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Biomedical subjects

Helge Prinz

Publications and source records attributed to Helge Prinz.

12 recordsLinked to original sources

9-Benzylidene-naphtho[2,3-b]thiophen-4-ones as novel antimicrotubule agents-synthesis, antiproliferative activity, and inhibition of tubulin polymerization.

A novel series of 9-benzylidene-naphtho[2,3-b]thiophen-4-ones and structurally related compounds were synthesized and evaluated for their ability to inhibit tubulin polymerization. The 4-hydroxy-3,5-dimethoxy-benzylidene analogue 15d was identified as a potent cytotoxic agent in an assay based on K562 leukemia cells. Antiproliferative activity of 15d and the 2,4-dimethoxy-3-hydroxy-benzylidene analogue 15e was additionally evaluated against a panel of 12 tumor cell lines, including multidrug resistant phenotypes. All resistant cell lines were sensitive to these compounds. Concentration-dependent flow cytometric studies showed that K562 cells as well as KB/HeLa cells treated by 15d were arrested in the G2/M phases of the cell cycle. Moreover, four compounds strongly inhibited tubulin polymerization with activities higher or comparable to those of the reference compounds. In competition experiments, the most active compounds strongly displaced radiolabeled colchicine from its binding site in the tubulin, showing IC50 values virtually 3- to 4-fold lower than that of colchicine.

Animals↗

Marked improvement in left ventricular function and significant reverse left ventricular remodeling within 3 months of cardiac resynchronization therapy in patients with dilated cardiomyopathy.

We monitored reverse left ventricular (LV) remodeling and LV function during the first 6 months of cardiac resynchronization therapy (CRT) in 34 patients (mean age = 55.3 +/- 13.6 years, 28 men) with dilated cardiomyopathy (DCM), left bundle branch block, in stable New York Heart Association class III, and on fixed drug regimen who underwent implantation of CRT systems with or without cardioverter defibrillator back-up. QRS-complex duration was reduced from 169.69 +/- 19.6 ms (SD) to 144.1 +/- 23.4 ms during CRT. Parasternal M-mode and apical 2D-echocardiography was performed before and 3 and 6 months after device implantation. LV enddiastolic (EDD) and endsystolic (ESD) diameters were measured, and biplane LV enddiastolic (EDV), and endsystolic (ESV) volumes and ejection fractions (EF) were calculated using a modified Simpson formula. Significant decreases in LVEDD (P = 0.0064 at 3 months and P = 0.021 at 6 months), LVESD (P = 0.023 at 3 months, and P = 0.003 at 6 months), and LVESV (P = 0.006 resp. P = 0.007), and increases in LVEF (P = 0.003 at 3 months and P < 0.001 at 6 months) were observed. Mean LVEF increased from 23% at baseline to 39% at 6 months. CRT induced prominent reverse LV remodeling and significantly increased LVEF within a few months in patients with DCM.

Cardiac Pacing, Artificial↗

Structure and markers of appropriateness, quality and performance of drug treatment over a 1-year period after hospital discharge in a cohort of elderly patients with cardiovascular diseases from Germany.

In a group of elderly patients over 65 years of age with at least two cardiovascular diagnoses requiring chronic medication (n=424), drug therapy at hospital discharge and at home thereafter was followed for a 1-year period. Two home visits took place at 3 months and 12 months after initial discharge. A median of six prescriptions had already been given at the time of discharge; this number increased slightly during ambulatory follow-up. After 1 year, about 30% of the patients had to take more than ten dosing units per day. After discharge, about 50% of all prescriptions were subject to changes in the choice of the preparation (brand-generic) or the agent used [within a class of similar agents, e.g. angiotensin converting enzyme inhibitors (ACIs)]. The prescription of some problematic agents (benzodiazepines, non-steroidal anti-inflammatory agents) increased during the ambulatory follow-up, but pivotal medications for cardiovascular indications (e.g., ACI) given at discharge were maintained. Over-the-counter (OTC) drugs-which were not part of the discharge medication-contributed to 12% of all drugs taken at V4. The majority of the prescriptions (95% of about 2,000 prescriptions surveyed at each visit) was in agreement with the drug's approval status and was appropriate in terms of absence of contraindications. At home visits, therapy with ACI or beta-blocking agents was in agreement with clinical guidelines, although under-dosing was obvious. Blood pressure control (<140/90 mmHg) was achieved in 61% of the patients at discharge and deteriorated to 45% after 1 year; international normalized ratio control in patients with oral anticoagulation also declined (control rate 57% at discharge, 46% after 1 year). Statins as secondary prevention were given at discharge in only 60% of suitable patients, declining to about 50% in ambulatory visits. Diabetic control was not present in 35% of the patients at discharge or at home. Properties of or reason for their medication could be given for the majority (70-80%) of the prescriptions; these quotations were, however, cursory and almost nothing was known about medication risks. At home visits, non-compliance was admitted for approximately 8% of the prescriptions. In conclusion, for pivotal indications, family doctors widely followed the discharge recommendations, but deficits in ambulatory prescriptions and poor performance of the medication were in part already employed at the time of discharge from the hospital. The lack of a patient's knowledge about their own medication is precarious.

Aged↗

Enhancing recognition of early Parkinsonism in the community.

Because Parkinsonism is underdiagnosed in the community, we have validated screening modalities in the field setting and developed a screening procedure to enhance recognition of undiagnosed patients. In a first survey, we identified suspect cases among patients consulting 9 general practitioners (GPs) over a 3-week period using in parallel: (1) a published questionnaire; (2) a standardized examination by the GPs; (3) clinical impression of the GPs; or (4) pre-established diagnoses. Parkinsonism was ascertained by two neurologists with a 1-year follow-up and FP-CIT-SPECT. In total, 1,411 patients consulted the GPs, 1,030 participated in the study, 87 possible cases were identified by at least one of four screening modalities, 12 suffered from Parkinsonism, and 4 of these 12 were de novo cases. Statistical analysis demonstrated that with appropriate evaluation, the questionnaire is highly sensitive and excludes most nonaffected persons, and that the GPs' clinical impression is more specific. We therefore tested in a second survey the efficacy of a serial screening, starting with the questionnaire, followed by a standardized GP evaluation, and then by neurological examination. Of 1,353 participants seen by 9 GPs during a 3-week period, 5 de novo cases were identified. This simple screening protocol significantly enhances recognition of incipient Parkinsonism.

Aged↗

Chlamydia pneumoniae IgA seropositivity and sudden sensorineural hearing loss.

A prospective study was designed to evaluate a possible role of an endured infection with Chlamydia pneumoniae or Chlamydia trachomatis as a cause for sudden sensorineural hearing loss. For this in 60 patients with a first episode of a sensorineural hearing loss and-60 sex-matched and aged-matched controls, following a complete otoneurological diagnosis blood tests for IgA, IgM and IgG with regard to Chlamydia pneumoniae and trachomatis were evaluated. We found a statistically significant higher prevalence of IgA positivity of Chlamydia pneumoniae in patients with sudden sensorineural hearing loss (chi2-test, p < 0.017). For this, Chlamydia pneumoniae may be a possible cause for sudden sensorineural hearing loss. A targeted antibiotic therapy, as it has been discussed for myocardial infarction, might possibly open an additional treatment option for sudden sensorineural hearing loss.

Adolescent↗

Novel benzylidene-9(10H)-anthracenones as highly active antimicrotubule agents. Synthesis, antiproliferative activity, and inhibition of tubulin polymerization.

A novel series of 10-benzylidene-9(10H)-anthracenones and 10-(phenylmethyl)-9(10H)-anthracenones were synthesized and evaluated for antiproliferative activity in an assay based on K562 leukemia cells. The 3-hydroxy-4-methoxybenzylidene analogue 9h was found to be the most active compound (IC(50) K562: 20 nM). Structure-activity relationships are also considered. The highly active compound 9h and the 2,4-dimethoxy-3-hydroxybenzylidene analogue 9l were tested against five tumor cell lines using the XTT assay, including multidrug resistant phenotypes. Induction of cell death in a variety of tumor cell lines was determined in a monolayer assay using propidium iodide. Noteworthy, all compounds within the series induced elongations in K562 cells similar to vinblastine-treated cells. The effect of the lead compound 9h on K562 cell growth was associated with cell cycle arrest in G2/M. Concentrations for 50% KB/HeLa cells arrested in G2/M after treatment with 9h and 9l were determined and found to be in the range of 0.2 microM. Additionally, we monitored the dose dependent caspase-3-like protease activity in K562 cells and MCF-7/Casp-3 cells treated with 9h, indicating induction of apoptosis. Western blotting analysis demonstrated that 9h caused a shift in tubulin concentration from the polymerized state found in the cell pellet to the unpolymerized state found in the cell supernatant. Seven compounds strongly inhibited tubulin polymerization with activities higher or comparable to those of the reference compounds such as colchicine, podophyllotoxin, and nocodazole. In general, the antiproliferative activity correlated with inhibition of tubulin polymerization. The most active compounds strongly displaced [(3)H]colchicine from its binding site in the tubulin, yielding IC(50) values 3- to 4-fold lower than that of colchicine. The novel benzylidene-9(10H)-anthracenones described in the present study constitute an interesting group of highly active and easily accessible antimitotic agents that inhibit tubulin polymerization.

Anthracenes↗

The German multicenter, randomized, partially blinded, prospective trial of acupuncture for chronic low-back pain: a preliminary report on the rationale and design of the trial.

BACKGROUND: The efficacy of acupuncture treatment for chronic low-back pain has not been reliably proven because of a lack of good quality studies, leading to the necessity of developing the German Acupuncture Trial for Chronic Low-Back Pain (GERAC-cLBP) study. OBJECTIVE: The aim is to assess the effectiveness of traditional Chinese acupuncture for chronic low-back pain compared to sham acupuncture and with a conventional standard therapy. METHODS: This trial is a nationwide, multicenter, randomized, prospective, partially blinded study. The primary endpoint is the success rate after 6 months. Success is defined as an improvement of 33% or more of three pain-related items on the Van-Korff Pain Score or an improvement of 12% or more in the disability measured by the Hanover Functional Ability Questionnaire. Assessment of the effectiveness of the blinding of patients to the form of acupuncture they received will be conducted. All clinical endpoints are assessed centrally by blinded independent observers. The sample size, with a total of 1062 patients to be enrolled, is based on power calculations. Independent central randomization, data collection, data processing, and statistical analysis are provided. Success rates will be tested for differences using two-sided Fisher exact tests. In the primary analysis, all tests will be carried out on the basis of the intention-to-treat principle. Secondary analyses will be conducted according to protocol approaches. TRIAL STATUS: The pilot phase of the trial started in February 2002, the estimated duration of the study is 2.5 years. Enrollment is anticipated to be completed in the winter of 2003. CONCLUSION: The GERAC-cLBP study is currently the world's largest controlled trial of the effectiveness of acupuncture treatment for low-back pain. It will contribute to the evaluation of efficacy by means of evidence based medicine.

Acupuncture Therapy↗

2-Arylalkyl-substituted anthracenones as inhibitors of 12-lipoxygenase enzymes. 2. Structure-activity relationships of the linker chain.

A series of 2-arylalkyl-substituted anthracenones were tested as inhibitors of three types of 12-lipoxygenase isoforms in epidermal homogenate of mice, bovine platelets and porcine leukocytes. Their inhibitory activities were compared with those to inhibit the 5-lipoxygenase enzyme in bovine leukocytes. The compounds were synthesised by Marschalk, Wittig or Horner-Emmons reaction at the anthracenedione stage and then reduced to the anthracenones. Structure-activity relationship for the chain linking the anthracenone nucleus and the phenyl ring terminus was investigated. The 2-phenylethyl analogues were among the most potent inhibitors, and 3,4-dimethoxy-substituted 10f was identified as a selective inhibitor of the 12-LO enzymes over 5-LO. Selectivity for 12-LO isoforms was observed with an increase in the overall lipophilicity of the inhibitors. However, none of the linker chains of the 2-substituted anthracenones provided inhibitors that were able to discriminate between the 12-LO isoforms.

Animals↗

Recent advances in the field of tubulin polymerization inhibitors.

In recent years, enormous progress has been made in the field of tubulin targeting agents. Several companies and academic laboratories have entered this field and competition has become very strong. Nevertheless, clinically promising compounds often face substantial limitations, such as high systemic toxicity, poor water solubility and bioavailability, as well as complex synthesis and isolation procedures. As a drawback of established drugs, like paclitaxel or the vinca alkaloids, the outcome of cancer chemotherapy is often affected by the emergence of the multidrug resistance phenotype. Among the recently disclosed tubulin polymerization inhibitors, there are several interesting low molecular weight compounds with improved oral bioavailability and demonstrated activity against multi-drug resistance positive phenotypes. As documented by the imidazole-based combretastatin analogs, to name just one example, chemical optimization of a lead structure resulted in compounds with potent in vitro and in vivo activity along with appropriate pharmacodynamic and pharmacokinetic requirements for a potential therapeutic candidate. Currently, several compounds are undergoing Phase I or Phase II clinical trials, among them orally bioavailable sulfonamides or dolastatin 10. Several other compounds are close to entering Phase I trials. The purpose of this review is to focus on the most recent advances in tubulin polymerization inhibitors from a survey of the published patent literature and related publications between late 1999 and April 2002. However, biological data, especially for the inhibition of tubulin polymerization, obtained from different laboratories cannot easily be compared.

Antineoplastic Agents↗

Syntheses of Anthracenones. 1. Sodium Dithionite Reduction of peri-Substituted Anthracenediones.

The reaction of peri-substituted anthracenediones with sodium dithionite in dimethylformamide and water has been investigated. The system selectively reduces the carbonyl group flanked by the peri substituents of the anthracenediones to give the corresponding 4,5-disubstituted 9(10H)-anthracenones and thus provides a route to anthracenones which are otherwise difficult to obtain. Many functional groups can be tolerated, the reaction is compatible with the presence of peri alkoxy groups and unsaturated side chains of the starting anthracenediones, and the reduction does not go beyond the anthracenone stage. However, the formation of anthracenones depends on the nature of the peri substituents. No products were obtained from the 1,8-dimethyl-substituted anthracenedione and the parent compound with no substituents.

Journal Article↗

Syntheses of Anthracenones. 2. Preparation of 1,8-Dimethoxy- (Dimethylanthralin) and 4,5-Dihydroxy-9(10H)-anthracenone (Isoanthralin): A Revision.

The reduction of 1,8-dimethoxyanthracenedione with zinc dust and aqueous ammonia gives a mixture of 1,8-dimethoxyanthracene and 4,5-dimethoxy-9(10H)-anthracenone, rather than the isomeric 1,8-dimethoxy-9(10H)-anthracenone (dimethylanthralin). This isomer was obtained exclusively using SnCl(2) in HCl and acetic acid as reducing agent at room temperature. The structure was confirmed to exist as the tautomeric 1,8-dimethoxy-9-hydroxyanthracene. Furthermore, the reduction of 1,8-diacetoxyanthracenedione with SnCl(2) in HCl and acetic acid leads to 1,8-dihydroxy-9(10H)-anthracenone (anthralin) rather than 4,5-dihydroxy-9(10H)-anthracenone (isoanthralin), which was prepared by ether cleavage of 4,5-dimethoxy-9(10H)-anthracenone. In light of these findings some biological studies on antipsoriatic anthracenones have to be reconsidered.

Journal Article↗

Syntheses of Anthracenones. 3. Revised Preparative Route to 10-Benzoyl-1,8-dihydroxy-9(10H)-anthracenones.

The acylation of anthralin (1,8-dihydroxy-9(10H)-anthracenone) with acetylsalicylic acid chloride in toluene and collidine was found to give the O-acylated product, rather than 10-(acetylsalicyl)anthralin. A procedure is described for benzoylation of anthralin in the 10-position which involves reaction of 1,8-diacetoxy-9(10H)-anthracenone with benzoyl chloride and sodium hydride in THF followed by hydrolysis of an intermediate enol ester. Furthermore, when benzoyl chloride and DMF were used for the acylation of anthralin, a Vilsmeier-type reaction was observed leading to a novel enamine derivative of anthralin which was hydrolyzed or benzoylated to an enol or enol ester, respectively.

Journal Article↗