Body-weight-dependent (BWD) treatment of psoriasis with cyclosporine A (CsA is well established. It has recently been reported that this is not necessary for the treatment of atopic dermatitis. OBJECTIVES: (1) To investigate the efficacy and safety of a CsA micro-emulsion administered in a new body-weight-independent (BWI) protocol and to compare it to a BWD dosage regimen in the treatment of severe psoriasis. (2) To investigate the duration of disease remission after intermittent treatment of psoriasis with CsA. PATIENTS AND METHODS: 122 adult patients with severe plaque-type psoriasis (PASI > or = 12) were included in this study which consisted of two treatment periods: period I was a randomised parallel-group comparison of daily CsA doses of 100-300 mg (BWI) or 1.25-5.0 mg/kg (BWD) for 12 weeks; period II was a randomised double-blind placebo-controlled extension treatment of patients, who had responded (>75% PASI recovery) to the treatment in period I and continued the treatment on their last effective dose or placebo 3 times weekly for a further 12 weeks. RESULTS: In period I, the increase in creatinine in the BWI group (2.7 micromol/l) was proven to be non-inferior to that of the BWD group (3.5 micromol/l) at a non-inferiority limit of 5 micromol/l (p < 0.05). The PASI decreased with BWI dosing from 22.0 to 3.0 and with the BWD scheme from 19.5 to 2.5 (p = 0.98). In period II, the relapse rates were 40.5% (17/42) with intermittent CsA and 56.9% (29/51) with placebo (p = 0.15). CONCLUSIONS: BWI dosing is as effective and safe as conventional BWD dosing for the short-term treatment of severe psoriasis. There was a tendency toward a prolongation of remission with intermittent CsA treatment.

Cyclosporine in severe psoriasis. Results of a meta-analysis in 579 patients.

OBJECTIVE: A meta-analysis of 3 major German studies conducted between 1989 and 1994 with cyclosporine in severe psoriasis was performed to allow an integrated evaluation of the efficacy and tolerability of cyclosporine in this indication. DESIGN AND SETTING: All 3 studies were prospective, randomized, parallel group studies. The studies were conducted in 61 dermatologic centers in Germany. PATIENTS AND INTERVENTIONS: The studies involved 597 patients with severe plaque type psoriasis. Treatment consisted of cyclosporine (at a dosage of 1.25, 2.5 or 5 mg/kg/day), etretinate (at a mean daily dose of 0.53 mg/kg/day) or placebo in a total of 756 treatment cycles with a maximum duration of 12 weeks. MAIN OUTCOME MEASURES: The main outcome measures were the psoriasis area and severity index (PASI) and serum creatinine level. RESULTS: The meta-analysis revealed that cyclosporine given in a dosage of 2.5 and 5 mg/kg/day was significantly superior to etretinate. In addition cyclosporine 1.25 mg/kg/day proved to be significantly more effective than placebo. An increase in serum creatinine level that required intervention occurred in 3.4% of cyclosporine treatment cycles. CONCLUSION: Cyclosporine is highly effective and well tolerated in the short term treatment of severe psoriasis.

Low-dose cyclosporin A microemulsion in children with severe atopic dermatitis: clinical and immunological effects.

Cyclosporin A (CsA) is an effective and well-tolerated treatment for severe childhood atopic dermatitis (AD). By starting at a low dose, the therapeutic safety should be further increased. The aim of this study was to evaluate low-dose CsA in childhood AD with respect to clinical outcome and modulation of T-cell dysregulation. In an open prospective study, 10 children (age: 22-106 months) with severe AD (mean objective SCORAD score > 40 on two baseline measurements at a minimum interval of 2 weeks) were treated with CsA solution for 8 weeks. All patients received a starting dose of 2.5 mg/kg/day, which was increased stepwise in non-responders to a maximum of dose of 5 mg/kg/day. Disease activity was monitored using the SCORAD index. The frequency of cytokine-producing peripheral blood T lymphocytes was analyzed by intracellular cytokine staining, and T-cell numbers were measured by fluorescence-activated cell sorter (FACS) analysis. Twenty healthy age-matched children were included as controls for the immunological data. Nine of the 10 patients had a SCORAD reduction of at least 35%. In seven patients this was achieved with low-dose CsA at 2.5 mg/kg/day (n = 4) and 3.5 mg kg/day (n = 3). Seven of the nine responders experienced no relapse within the 4-week follow-up period. At baseline the percentage of interleukin-4 (IL-4), IL-13, and human leucocyte antigen (HLA)-DR-positive CD3(+) cells was higher in the patient group than in the controls. After CsA treatment there was a significant reduction in interferon-gamma (IFN-gamma), IL-2, IL-4, IL-13, and HLA-DR-positive CD3(+) cells. Hence, in severe pediatric AD, CsA microemulsion, when started at a low dose (2.5 mg/kg/day), improves clinical measures of disease, reduces T-lymphocyte cytokine production, and regulates T-cell activation.

Vaccination with recombinant modified vaccinia virus Ankara protects against measles virus infection in the mouse and cotton rat model.

Modified vaccinia virus Ankara (MVA) has been used as an experimental vaccine vector against respiratory infections. We have tested the safety and immunogenicity of a recombinant virus expressing the hemagglutinin of measles virus (MVA-MV-H) using the mouse model of measles virus induced encephalitis and the cotton rat model for respiratory infection. MVA-MV-H proved to induce a TH1 response, neutralizing antibodies and conferred protection against both encephalitis and lung infection. The cotton rat is very sensitive to infection with replication competent vaccinia virus. In these animals MVA-MV-H proved to be a very well tolerated vaccine. However, the efficiency in the presence of MV specific maternal antibodies was low (even using a prime-boost strategy) and therefore might have to be improved.

Inhibition of major histocompatibility complex class II-dependent antigen presentation by neutralization of gamma interferon leads to breakdown of resistance against measles virus-induced encephalitis.

BALB/c mice are resistant to measles virus (MV)-induced encephalitis due to their strong MV-specific CD4(+) T-cell response. Resistance is broken by neutralization of gamma interferon with monoclonal antibodies, indicating an important role for this pleiotropic cytokine. Here, we demonstrate that mouse gamma interferon has no direct antiviral effect in vitro and in vivo. The breakdown of resistance is due neither to a switch in the T-helper response nor to an impaired migration of CD4(+) T cells. Neutralization of gamma interferon interferes with the major histocompatibility complex class II-dependent antigen presentation and subsequent proliferation of CD4(+) T cells in vitro and in vivo. In consequence, the reduction in numbers of CD4(+) T cells below a protective threshold leads to susceptibility to MV-induced encephalitis.

Treatment of acute ischemic stroke with the low-molecular-weight heparin certoparin: results of the TOPAS trial. Therapy of Patients With Acute Stroke (TOPAS) Investigators.

BACKGROUND AND PURPOSE: To study the safety and efficacy of the low-molecular-weight heparin certoparin, we performed a randomized, double-blind, dose-finding multicenter trial in patients with acute ischemic stroke (Therapy of Patients With Acute Stroke [TOPAS]). METHODS: We randomized 404 patients to 4 treatment groups within 12 hours of stroke onset: 3000 U anti-factor Xa (aXa) certoparin once daily (treatment group 1); 3000 U aXa twice daily (group 2); 5000 U aXa twice daily (group 3); and 8000 U aXa twice daily (group 4). The primary efficacy variable was the proportion of patients reaching a favorable functional outcome (Barthel Index >/=90 points) at 3 months. CT was performed at trial entry, after 7 days, and on clinical deterioration. RESULTS: The proportion of patients with Barthel Index >/=90 was not different between treatment arms (61.5%, 60.8%, 63.3%, and 56.3% in the 4 groups, respectively; intent-to-treat population). European Stroke Scale scores improved in all treatment groups within the first 14 days to a similar extent. During the follow-up of 6 months, percentages of patients with recurrent stroke/transient ischemic attack were 11.0%, 5.9%, 9.7%, and 13.0% in the 4 groups, respectively. Overall mortality was only 7.4%. Two parenchymal cerebral hematomas and 1 extracranial bleeding episode occurred in treatment group 1 versus 1 and 0 in group 2, 2 and 0 in group 3, and 4 and 5 in group 4, respectively. During certoparin treatment, 1 deep vein thrombosis but no pulmonary embolism was observed. CONCLUSIONS: Dose increase of certoparin up to 8000 U aXa twice daily did not improve the functional outcome of patients with ischemic stroke. Severe bleeding tended to be more frequent in the highest dose group only.

Influence of low molecular weight heparin (certoparin) and unfractionated heparin on the release of cytokines from human leukocytes.

We analyzed the influence of heparins (unfractionated heparin, UFH and low molecular weight heparin certoparin) on the generation of IL-1ra, IL-6, IL-10, and IL-12p40 and from leukocyte fractions in vitro. Polymorphonuclear neutrophil leukocytes (PMN) and peripheral blood mononuclear cells (PBMC) from 16 different healthy donors were isolated and adjusted to 1 x 10(6) cells/ml supplemented RPMI 1640. Leukocyte fractions were differentially stimulated (PMN with 1 microg and 5 microg LPS, PBMC with 10 ng TSST- 1 or 2 microg ConA) in the presence or absence of heparins (1 U/ml, 2 U/ml, and 4 U/ml) for 24 h at 37 degrees C. Cytokine release was analyzed by ELISA. Certoparin but not UFH led to a dose-dependent increase in IL-6 from non-stimulated PBMC. In contrast, the release of IL-1ra, IL-10, and IL-12p40 was not modulated by heparins in a dose-dependent fashion. Increases in these cytokines occurred only as single incidents at intermediate heparin levels. An influence of the heparins on the apoptosis of PMN (measured as DNA-fragmentation in non-stimulated or LPS-stimulated cell-fractions) was not observed.

Antihypertensive effects of valsartan/hydrochlorothiazide combination in essential hypertension.

Fixed-dose combination therapy has received increased interest since publication of JNC-VI report and WHO/ISH guidelines 1999. We compared in a randomized, double-blind study the efficacy and tolerability of valsartan 80 mg combined with hydrochlorothiazide (HCTZ) 12.5 mg to monotherapy with either HCTZ 12.5 mg or 25 mg in patients with essential hypertension inadequately controlled by previous HCTZ 12.5 mg monotherapy. Two hundred and seventeen patients whose blood pressure (BP) control remained poor (95 mmHg < or = sitting diastolic BP < 115 mmHg) after a 4-week single-blind period with HCTZ 12.5 mg were randomized to receive either combination therapy with valsartan 80 mg plus HCTZ 12.5 mg (V/HCTZ) or monotherapy with HCTZ 12.5 mg or HCTZ 25 mg for 8 weeks. Reduction of sitting trough diastolic BP between baseline and week 8 as well as tolerability was evaluated. Reduction in trough diastolic BP was most pronounced in the V/HCTZ group (-11.3 mmHg) and significantly greater than in the HCTZ 12.5 mg group (-2.9 mmHg, p < 0.001) and the HCTZ 25 mg group (-5.7 mmHg, p < 0.001). Tolerability of study medication was comparable between all three groups. In conclusion, switching to V/HCTZ combination therapy provides an additional lowering of BP compared to dosage increase of the thiazide in patients with BP insufficiently controlled by HCTZ 12.5 mg monotherapy.

Treatment of cells with detergent activates caspases and induces apoptotic cell death.

Due to their amphiphilic properties, detergents readily disrupt cellular membranes and cause rapid cytolysis. In this study we demonstrate that treatment of cells with sublytic concentrations of detergents such as Triton X-100, Nonidet P-40, n-octylglucoside and the bile salt sodium deoxycholate induce typical signs of apoptosis including DNA fragmentation and cleavage of poly(ADP-ribose) polymerase molecules. The detergent concentration required for apoptosis was below the critical micellar concentration. Induction of apoptosis was not restricted to human cells but similarly occurred in a variety of other vertebrate cell lines. Unstimulated peripheral blood mononuclear cells were susceptible to apoptosis induction by detergent suggesting that apoptosis in this circumstance is not mediated by CD95. Cell death was not due to influx of calcium from the medium. Apoptosis was blocked and cytolysis prevented by treatment with peptide inhibitors of caspases. These findings suggest a process of apoptosis that is initiated upon nonspecific alterations at the cell membrane level. Physiologic correlates of this process still have to be defined.

Effect of reserpine treatment on low-density lipoproteins in arterial wall and internal organs of rats.

The effects were determined in rats of single injections of reserpine at increasing doses (0.5, 1.58, and 5.0 mg/kg) on low-density lipoprotein (LDL) and cholesterol in aortic wall, heart, liver, kidney, and adrenal gland. Catecholamine levels in plasma, heart, and liver, arterial blood pressure, and heart rate were also monitored. Reserpine was injected intraperitoneally, followed immediately by the administration of [3H]cholesterol by gavage. Twelve hours later, homologous 125I-tyramine cellobiose-labeled LDL (125I-TC-LDL) was injected intravenously. Twenty-four hours later, the rats were killed, and the radioactivities of aortic walls, heart, liver, kidney, and adrenal glands were determined. The results showed that after reserpine treatment the accumulation of both the 125I-TC label derived from LDL and total [3H]cholesterol was significantly reduced in aortic wall and heart, increased in liver, and unchanged in the kidney and adrenal gland. At higher doses (1.58 and 5.0 mg/kg), reserpine significantly accelerated the plasma clearance of radiolabelled LDL. Plasma noradrenaline in reserpine-treated animals decreased maximally (86%) by 12 h and by 61-71% at 36 h compared with the control. Plasma adrenaline increased transiently after injection of reserpine and then returned to the basal levels. Reserpine greatly decreased noradrenaline and adrenaline levels in heart and liver. Arterial blood pressure was decreased significantly (0.001 < p < 0.05) at 12 h by the two lower doses of reserpine and then returned to normal values over the next 24 h. The results indicate that reserpine decreases LDL cholesterol in artery wall and heart and increases it in liver. These findings suggest that reserpine could find a new use as a cholesterol-lowering drug for the prevention of atherosclerosis.

Beneficial effects of fluvastatin on myocardial blood flow at two time-points in hypercholesterolemic patients with coronary artery disease.

Hypercholesterolemia is a major risk factor initiating and accelerating atherosclerosis and leading to severe stages of coronary artery disease (CAD) with a high risk of cardiovascular events. We investigated the impact of lipid lowering in patients with hypercholesterolemia and evident CAD on clinically relevant parameters like myocardial perfusion. Myocardial imaging was performed with thallium-201 single photon-emission computed tomography at rest and after maximal bicycle exercise in 22 patients after a 4-week lead-in period, and after 12 and 24 weeks of therapy with fluvastatin. Perfusion defects occurred in all patients, indicating stress-induced myocardial ischemia. After 12 weeks of therapy, the perfusion of the ischemic segments increased by 26% (277+/-99 to 349+/-96 cpm; p < 0.001), whereas the value of the normal segments was augmented only by 4% (478+/-44 to 497+/-28 cpm; p < 0.05). The results slightly improved further after 24 weeks. Moreover, a subgroup analysis elucidated a more pronounced effect in patients without lipid-lowering premedication. This nonpretreated group (n = 11) revealed an improvement of ischemic segments at stress by 42% at week 24. In contrast, pretreated patients had an increase of only 18% (between groups, p < 0.05), indicating a carryover effect of premedication. In conclusion, short-term therapy with fluvastatin acts beneficially on impaired vascular function in hypercholesterolemic patients with CAD.

A body-weight-independent dosing regimen of cyclosporine microemulsion is effective in severe atopic dermatitis and improves the quality of life.

BACKGROUND: Cyclosporine has shown to be effective in severe atopic dermatitis. Little has been reported on the new microemulsion form (Sandimmune, Neoral) in the treatment of this disease. Also, it has not been investigated whether a body-weight-independent dosing regimen of cyclosporine is appropriate for the treatment of atopic dermatitis. OBJECTIVE: The goal of this study was to investigate a body-weight-independent dosing regimen of cyclosporine microemulsion in severe atopic dermatitis by comparing high and low starting doses of treatment. METHODS: A total of 106 adults with severe atopic dermatitis were enrolled in this double-blind study and randomized to receive a starting dose of either 150 mg (low) or 300 mg (high) of cyclosporine microemulsion daily. After 2 weeks the dose could be reduced by 50% if the clinical symptom score was reduced by 50% or more. After 8 weeks the responders entered a 4-week follow-up phase and were randomized to either stop treatment or to continue on their last effective dose every second day. RESULTS: After 2 weeks of treatment the total symptom score decreased from 59.0 to 39.3 with 150 mg and from 60.7 to 33.2 with 300 mg cyclosporine (P <.05). Until week 8 there was a further decrease in the clinical symptom score to 30.8 with low-dose therapy and 25.5 with high-dose therapy. Similar positive effects could be observed in assessments of affected body surface area, itching, sleep loss, and quality of life. At week 2, there was an increase of 0.6% in serum creatinine in patients receiving 150 mg, and 5.8% in the 300 mg group (P <.01). At week 8, the effect on serum creatinine was similar, with a 1.1% rise in the low dose group and a 6.0% increase in the high dose group. Body weight had no influence on efficacy or tolerability in this study. CONCLUSION: Body-weight-independent dosing with cyclosporine seems to be feasible in the short-term treatment of severe atopic dermatitis. Although the starting dose of 300 mg/day is more effective than 150 mg/day, the 150 mg dose would be preferable for the initiation of therapy because of its excellent renal tolerability.

Salmonella vaccines secreting measles virus epitopes induce protective immune responses against measles virus encephalitis.

In the present study we describe a live vaccine against measles virus (MV) infection on the basis of attenuated Salmonella typhimurium aroA secreting MV antigens via the Escherichia coli alpha-hemolysin secretion system. Two well-characterized MV epitopes, a B-cell epitope of the MV fusion protein (amino acids 404-414) and a T-cell epitope of the MV nucleocapsid protein (amino acids 79-99) were fused as single or repeating units to the C-terminal secretion signal of the E. coli hemolysin and expressed in secreted form by the attenuated S. typhimurium aroA SL7207. Immunization of MV-susceptible C3H mice revealed that S. typhimurium SL7207 secreting these antigens provoked a humoral and a cellular MV-specific immune response, respectively. Mice vaccinated orally with a combination of both recombinant S. typhimurium strains showed partial protection against a lethal MV encephalitis after intracerebral challenge with a rodent-adapted, neurotropic MV strain.