EGFR-Targeted Pentacyclic Triterpene Analogues for Glioma Therapy.

Glioma, particularly its most malignant form, glioblastoma multiforme (GBM), is the most common and aggressive malignant central nervous system tumor. The drawbacks of the current chemotherapy for GBM have aroused curiosity in the search for targeted therapies. Aberrantly overexpressed epidermal growth factor receptor (EGFR) in GBM results in poor prognosis, low survival rates, poor responses to therapy and recurrence, and therefore EGFR-targeted therapy stands out as a promising approach for the treatment of gliomas. In this context, a series of pentacyclic triterpene analogues were subjected to in vitro and in silico assays, which were conducted to assess their potency as EGFR-targeted anti-glioma agents. In particular, compound 10 was the most potent anti-glioma agent with an IC50 value of 5.82 µM towards U251 human glioblastoma cells. Taking into account its low cytotoxicity to peripheral blood mononuclear cells (PBMCs), compound 10 exerts selective antitumor action towards Jurkat human leukemic T-cells. This compound also induced apoptosis and inhibited EGFR with an IC50 value of 9.43 µM compared to erlotinib (IC50 = 0.06 µM). Based on in vitro and in silico data, compound 10 stands out as a potential orally bioavailable EGFR-targeted anti-glioma agent endowed with the ability to cross the blood-brain barrier (BBB).

Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity.

Imatinib, an Abelson (ABL) tyrosine kinase inhibitor, is a lead molecular-targeted drug against chronic myelogenous leukemia (CML). To overcome its resistance and adverse effects, new inhibitors of ABL kinase are needed. Our previous study showed that the benzyl ester of gypsogenin (1c), a pentacyclic triterpene, has anti-ABL kinase and a subsequent anti-CML activity. To optimize its activities, benzyl esters of carefully selected triterpenes (PT1-PT6), from different classes comprising oleanane, ursane and lupane, and new substituted benzyl esters of gypsogenin (GP1-GP5) were synthesized. All of the synthesized compounds were purified and charachterized by different spectroscopic methods. Cytotoxicity of the parent triterpenes and the synthesized compounds against CML cell line K562 was examined; revealing three promising compounds PT5, GP2 and GP5 (IC50 5.46, 4.78 and 3.19 µM, respectively). These compounds were shown to inhibit extracellular signal-regulated kinase (ERK) downstream signaling, and induce apoptosis in K562 cells. Among them, PT5 was identified to have in vitro activity (IC50 = 1.44 µM) against ABL1 kinase, about sixfold of 1c, which was justified by molecular docking. The in vitro activities of GP2 and GP5 are less than PT5, hence they were supposed to possess other more mechanisms of cytotoxicity. In general, our design and derivatizations resulted in enhancing the activity against ABL1 kinase and CML cells.

[Psychosocial burden and strains in geriatric nursing: comparison of nursing personnel with and without migration background]. / Psychosoziale Belastungen und Beanspruchungen in der Altenpflege: Vergleich zwischen Pflegekräften mit und ohne Migrationshintergrund.

BACKGROUND: Because of demographic changes the nursing care sector is faced with a lack of qualified employees in the medium and long term. The shortage in the work force is caused by high workloads and unfavorable working conditions. In response to this shortage, there have been attempts to recruit qualified nursing staff from abroad and also to improve the integration of people with a migration background living in Germany into the job market. METHODOLOGY: Based on a quantitative cross-sectional study of 366 nurses, the psychosocial burden and strains among employees with a migration background (n = 112) and without a migration background (n = 254) were examined. For this purpose, 13 scales of the German version of the Copenhagen Psychosocial Questionnaire (COPSOQ) were used for the assessment of psychosocial factors at work. The results were compared with professional group-specific reference values (geriatric care) from the COPSOQ database. RESULTS: The comparison of nursing staff with and without a migration background revealed that the emotional demands, work-privacy conflict and role conflicts factors received a significantly better rating among nursing staff with a migration background, while development opportunities were rated worse by this population group. The surveyed nursing staff exhibited higher stress values compared to the COPSOQ reference group in almost all scales. CONCLUSION: Nursing staff with a migration background need to be supported with respect to development opportunities. Suitable education and training measures may offer adequate career perspectives and may encourage employees to stay in their jobs.

Subjective burden of family caregivers with Turkish immigration background in Germany : Validation of the Turkish version of the Burden Scale for Family Caregivers.

BACKGROUND: Subjective burden is a central variable for describing the situation of family caregivers. Up to now the subjective burden of family caregivers with Turkish immigration background in Germany has not been quantitatively investigated. OBJECTIVES: The aim of this study was the validation of the Turkish version of the Burden Scale for Family Caregivers (BSFCtr). MATERIAL AND METHODS: In order to measure the subjective burden of family caregivers with Turkish immigration background, the BSFC was translated into Turkish. The internal consistency of the 28-item BSFCtr was calculated using Cronbach's alpha. The difficulty indices and discriminating powers of the items were analyzed. The construct validity was examined by using three hypotheses of association. RESULTS: The cross-sectional study was conducted on 49 family caregivers with a Turkish immigration background in Germany who care for older, chronically ill persons. Cronbach's alpha for the total scale was 0.89. The caregiver burden was greater when the care recipient had substantial regular nursing care needs and when the spouse or partner had assumed the care as compared with the children or children-in-law. Caregiver burden significantly increased with the extent of psychosomatic symptoms of the caregiver. CONCLUSION: The Turkish version of the BSFC proved to be a reliable and valid measure for determining the subjective burden of family caregivers.

[Turkish emigrants in Germany. Deficits in home care knowledge and health services - a review]. / Türkische Migranten in Deutschland. Wissens- und Versorgungsdefizite im Bereich häuslicher Pflege - ein Überblick.

Family members caring for relatives at home are often under great stress. Numerous studies have shown that taking care of a chronically ill family member may have negative effects on physical and emotional health. Frequent symptoms observed in family caregivers are insomnia, joint pain, physical exhaustion, and depression. There are, as yet, no definitive empirical studies in Germany on the subjective burden of family caregivers in Turkish families and on their specific needs for help, although their numbers are increasing exponentially. The statement based on the low rate of use of professional care by Turkish families in Germany that there is great willingness among Turkish families to take care of family members at home - a self-evident part of the concept of family - should not lead to the assumption that care causes less stress in this population. There is a great need for research into the way in which the care situation and the changes attendant thereon are experienced by Turkish family caregivers. Recording of subjective burden and individual needs is important to develop accepted strategies to relief Turkish family caregivers.

Effect of mouthwashes on the discolouration of restorative materials commonly used in paediatric dentistry.

AIM: This was to investigate the effects of Klorhex, Tantum Verde, Kloroben, and Listerine on the discolouration of composite resin, compomer, giomer, and resin-modified glass ionomer. METHODS: Fifty disc-shaped specimens from each restorative material (n = 50) were prepared; initial colour values were measured with a spectrophotometer. Forty specimens from each group were placed in the four different types of mouthwashes (n = 10), while the remaining 10 specimens were immersed in distilled water for 2 min, twice a day for a period of 3 weeks. Colour change (ΔE*) values were obtained and the results were evaluated statistically. RESULTS: The ΔE* of composite resin in Klorhex (0.84 ± 0.37) was significantly lower than that of the other mouthwash groups. Moreover, composite resin showed the least colour change when compared with the other materials in all four mouthwashes. Resin-modified glass ionomer values were significantly higher in Tantum Verde (6.36 ± 2.82) when compared with the other mouthwashes (p < 0.05). Clinically appreciable discolourations were observed in the resin-modified glass ionomer specimens placed in Tantum Verde and Listerine. CONCLUSIONS: Nano-filling composite resins are the most successful aesthetic restorative materials, whereas the commonly used resin-modified glass ionomers exhibit more aesthetically divergent results following the use of mouthwashes.

The risk of malignancy index in discrimination of adnexal masses.

OBJECTIVE: To assess the ability of the risk of malignancy index (RMI) based on a serum CA125 level, ultrasound findings and menopausal status, to discriminate benign from malignant adnexal masses. METHOD: Between September 2002 and November 2004, 296 women with adnexal masses were enrolled. The sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of the CA125 serum level, ultrasound findings and menopausal status in prediction of ovarian cancer were calculated and compared individually or combined into the RMI. RESULTS: The RMI identified malignant cases more accurately than any individual criterion in diagnosing ovarian cancer. Using a cut-off level of 153 to indicate malignancy, the RMI showed a sensitivity of 76.4%, a specificity of 77.9%, a PPV of 65.9%, a NPV of 85.5% with 79.4% correct diagnosis rate. CONCLUSION: The RMI is an appropriate method in diagnosing adnexal masses with high risk of malignancy and forwarding to gynecological oncology centers for suitable surgical operations.

[Name-based identification of cases of Turkish origin in the childhood cancer registry in Mainz]. / Namensbasierte Identifizierung von Fällen mit türkischer Herkunft im Kinderkrebsregister Mainz.

Until now few analyses of routine data relating to the health of migrants have been conducted in Germany. A major obstacle is that most data sources do not provide reliable information on the origin of migrants. While some sources contain the nationality of persons registered, this information does not allow one to identify migrants who have taken up German citizenship, i.e., a substantial part of second-generation migrants. In this paper we demonstrate how a computer-aided, name-based algorithm can be used to identify persons of Turkish origin in the German Childhood Cancer Registry in Mainz, Germany. The performance of the algorithm, as assessed against the gold standard of assessing names manually, was very good (sensitivity and specificity > or = 0.975). In total, we identified 1774 of the 37,259 cases in the registry as being of Turkish origin. The name algorithm proved to be a useful tool to identify Turkish migrants in routine data sources, thus avoiding potential bias due to changes in citizenship. This approach aims at improving migrant-sensitive health reporting and research in Germany. In future, additional information on migrant status should be obtained already during primary data collection so that health data for all migrant groups can be provided.

Refractory duodenal ulcer healing and relapse: comparison of omeprazole with Helicobacter pylori eradication.

OBJECTIVE: To investigate differences between omeprazole and Helicobacter pylori eradication in patients with duodenal ulcers refractory to H2-receptor antagonists and to compare the recurrence rates after the two treatments. DESIGN AND METHODS: Forty-five patients with endoscopically proven duodenal ulcers refractory to H2-receptor antagonists and H. pylori infection were randomly assigned to 8 weeks of treatment with omeprazole 40 mg/day or 4 weeks of treatment with colloidal bismuth subcitrate 480 mg/day plus metronidazole 750 mg/day and tetracycline 1000 mg/day from day 1 to day 14. Patients were evaluated endoscopically and clinically at the end of treatment. Patients with healed ulcers were followed up for 1 year after cessation of the treatment. Endoscopy was performed at 3 and 12 months. RESULTS: Ulcer healing occurred in 100% (21/21) of patients on triple therapy and 70.5% (12/17) of those treated with omeprazole alone (P = 0.0123). The relapse rate at the 3rd month was 11.7% (2/17) in the triple therapy group and 60% (6/10) in the omeprazole group (P = 0.0248). Of the patients followed to study endpoint (relapse or endoscopy at 12 months) three of 12 (25%) receiving triple therapy, compared to six of eight (75%) receiving omeprazole, relapsed (P = 0.0648). CONCLUSION: These results show that triple therapy is more effective than omeprazole in the treatment of refractory duodenal ulcers and reduces the rate of ulcer relapse.

Thrombophilia and inflammatory bowel disease: does factor V mutation have a role?

BACKGROUND: An increased tendency for thromboembolism is a well known problem of inflammatory bowel disease (IBD). Microvascular thrombosis has also been claimed as a pathogenic factor in IBD. Recently a point mutation in the gene coding factor V (FV Leiden) has been identified in various thromboembolic diseases, but the role in IBD is unknown. OBJECTIVE: To determine the frequency of FV Leiden in IBD patients and compare with a group of controls. METHODS: Sixty-three IBD patients [43 ulcerative colitis (UC) patients and 20 Crohn's disease (CD) patients] and 36 healthy controls were included in the study. Only one of the UC patients had a history of cerebral thromboembolism. The extracted DNA from frozen blood was subjected to polymerase chain reaction for the amplification of FV gene. The amplicons were hybridized both with the mutant and wild-type probes to detect FV mutation. Readings of optical density above 0.3 were considered as positive results. According to the patterns of ELISA, heterozygosity and homozygosity for normal and mutant alleles were determined. RESULTS: Eight (18%) of UC patients were heterozygous normal and one (2%) patient had homozygous mutation. Eight (45%) of the 20 CD patients had a heterozygous pattern and one (5%) had a homozygous pattern. In the control group four (11%) subjects showed a heterozygous genotype. FV Leiden was found to be statistically more frequent in CD patients (P < 0.005) (odds ratio 6.5, 95% confidence interval 1.3-18.), but not in the UC patients as compared with controls (P> 0.05). There was no significant correlation between FV Leiden presence and disease activity, gender or disease duration for both UC and CD. CONCLUSION: The results suggest that FV Leiden is more frequent in CD patients, but not in the UC patients as compared with controls. The high rate of factor V mutation in our CD patients suggests the need for further studies to confirm a relationship between this mutation and aetiology of the disease.

Interaction of omeprazole with enteric-coated salicylate tablets.

OBJECTIVE: Enteric-coated tablets are designed to resist gastric fluids and to disrupt and dissolve in the alkaline medium of the small intestine. Main objective of the present study was to investigate whether the increase in gastric pH due to omeprazole treatment alters the release rate of a drug from enteric-coated formulation. To this end, we have compared the single dose pharmacokinetics of a single-unit enteric-coated salicylate to that of uncoated acetylsalicylic acid tablets in the presence and absence of omeprazole treatment. METHODS: Study was carried out according to 4 x 4 Latin square design. Eight healthy subjects received either uncoated acetylsalicylic acid tablets or single-unit enteric-coated sodium salicylate tablets alone or following 4 days of treatment with single-dose 20 mg omeprazole, and blood samples were collected for 24 hours. Serum salicylate levels were determined by the modified spectrophotometric method of Brodie et al. [1994]. RESULTS: Salicylate was absorbed rapidly from uncoated tablets but absorption of salicylate from enteric-coated tablets was delayed, as expected. According to our results, omeprazole treatment did not influence the bioavailability from uncoated acetylsalicylic acid tablets but the absorption rate of salicylate from enteric-coated tablets was increased significantly. CONCLUSION: Findings of the present study demonstrate that omeprazole treatment significantly increases the rate of absorption of single-unit enteric-coated medication. Enhanced rate of absorption is most probably due to an early disruption of enteric coating and the intragastric release of the drug secondary to an omeprazole-mediated increase in gastric pH. The results of the present study also corroborate previous findings which have demonstrated highly variable absorption of enteric-coated single units.

Synthesis and antimicrobial activity of some 1,2,4-triazole-3-mercaptoacetic acid derivatives.

Ethyl 5-(2-furyl)-4-ethyl-1,2,4-triazole-3-mercaptoacetate (2), 5-(2-furyl)-4-ethyl-1,2,4-triazole-3-mercaptoacetic acid hydrazide (3) and a series of new N-alkylidene/arylidene-5-(2-furyl)-4-ethyl-1,2,4-triazole-3-mercaptoacetic acid hydrazides (4a-f) were synthesized and evaluated for in vitro antibacterial activity against Staphylococcus aureus ATCC 6538. Staphylococcus epidermidis ATCC 12228, Klebsiella pneumoniae ATCC 4352, Pseudomonas aeruginosa ATCC 1539, Escherichia coli ATCC 8739, Shigella flexneri, Salmonella typhi, Proteus mirabilis and antifungal activity against Candida albicans ATCC 10231 using the disk diffusion and microdilution methods. Compound 4f showed antibacterial activity against some bacteria. The in vitro antimycobacterial activity of the new compounds against Mycobacterium tuberculosis H37Rv was evaluated employing the BACTEC 460 radiometric system. The highest inhibition observed was 61% at > 6.25 microg/ml.

Synthesis and anticonvulsant activity of some new 1,1-bis(4-substituted 1,2,4-triazoline-5-thione-3-yl)-2-methylbutanes.

Several 1,1-bis(4-alkyl/aryl-1,2,4-triazoline-5-thione-3-yl)-2- methylbutane derivatives 13-21 were obtained from the cyclization of mono(1-methylpropyl)malonylbis(4-alkyl/aryl)thiosemicarbazides 2-12 in the presence of sodium hydroxide. Their chemical structures were proven by spectral data (UV, IR, 1H-NMR, MS) and elemental analysis. The anticonvulsant activity of the title compounds were determined against pentylenetetrazole induced seizures. Six of the tested compounds showed anticonvulsant activity (10 to 20% protection).

Synthesis and anticonvulsant activity of new 3-[(2-furyl)carbonyl]amino-4-thiazolidinone and 2-[(2-furyl)carbonyl]hydrazono-4-thiazoline derivatives.

A series of new 2-aryl-3-[(2-furyl)carbonyl]amino-5-nonsubstituted/methyl-4-thi azolidinones (3) and 2-[(2-furyl)carbonyl]hydrazono-3-alkyl-4-aryl-4-thiazolines (5) was synthesized and evaluated for anticonvulsant activity against pentylenetetrazole induced seizures. Preliminary results indicated that potency was sensitive to substituents at the 2 and 5 positions of the 4-thiazolidinone and 3 and 4 positions of the 4-thiazoline rings. Among 3,2-(phenyl)/ (4-fluorophenyl)-3-[(2-furyl)carbonyl]amino-5-methyl-4-thiazolidinone s (3e and 3f) and among 5, 2-[(2-furyl)carbonyl]hydrazono-3-allyl-4-(4-bromophenyl)-4-thiazol ine (5e), showed the highest protection (40%).

5-Nitroimidazole derivatives as possible antibacterial and antifungal agents.

Some novel 1-[2-[[5-(2-furanyl)-4-substituted 4H-1,2,4-triazol-3-yl[thio[ethyl[-2-methyl-5-nitro-1H-imidazoles (3), 1-[3-[[5-(2-furanyl/2-thienyl)-4-substituted 4H-1,2,4-triazol-3-yl[-thio]-2-hydroxypropyl[-2-methyl-5-nitro-1H- imidazoles (5) and 1-[3-[(N,N-disubstituted thiocarbamoyl)-thio[-2-hydroxypropyl]-2-methyl-5-nitro-1H-imidazoles (7) were synthesized and evaluated for in vitro antibacterial and antifungal activity. Some of 5 were found to be effective against bacteria and fungi (minimum inhibitory concentration (MIC) 7.3-125 micrograms/ml), whereas 7 were found to be effective against fungi (MIC 3-25 micrograms/ml).

Synthesis and preliminary anticonvulsant activity evaluation of new 2-thioxo-4,5-imidazolidinedione derivatives.

A series of 1-substituted benzylideneamino-2-thioxo-3-allyl-4,5-imidazolidinediones (2a-j) were synthesized by the cyclization of 1-substituted benzylidene-4-allylthiosemicarbazides (1a-j) with oxalyl chloride in anhydrous ethereal medium. The structures of 2a-j were confirmed by analytical and spectral data (IR, 1H-NMR and EIMS). All synthesized compounds were evaluated for anticonvulsant activity against maximal electroshock (MES) and subcutaneous pentylenetetrazole (ScMet) induced seizures. Among the compounds tested, 2b and 2h exhibited some activity in anticonvulsant identification (Phase I) trials in mice.

Synthesis of some 4-(alkylidene/arylidene)amino-2,4-dihydro-5- (2-thienyl)-3H-1,2,4-triazole-3-thiones tested for antimicrobial activity.

A series of 4-(alkylidene/arylidene)amino-2,4-dihydro-5- (2-thienyl)-3H-1,2,4-triazole-3-thiones (2a-h) were synthesized. The structural elucidation of all the compounds was made on the basis of analytical and spectral data (IR, 1H-NMR and EIMS). All synthesized compounds were evaluated for in vitro antimicrobial activity against various bacteria and fungi. Some of the compounds demonstrated antimicrobial activity against Staphylococcus aureus ATCC 6538, Staphylococcus epidermidis ATCC 12228, Trichophyton rubrum, Trichophyton mentagrophytes var. erinacei NCPF-375 and Microsporum canis (MIC 50-6.25 mg/ml). The in vitro antimycobacterial activity of the new compounds was also investigated. Some of the compounds showed varying degrees of inhibition (2-40%) against Mycobacterium tuberculosis H37Rv in the primary screen that was conducted at 12.5 mg/ml using the BACTEC 460 radiometric system.

Synthesis and antimicrobial activity of new 6-phenylimidazo[2,1-b]thiazole derivatives.

A series of new N2-substituted-6-phenylimidazo[2,1-b]thiazole-3-acetic acid hydrazides (2a-j) were synthesized and evaluated for in vitro antimicrobial activity against various bacteria and fungi. Some of the compounds showed antimicrobial activity against Staphylococcus aureus ATCC 6538, Staphylococcus epidermidis ATCC 12228, Trichophyton mentagrophytes var. Erinacei NCPF-375, Trichophyton rubrum and Microsporum audounii (MIC 25-0.24 micrograms/ml). The in vitro antimycobacterial activity of the new compounds was also investigated. The compounds exhibited different degrees of inhibition (17.98%) against Mycobacterium tuberculosis H37Rv in the primary screen that was conducted at 12.5 micrograms/ml using the BACTEC 460 radiometric system.