Population PK-PD Model for Tolerance Evaluation to the p38 MAP Kinase Inhibitor BCT197.

The p38 mitogen-activated protein kinase (p38) is a key signaling pathway involved in regulation of inflammatory cytokines. Unexpectedly, several clinical studies using p38 inhibitors found no convincing clinical efficacy in the treatment of chronic inflammation. It was the objective of this study to characterize the population pharmacokinetics (PK) of BCT197 in healthy volunteers and to examine the relationship between BCT197 exposure and pharmacodynamics (PD) measured as inhibition of ex vivo lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFα), a downstream marker of p38 activity. PK was characterized using a two-compartment model with mixed-order absorption and limited-capacity tissue binding. The PK-PD relationship revealed that suppression of TNFα was partly offset over time, despite continuous drug exposure. This may indicate a mechanism by which the inflammatory response acquires the ability to bypass p38. Simulations of posology dependence in drug effect suggest that an intermittent regimen may offer clinical benefit over continuous dosing and limit the impact of tolerance development.

Indacaterol once-daily is equally effective dosed in the evening or morning in COPD.

UNLABELLED: Indacaterol is a novel, inhaled, long-acting ß(2)-agonist providing 24-h bronchodilation with once-daily (o.d.) dosing in patients with COPD. In this double-blind, incomplete block crossover study, patients with moderate-to-severe COPD were randomised to receive three treatment cycles from: indacaterol 300 µg o.d. dosed PM or AM, salmeterol 50 µg twice daily or placebo, each for 14 days. Trough FEV(1) was measured 24 h after indacaterol, and 12 h after salmeterol. Ninety-six patients (mean age: 64 years; post-bronchodilator FEV(1) 57% predicted, FEV(1)/FVC 55%) were randomised; 83 completed. After 14 days, the difference vs. placebo in trough FEV(1) for PM indacaterol was 200 mL (p < 0.001 [primary analysis]) and for AM indacaterol was 200 mL (p < 0.001). Compared with salmeterol, trough FEV(1) for PM indacaterol was 110 mL higher (p < 0.001), and for AM indacaterol was 50 mL higher (p = NS). Over 14 days, vs. placebo, both PM and AM indacaterol improved the % of nights with no awakenings (by 11.9 and 8.1 points; p < 0.01); the % of days with no daytime symptoms (by 6.7 and 5.5 points; p < 0.05); and the % of days able to perform usual activities (by 6.7 and 7.8 points; p < 0.05). Indacaterol provided 24-h bronchodilation and improvement in symptoms regardless of whether taken regularly in the morning or evening. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00615030.

Inhibition of KSP by ARRY-520 induces cell cycle block and cell death via the mitochondrial pathway in AML cells.

Kinesin spindle protein (KSP), a microtubule-associated motor protein essential for cell cycle progression, is overexpressed in many cancers and is a potential anti-tumor target. We found that inhibition of KSP by a selective inhibitor, ARRY-520, blocked cell cycle progression, leading to apoptosis in acute myeloid leukemia cell lines that express high levels of KSP. Knockdown of p53, overexpression of XIAP and mutation in caspase-8 did not significantly affect sensitivity to ARRY-520, suggesting that the response is independent of p53, XIAP and the extrinsic apoptotic pathway. Although ARRY-520 induced mitotic arrest in both HL-60 and Bcl-2-overexpressing HL-60Bcl-2 cells, cell death was blunted in HL-60Bcl-2 cells, suggesting that the apoptotic program is executed through the mitochondrial pathway. Accordingly, inhibition of Bcl-2 by ABT-737 was synergistic with ARRY-520 in HL-60Bcl-2 cells. Furthermore, ARRY-520 increased Bim protein levels prior to caspase activation in HL-60 cells. ARRY-520 significantly inhibited tumor growth of xenografts in SCID mice and inhibited AML blast but not normal colony formation, supporting a critical role for KSP in proliferation of leukemic progenitor cells. These results demonstrate that ARRY-520 potently induces cell cycle block and subsequent death in leukemic cells via the mitochondrial pathway and has the potential to eradicate AML progenitor cells.

Long-term antibiotic treatment with roxithromycin in patients with multiple sclerosis.

BACKGROUND: There are conflicting results concerning an association between Chlamydia pneumoniae and MS (multiple sclerosis). In the present study, we investigated a possible therapeutic option with antibiotics. PATIENTS AND METHODS: In our randomized, placebo-controlled double-blind study, 28 patients with the confirmed diagnosis of MS [61% relapsing-remitting MS (RR-MS), 32% secondary chronic-progressive MS (SP-MS) and 7% primary chronic progressive MS (PP-MS)] were treated over a time period of 12 months with three cycles of a 6-week oral antibiotic therapy with roxithromycin (300 mg per day) or placebo. RESULTS: No significant differences were observed in patients with RR-MS regarding the expanded disability status scale (EDSS) and the relapse rate when comparing treatment with roxithromycin and placebo. CONCLUSION: Our study shows that the patients with MS do not profit from a long-term antibiotic treatment with roxithromycin compared to placebo treatment. A causative connection between bacterial infections with C. pneumonia and MS therefore does seem very unlikely.

[Pain, fatigue, depression after borreliosis. Antibiotics used up--what next?]. / Schmerzen, Müdigkeit, Depressionen nach Borrelieninfektion. Antibiotika ausgereizt--was jetzt?

Antibiotic treatment--usually stage-dependent in terms of the active agent, duration and form of application--is the central pillar in the management of Lyme disease. In the late stages of borreliosis, symptoms may persist despite extensive and repeated antibiotic treatment. In this phase, borreliosis-typical neuropathy and neuralgia, chronic fatigue and neuropsychological deficits predominate. Irrespective of whether renewed antibiotic treatment is indicated or not, symptomatic treatment must be continued.

[Differential diagnosis of Lyme borreliosis]. / Die wichtigsten Differenzialdiagnosen: Wanderröte oder Arzneimittelexanthem--Neuroborreliose oder MS?

In all three stages, Lyme borreliosis offers a wide range of possible differential diagnoses: even the "typical" erythema chronicum migrans may present as erysipelas, erysipeloid, erythema annulare centrifugum or a drug-induced exanthema. In the advanced stages II and III, neuroborreliosis in particular may be mimicked by various other conditions of both infectious and noninfectious etiology. Major examples are CEE (Central European Encephalitis), ehrlichiosis, chlamydial infections and multiple sclerosis. Currently, the biggest diagnostic problem is the non-standardized laboratory diagnostic work-up. For this reason, even in the presence of a positive or borderline IgG antibody result, unclear symptoms should prompt a differential diagnostic investigation.

[Studies on the importance of tick-borne encephalitis in Rhineland-Pfalz]. / Untersuchungen zur Bedeutung der Frühsommer-Meningoenzephalitis in Rheinland-Pfalz.

Within the scope of a prospective clinical study during 2001 in Rhineland-Palatinate specimen from sera and cerebrospinal fluids of 163 patients with suspected meningitis were controlled in an enzyme immunoassay concerning a TBE infection. Questionable results were checked via a neutralisation test. In no case such an infection was confirmed. No virus specific nucleic acids could be detected in 998 nymphs and adults of Ixodes ricinus in an additional investigation in 2000. Therefore Rhineland-Palatinate has to be considered as a region with low virus prevalence. A general recommendation for vaccination is not necessary.

[Stroke therapy. What is established, what is new?]. / Schlaganfalltherapie. Was hat sich bewährt, was ist neu?

Early treatment of a stroke, for example, on a stroke unit reduces neurological deficits and decisively improves survival. Of initial importance is an optimal supply of oxygen. Fever should be rapidly reduced, and blood sugar within the normal range also improves the prognosis. Only when blood pressure is very high is--moderate--lowering recommended. On the contrary, raising the blood pressure and cardiac output may have a positive effect on cerebral bloodflow with fewer neurological deficits resulting. In the case of immobile patients or patients with higher-grade paralysis, antithrombotic measures--increasingly utilizing low molecular-weight heparins--are indicated. Last but not least, early physiotherapy and logopedic treatment have an important role to play. Special forms of therapy such as thrombolysis can be carried out only in well equipped centers with experienced personnel. The use of oxygen-binding plasma substitutes and hypervolemic hemodilution are highly promising future therapeutic options.

[Ischemic or hemorrhagic stroke? Rapid diagnosis improves prognosis for the patient]. / Ischämischer oder hämorrhagischer Schlaganfall? Schnelle Diagnostik verbessert die Prognose des Patienten.

In industrialized countries, stroke is the third most common cause of death, and often leads to permanent disability. When clinical suspicion is raised, a thorough diagnostic work-up and treatment must be initiated without delay. In recent years, decisive advances have been made in this area, and the pathophysiological categorization of ischemic cerebral infarction has become accepted, with the modern imaging procedures having played a significant role. Reliable differentiation from intracerebral hemorrhage is enabled in particular by CCT and MRI, and is of great importance both for acute treatment and secondary prevention. Stroke units make available the necessary equipment and personnel. Patients who receive initial treatment on a stroke unit are already benefiting from a 31% reduction in mortality and severe disability.

Incidence and prevalence of infection with human granulocytic ehrlichiosis agent in Germany. A prospective study in young healthy subjects.

BACKGROUND: Only limited data are available on incidence and prevalence of infection with the human granulocytic ehrlichiosis (HGE) agent in a healthy population. MATERIALS AND METHODS: In a prospective study, we tested 361 male soldiers (age 18-29 years) from southwestern Germany for the HGE agent immunoglobulin G (IgG) using an indirect immunofluorescence antibody assay and for Borrelia burgdorferi IgG with an ELISA at the beginning and the end of their 10-month military service. Using a standardized questionnaire, the subjects were asked about clinical symptoms at the beginning and the end of the observation period. RESULTS: Of these 361 subjects, 14.9% were HGE agent IgG positive at study entry. 19 participants (5.3%) seroconverted from IgG negative to positive during the observation period resulting in an incidence rate of 6.4% per year. 20 subjects converted from initially HGE agent IgG positive to negative resulting in a reconversion rate of 6.6% per year. Concurrence of Borrelia IgG and HGE agent IgG was observed in 21.1%, whereas 13.7% were HGE agent IgG positive but Borrelia IgG negative (not significant). Clinical symptoms associated with HGE were not present in seroconverting subjects. CONCLUSION: Infection with the HGE agent occurs frequently in southwestern Germany but was asymptomatic in these young subjects.

[Autochthonous cases of tick-borne encephalitis in Rhineland-Palatinate]. / Autochthone Fälle der Frühsommer-Meningoenzephalitis in Rheinland-Pfalz.

Tick-borne encephalitis (TBE) is a neurotrophic viral disease which is endemic to certain regions. Such areas in Germany include Bavaria, Baden-Württemberg, and the Odenwald region in Hessen. So far, it has not been endemic to Rhineland-Palatinate. There, only two single cases of TBE occurred in the years 1992 and 1997, near the town of Idar-Oberstein. We report two new cases of TBE which appeared in 1999 and two current cases from the Idar-Oberstein region which have been verified clinically and serologically. At admission, the patients suffered from headache, muscle pains, and high fever, in one case meningitis was suspected. In all four patients, serology for borrelia was negative in serum and CSF. The described cases indicate that it is possible to acquire TBE in Rhineland-Palatinate, although only two cases have been reported in this area over the previous 10 years. Particularly in regions with a low incidence of TBE, the disease should be taken into consideration as a differential diagnosis. Studies of tick populations in regions with a low incidence can help in evaluating the benefit of possible vaccine recommendations by local public health authorities.

Comparison of three approaches to doxorubicin therapy: free doxorubicin, liposomal doxorubicin, and beta-glucuronidase-activated prodrug (HMR 1826).

BACKGROUND: Three approaches to doxorubicin therapy are directly compared: free doxorubicin, liposomal doxorubicin and beta-glucuronidase-activated prodrug (HMR 1826). MATERIALS AND METHODS: The optimal dose of HMR 1826 was determined to be 200 mg/kg once a week and subsequent studies were carried out comparing HMR 1826 at 200 mg/kg 1x/wk, liposomal doxorubicin (Doxil) at 9 mg/kg 1x/wk and free doxorubicin at 7 mg/kg 1x/wk in seven different human tumor xenograft models. RESULTS: All three forms of doxorubicin inhibited tumor growth with similar efficacy in each of the tumor models with the exception of MDA-MB-231 tumor xenografts, which were resistant to free doxorubicin but sensitive to Doxil and HMR 1826. Overall less weight loss was observed with HMR 1826 treatment. CONCLUSIONS: The efficacy of HMR 1826 is equal to or better than that of doxorubicin and Doxil at a safe dose and schedule, indicating that the beta-glucuronidase activated prodrug approach is safe and effective.

Fractioning the Hooper: a multiple-choice response format.

The Hooper Visual Organization Test (HVOT) provides an excellent illustration of the multifactorial nature of most neuropsychological tests. Although the HVOT clearly requires certain visual perceptual skills, the test also demands that the subject produce an overt verbal response - i.e., the name of the object that has been cut up and rearranged. Thus, individuals with disorders of confrontation naming may obtain low scores on the HVOT by virtue of their anomia, even if the primary perceptual skills that the HVOT purports to assess are intact. The present study was designed to minimize the demands of object naming on HVOT performance, by using a multiple choice format of the HVOT. Fourteen individuals with lateralized injury resulting from either cerebral vascular accident or cerebral contusion were administered the Boston Naming Test (BNT) and the standard version of the HVOT. Approximately 24 hours later, subjects were administered the Multiple-Choice Hooper Visual Organization Test (MC-HVOT). The MC-HVOT consisted of the 30 original HVOT stimuli presented with four response choices, including the correct response and three foils. A paired sample t test revealed that anomic subjects achieved a significantly greater number of correct responses on the MC-HVOT then under the standard HVOT administration. Subjects with both right and left hemisphere involvement benefited from diminished naming demands. Overall HVOT performance significantly improved when the object naming demand was reduced, resulting in a clearer assessment of visual integration skills. These findings may have significant implications for both interpretation of impairment and formulation of treatment recommendations.

The Erve virus: possible mode of transmission and reservoir.

The Erve virus is suspected to cause severe headache in humans, lasting several days (thunderclap headache). Mice are characterized as a probable reservoir for the Erve virus. We tested 396 wild mice for Erve virus using an immunofluorescence test and found Erve virus antibodies in five cases, showing that small mammals form a reservoir for Erve virus. If ticks are the vector for the virus, a coincidence with borreliosis should exist. We were unable to confirm this in a homogeneous cohort of 955 young men, 62 of whom tested positive for borreliosis. This group did not test positive significantly more often in the immunofluorescence test than a gender- and age-matched control group.

Support and faculty mentoring programmes for medical students in Germany, Switzerland and Austria.

OBJECTIVES: To study what is being done at German-speaking universities regarding the counselling and tutoring of students, we carried out a survey among the deans of medical faculties in Germany, Austria and Switzerland. Our main concern was if any such projects were already available to the medical student or whether efforts to this purpose were under way. DESIGN: We focused in particular on faculty mentoring programmes, a continuous tutoring by designated members of the faculty on a person-to-person basis. SETTING: German, Austrian and Swiss medical faculties. SUBJECTS: Medical faculty deans. RESULTS: The return rate was 80%. While general student counselling is, if required, available at nearly all of the faculties, faculty mentoring programmes are offered by only 36.1% of the medical schools, and individualized career counselling by 30.6%. CONCLUSIONS: Compared to other countries, such as the United Kingdom or the United States, counselling and tutoring programmes, e.g. career planning or faculty mentoring, are not generally available to the German medical student. Regional differences are evident, which can be attributed to differences in the universities' legal and financial situation. The medical faculties at German-speaking universities should make it their priority to offer these services to the student on a permanent basis.

Chronic fatigue syndrome in patients with Lyme borreliosis.

Several authors have reported a chronic fatigue-like syndrome in patients that have suffered from Lyme borreliosis in the past. To further investigate this suspicion of an association without sample bias, we carried out a prospective, double-blind study and tested 1, 156 healthy young males for Borrelia antibodies. Seropositive subjects who had never suffered from clinically manifest Lyme borreliosis or neuroborreliosis showed significantly more often chronic fatigue (p = 0.02) and malaise (p = 0.01) than seronegative recruits. Therefore we believe it is worth examining whether an antibiotic therapy should be considered in patients with chronic fatigue syndrome and positive Borrelia serology.

Treatment of stroke on an intensive stroke unit: a novel concept.

In industrialised nations stroke ranks as number three among causes of death and is the most frequent cause of disability in old age. Demographic changes will result in stroke gaining increasing importance for individuals as well as for society as a whole. Stroke is already a major cost factor for healthcare and social security systems because of its high long-term costs. Therapeutic nihilism, although still widespread among patients and some physicians, is no longer justified. Long-term outcome after stroke can be significantly improved by providing therapy in wards specialised in early rehabilitation, so-called 'stroke units'. Recent magnetic resonance imaging (MRI) and positron emission tomography (PET) studies, as well as lysis therapy studies have shown that the first 3-6 h are crucially important. For this reason, the concept of "intensive stroke units" also called "intensive care stroke units" has been implemented in Germany. The goal of an intensive stroke unit is the optimal care of stroke patients under intensive care conditions for the first 3-4 days with the aim of improving outcome, long-term morbidity, and reducing long-term healthcare costs. Another important objective is the development and research of new therapeutic concepts and approaches that are based on pathophysiological considerations. A further goal is the initiation of specific therapies depending on the suspected underlying pathophysiology, for example, local or systemic thrombolysis, full-dose heparinisation, platelet aggregation inhibitors, oral anticoagulants, neuroprotective agents, decompression craniotomy, sympathomimetically supported volume therapy and hypothermia. A final objective is to minimise the number of complications through intensive monitoring. Basic acute management includes optimal oxygen supply, rapid normalisation of blood glucose and body temperature, volume therapy, maintaining a high blood pressure and cardiac output to improve remaining cerebral perfusion in the presence of ischaemically impaired autoregulation, treating cerebral oedema, prophylaxis of thrombosis, and early mobilisation. Rapid and easy access to computerised tomography (CT), MRI, Doppler and duplex scanning of the brain-supplying blood vessels, and echocardiography is essential. The ready availability of intensive care monitoring (blood pressure, electrocardiography, central venous pressure, transcranial Doppler (TCD), TCD embolism detection, cerebral pressure, electroencephalography and cardiac output is also imperative. We would like to stress at this point that this manuscript is a personal view describing stroke care in Germany. Many of the principles described have not been widely adopted elsewhere, perhaps in part due to a lack of available facilities. However, many of our recommendations are based on logical principles and thus, we feel, bear further scrutiny.