Publications by authors named "Fatih Ozdener"

18 Publications

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A Phase II Study of the Combination of Oxaliplatin, Capecitabine, and Trastuzumab and Chemoradiotherapy in the Adjuvant Setting in Operated Patients With HER2-positive Gastric or Gastroesophageal Junction Cancer (TOXAG Study): A Turkish Oncology Group Study.

Am J Clin Oncol 2021 May 12. Epub 2021 May 12.

Department of Medical Oncology, Acibadem Adana Hospital Departments of Radiation Medical Oncology, Baskent University, Adana Department of Medical Oncology, Hacettepe University Department of Medical Oncology, Dr. A.Y. Ankara Oncology Training and Research Hospital Department of Medical Oncology, Gazi University Department of Medical Oncology, Medical Park Ankara Hospital Department of Medical Oncology, Ankara Yildirim Beyazit University, Ankara Department of Medical Oncology, Marmara University Department of Medical Oncology, Ethica Incirli Hospital Roche Pharmaceuticals Department of Medical Pharmacology, Bahcesehir University School of Medicine Department of Biostatistics and Medical Informatics, Koc University/MedStats Consulting, Istanbul Department of Medical Oncology, Necmettin Erbakan University Meram School of Medicine, Konya Department of Medical Oncology, Ege University, Izmir, Turkey.

Background: Trastuzumab prolonged the overall survival in patients with advanced gastric cancer with human epidermal growth factor receptor 2 (HER2) overexpression in combination with chemotherapy. In this phase II open-label prospective study, the tolerability and safety of trastuzumab with chemotherapy, and chemoradiotherapy for curatively resected patients with HER2-positive gastric carcinoma was investigated.

Methods: The patients with HER2-positive gastric, or gastroesophageal junction adenocarcinoma, after gastrectomy plus D2 dissection, were included. They received 3 cycles of oxaliplatin (100 mg/m2 intravenously day 1) plus capecitabine (850 mg/m2 orally days 1 to 14), trastuzumab (8 mg/kg intravenously day 1 in cycle 1, 6 mg/kg thereafter) every 21 days, followed by chemoradiotherapy. Trastuzumab was given for 1 year.

Results: Of the 212 patients screened, 35 were eligible, and 34 were treated. The median age was 56 years (minimum to maximum: 35 to 75 y), male patients constituted 73.5% (n=25), and 33 (97.1%) had gastric adenocarcinoma. R0 resection was performed in 30 (88.2%). The majority (26, 61.7%) were in stage III disease. Most of the adverse events were grade I/II, the most frequent grade III side effects were nausea (3, 8.8%), vomiting (3, 8.8%), diarrhea (2, 5.9%), and weight loss (n=2, 5.9%). Two patients died during the first 3 cycles of chemotherapy and chemoradiotherapy; 1 secondary to pulmonary thromboembolism, and the other due to cerebral ischemia. After excluding 2 with early progression and 1 consent withdrawal, of the remaining 31 patients, 28 (90.3%) were able to complete the chemotherapy and chemoradiotherapy part of the trial. After the 25 months follow-up period, 21 patients (61.8%) were alive. Overall survival at 12 and 24 months was 75.0% and 58.0%, while disease-free survival at 12 and 24 months was 65.7% and 55.0%, respectively.

Conclusions: Trastuzumab in combination with capecitabine, oxaliplatin following chemoradiotherapy as the adjuvant therapy for gastric or gastroesophageal junction adenocarcinoma was considered as safe and tolerable. The frequency of HER2 overexpression in curatively resected patients is comparable to that in patients with metastatic disease (trial registration: clinicaltrials.gov the identifier: NCT01748773, December 13, 2012, https://clinicaltrials.gov/ct2/show/NCT01748773).
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http://dx.doi.org/10.1097/COC.0000000000000825DOI Listing
May 2021

Evaluation of parameters associated with growth retardation in children with coeliac disease.

J Paediatr Child Health 2021 Apr 28. Epub 2021 Apr 28.

Department of Pharmacology, Bahcesehir University, School of Medicine, Istanbul, Turkey.

Aims: Coeliac disease (CD) is an autoimmune disorder with a prevalence ≤2% that causes an immune reaction to gluten. Growth retardation (GR) generally accompanies CD due to gastrointestinal complications and should be treated as early as possible along with initiation of a gluten-free diet. The aim of this study was to determine the indicators of GR in patients with CD.

Methods: This single-centre retrospective study included paediatric outpatients with CD. All patients were diagnosed with CD via serological analysis and upper gastrointestinal endoscopy if necessary. Patient records were obtained from Adana City Training and Research Hospital. Patients that were diagnosed with GR accompanying CD were given oral nutritional supplements and followed-up every 3-6 months. Statistical relationships between demographics, and anthropometric measurements, duration of breastfeeding, gluten contact time, diet duration, presenting complaints and serological findings were evaluated.

Results: This study included 169 paediatric outpatients between ages 1 and 18. Longer symptom duration and shorter breastfeeding duration were significantly correlated with GR accompanying CD (P = 0.007 and P = 0.029, respectively). Vomiting was the only symptom that was correlated with the presence of GR (P = 0.010). Helicobacter pylori infection was not correlated with the presence of GR (P = 0.277).

Conclusions: GR should be treated as early as possible to reduce the severity of CD and a 6 months sole breastfeeding followed by solid foods accompanied by breastfeeding for 2 years is crucial for preventing GR. Moreover, vomiting as a presenting complaint in patients with CD might be indicative of the presence of GR.
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http://dx.doi.org/10.1111/jpc.15525DOI Listing
April 2021

Evaluation of Anxiety, Depression and Burden on Caregivers of Children with Cerebral Palsy.

Dev Neurorehabil 2021 Apr 24:1-6. Epub 2021 Apr 24.

Department of Pharmacology, Bahcesehir University, School of Medicine, Istanbul, Turkey.

In this study, we investigated the relationship of demographic variables with mental disorders generally encountered by the caregivers. The cohort includes 109 caregivers (38.53 ± 9.62 year-old) of pediatric cerebral palsy patients (1-18 year-old) taken more than 3 months of caregiving. Data were obtained via face-to-face interviews and a 13-questioned survey followed by a statistical correlation with Zarit-Caregiver-Burden-Scale (Zarit-CBS), Beck Anxiety Inventory (BAI), and Beck Depression Inventory-II scores (BDI-II). BAI scores were lower in the case of collaborative caregiving ( = .034) and a better financial status ( = .045) but higher in families having more than 1 disabled child ( = .019). Zarit-CBS scores were significantly higher in caregiving mothers with older age ( = .027) and lower in families having only 1 disabled child ( = .025). Mental disorders related to caregiving are dependent on the burden directed on the caregivers and having collaboration decreases anxiety. Medical assistance should be provided to caregivers showing signs of a mental disorder.
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http://dx.doi.org/10.1080/17518423.2021.1917718DOI Listing
April 2021

Analysis of nutrition clinical studies involving children in the Middle East and globally.

Future Sci OA 2018 Oct 31;4(9):FSO334. Epub 2018 Jul 31.

Medical Department, Nutricia Advanced Medical Nutrition, 34330, Turkey.

Aim: To assess pediatric clinical nutrition research by analyzing clinical studies in the Middle East (ME) and globally.

Methods: Using ClinicalTrials.gov, the numbers of clinical studies in the ME and globally were analyzed.

Results: The majority of clinical nutrition trials are in North America and Europe. The ME accounts for 4% of all nutrition trials. The majority of pediatric nutrition studies in the ME are in the later phases or are observational and/or epidemiological studies with a focus on poor nutrition or nutrition disorders. Industry funding in the ME is mostly by regional or local companies; few major global companies are involved.

Conclusion: The ME is not well represented in clinical nutrition studies involving children. Effort should be expended to rectify this.
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http://dx.doi.org/10.4155/fsoa-2018-0067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222273PMC
October 2018

Diagnostic value of combined serum biomarkers for the evaluation of liver fibrosis in chronic hepatitis C infection: A multicenter, noninterventional, observational study.

Turk J Gastroenterol 2018 07;29(4):464-472

Department of Clinical Research, Roche Pharmaceuticals, İstanbul, Turkey.

Background/aims: The hepatitis C virus (HCV) infection is important cause of chronic hepatitis. Liver biopsy is considered the gold standard for assessment of fibrosis but this procedure is an invasive procedure. We aimed to evaluate the diagnostic efficiency of non-invasive serum biomarkers, separately and in combinations, on liver fibrosis in treatment-naive chronic hepatitis C (CHC) patients.

Materials And Methods: Two hundred and sixteen treatment-naive CHC patients were enrolled from 32 locations across Turkey in this open-labelled, non-interventional prospective observational study. FibroTest®, aspartate aminotransferase-to-platelet ratio index(APRI), aspartate aminotransferase and alanine aminotransferase ratio (AAR), fibrosis index based on four factors (FIB-4), Age-platelet(AP) index and Forns index were measured and compared with Metavir scores got from liver biopsies.

Results: Data from 182 patients with baseline liver biopsy were suitable for analysis. One hundred and twenty patients (65.9%) had F0-F1 fibrosis and 62 patients (34.1%) had F2-F4 fibrosis. APRI 0.732 area under the curve(AUC) indicated advanced fibrosis with 69% sensitivity and 77% specificity. FIB-4 0.732 AUC and FibroTest 0.715 AUC indicated advanced fibrosis with 69% and 78.4% sensitivity, and 75% and 71.4% specificity, respectively. The combined use of tests also led to an increase in AUC and specificity. Combinations of FibroTest with APRI and/or FIB-4, and FIB-4 with APRI were optimal for the evaluation of liver fibrosis.

Conclusion: Fibrotest, FIB-4, APRI, AP index and Forns index exhibit good diagnostic performance for determining liver fibrosis in CHC patients, and the use of at least two tests together will increase their diagnostic value still further.
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http://dx.doi.org/10.5152/tjg.2018.16597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284637PMC
July 2018

Subcutaneous C.E.R.A. for the Treatment of Chronic Renal Anemia in Predialysis Patients.

Balkan Med J 2016 May 1;33(3):322-30. Epub 2016 May 1.

Department of Internal Medicine, Division of Nephrology, İstanbul University İstanbul School of Medicine, İstanbul, Turkey.

Background: We investigated the efficacy, safety and tolerability of once-monthly administration of C.E.R.A. in erythropoiesis stimulating agents (ESAs) naive predialysis patients with CKD for anemia treatment.

Study Design: Single arm, open label study.

Methods: A total of 75 patients (mean (SD) age was 52.8 (16.4) years, 76.0% were female) were included in this study conducted between 12 August 2008 and 30 October 2009 in 9 centers across Turkey. The mean change in Hb concentration (g/dL) between baseline (week 0) and the efficacy evaluation period (EEP) was the primary efficacy parameter evaluated in three consecutive periods including a dose titration period (DTP; with initial 1.2 μg/kg dose of C.E.R.A., subcutaneously, 28 weeks), EEP (8 weeks) and a long-term safety period (16 weeks).

Results: Our analysis revealed an improvement in Hb levels from baseline value of 9.4 (0.4) g/dL to time adjusted average level of 11.4 (0.7) g/dL in EEP in the per protocol (PP) population and from 9.3 (0.5) g/dL to 11.1 (1.0) g/dL in intent-to-treat (ITT) population. Mean (SD) change in Hb levels from baseline to EEP was 2.0 (0.7) g/dl in the PP population (primary endpoint) and 1.7 (1.1) g/dL in the ITT population. The percentage of patients whose Hb concentrations remained within the target range of 10.0-12.0 g/dL throughout the EEP was 43.9% (95% CI: 28.5-60.3%) in the PP population and 38.7% (95% CI: 27.6% to 50.6%) in the ITP population. A total of 206 adverse events (AE) were reported in 77.0% of patients with hypertension (20%) as the most frequent AE.

Conclusion: Once-monthly subcutaneous C.E.R.A. administration is effective and safe in the treatment of anemia in pre-dialysis patients with CKD, who are not currently treated with ESAs.
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http://dx.doi.org/10.5152/balkanmedj.2016.141173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4898992PMC
May 2016

Once-monthly continuous erythropoietin receptor activator (CERA) for haemoglobin maintenance in haemodialysis patients with chronic renal anaemia.

Clin Kidney J 2014 Oct 29;7(5):464-9. Epub 2014 Jul 29.

Roche Pharmaceuticals Medical Department, Istanbul , Turkey.

Background: This study was conducted to evaluate the efficacy and safety of once-monthly continuous erythropoietin receptor activator (CERA) for maintenance of stable haemoglobin (Hb) levels in adult chronic renal anaemia patients on dialysis according to local clinical judgment in Turkey.

Methods: This was a prospective, open-label, single-arm, multi-centre study conducted in 20 centres in Turkey. After a 4-week screening period, eligible patients receiving conventional erythropoiesis-stimulating agents were converted to monthly intravenous CERA and entered a 16-week CERA dose-titration period (DTP) followed by an 8-week efficacy evaluation period (EEP) and a 4-week safety follow-up. The primary endpoint was the proportion of patients whose Hb concentration remained stable within ±1.0 g/dL of their reference Hb and within the range of 10.0-12.0 g/dL during the EEP.

Results: A total of 173 patients were screened, 132 entered the DTP and 84 completed the study. Thirty-nine patients [46.4% (95% confidence interval: 35.5-57.7%)] maintained stable target Hb concentrations. The mean change in time-adjusted average Hb concentration was 0.29 ± 1.08 g/dL between baseline and the EEP. The mean CERA monthly dose was 112.4 ± 76.78 µg during the EEP, and the CERA dose was adjusted in 39 patients (36.4%). Eleven patients (8.4%) reported 13 treatment-related adverse events, the most frequent adverse events being infections and infestations, gastrointestinal and vascular disorders.

Conclusions: Once-monthly CERA maintains stable Hb concentrations in chronic renal anaemia patients on dialysis in Turkey. The study results confirm the known efficacy and safety profile of CERA.
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http://dx.doi.org/10.1093/ckj/sfu079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257910PMC
October 2014

The association between insulin resistance and hepatic fibrosis in patients with chronic hepatitis C: an observational, multicenter study in Turkey.

Turk J Gastroenterol 2014 Oct;25(5):546-52

Department of Gastroenterology, Ankara University Faculty of Medicine, Ankara, Turkey.

Background/aims: To evaluate the association between insulin resistance and hepatic fibrosis in patients with chronic hepatitis C.

Materials And Methods: A total of 104 chronic hepatitis C patients were included in this non-interventional, open-label, observational, multicenter, cross-sectional study conducted at 20 gastroenterology clinics in Turkey. The primary end point was the correlation between stage of hepatic fibrosis and insulin resistance evaluated via the homeostasis model of assessment-insulin resistance index. Confounders of hepatic fibrosis and insulin resistance were the secondary end points.

Results: The mean age of patients was 52.8 years; 65.4% were female. Type 2 diabetes was present in 6.8% and insulin resistance noted in 38.0% of patients. Further, 45.7% of the patients had mild (A0/A1) and the remaining had moderate/severe (A2/A3) hepatic necroinflammatory activity. Patient distribution according to Metavir fibrosis stage was as follows: F0/F1 (57.0%); F2 (6.5%); F3 (23.7%); and F4 (12.9%). A univariate analysis revealed significant positive correlations between Metavir fibrosis stage and insulin resistance (r=0.297; p=0.007). Logistic regression analysis showed that significant predictors of insulin resistance were high alanine transaminase levels (odds ratio, 0.97; 95% confidence interval, 0.944-0.997) and liver fibrosis stage (odds ratio, 0.114; 95% confidence interval, 0.021-0.607).

Conclusion: Our findings revealed significant associations between insulin resistance and hepatic fibrosis.
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http://dx.doi.org/10.5152/tjg.2014.7829DOI Listing
October 2014

Factors affecting breast cancer treatment delay in Turkey: a study from Turkish Federation of Breast Diseases Societies.

Eur J Public Health 2015 Feb 5;25(1):9-14. Epub 2014 Aug 5.

15 Collegium of World Economy, Warsaw School of Economics, Warsaw, Poland.

Background: One of the most important factors in breast cancer (BC) mortality is treatment delay. The primary goal of this survey was to identify factors affecting the total delay time (TDT) in Turkish BC patients.

Methods: A total of 1031 patients with BC were surveyed using a uniform questionnaire. The time between discovering the first symptom and signing up for the first medical visit (patient delay time; PDT) and the time between the first medical visit and the start of therapy (system delay time; SDT) were modelled separately with multilevel regression.

Results: The mean PDT, SDT and TDT were 4.8, 10.5 and 13.8 weeks, respectively. In all, 42% of the patients had a TDT >12 weeks. Longer PDT was significantly correlated with disregarding symptoms and having age of between 30 and 39 years. Shorter PDT was characteristic of patients who: had stronger self-examination habits, received more support from family and friends and had at least secondary education. Predictors of longer SDT included disregard of symptoms, distrust in success of therapy and medical system and having PDT in excess of 4 weeks. Shorter SDT was linked to the age of >60 years. Patients who were diagnosed during a periodic check-up or opportunistic mammography displayed shorter SDT compared with those who had symptomatic BC and their first medical examination was by a surgeon.

Conclusion: TDT in Turkey is long and remains a major problem. Delays can be reduced by increasing BC awareness, implementing organized population-based screening programmes and founding cancer centres.
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http://dx.doi.org/10.1093/eurpub/cku086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304375PMC
February 2015

In situ hybridization analysis of invasive breast carcinomas with immunohistochemically negative Her-2 status (a national multicenter study).

Turk Patoloji Derg 2014 ;30(2):87-93

Department of Pathology, 1İstanbul University, İstanbul Faculty of Medicine, İSTANBUL, TURKEY.

Objective: The aim of this study was to determine the rate of Her-2 gene amplification in breast cancer cases with a previous negative Her-2 result as determined by immunohistochemistry (score 0 or 1).

Material And Method: 552 cases of invasive breast carcinoma were assessed with the contribution of 9 centers. Previous immunohistochemistry score was either 0 or 1+ in all cases. These cases were re-tested by Her-2 silver in situ hybridization in the central laboratory. Her-2 gene amplification was defined as Her-2/CEP 17 ratio of more than 2.2. Cases with a ratio between 1.8 and 2.0 were defined as equivocal and cases with a ratio of less than 1.8 were defined as negative.

Results: Re-testing of the 552 cases with silver in situ hybridization showed a total of 22 cases with Her-2 gene amplification, of which 11 (3.2%) were found to be score 0, and 11 were found to be score 1+ (5.3%) by immunohistochemistry previously. Her-2 gene amplification rate of cases (score 0 and 1+) ranged from 0% to 10.48% among the centers. Polysomy was found in 28 (8.1%) of the score 0 cases and 25 (12.1%) among the score 1+ cases. Five (9.4%) of the cases with polysomy were found to be amplified, and 48 (90.6%) were not.

Conclusion: The results of the study show that a group of cases (3.98%) with a potential to benefit from anti-Her-2 therapy may be missed with the immunohistochemical method. This indicates the importance of quality assurance, especially in central laboratories with many breast cancer cases in daily practice.
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http://dx.doi.org/10.5146/tjpath.2014.01240DOI Listing
April 2015

A cross-sectional survey of the diagnosis and management of bone metastasis in breast cancer patients in Turkey.

Support Care Cancer 2014 Oct 22;22(10):2629-34. Epub 2014 Apr 22.

Department of Medical Oncology, Mersin University Hospital, Mersin, Turkey,

Purpose: This study aimed to report the practice of managing breast cancer with bone metastasis in Turkey and to determine the adherence to the British Association of Surgical Oncology (BASO) guidelines.

Methods: This multicenter, cross-sectional epidemiological survey was conducted in 38 centers across Turkey. Data from 1,026 breast cancer patients with bone metastases (mean age 54.0 ± 11.9 years) were analyzed.

Results: Over 30 % of patients had a diagnosis of metastatic breast cancer (stage IV) at the time of primary diagnosis. The imaging modalities used for diagnosing bone metastases were bone scintigraphy (57.8 %), radiography (22.8 %), and bone survey (4.4 %). Tumor markers were detected in 94.9 %, and markers of bone metabolism were measured in 90.4 % of patients. A total of 3.5 % of patients underwent surgery for bone metastasis, 26.4 % underwent palliative chemotherapy (most commonly docetaxel + capecitabine), and 56.5 % endured radiotherapy. Most patients (96 %) also received bisphosphonate. Radiography, bone scintigraphy, and CT were the main imaging tools used for postoperative follow-up of bone metastasis. Our results were >95 % in line with the BASO guidelines for the management of bone metastasis, except that interventional procedures, such as biopsy, were applied less frequently in our survey.

Conclusions: The diagnosis and management practices of breast cancer with bone metastasis in Turkey were generally compatible with international guidelines. However, the awareness and knowledge of physicians on the current guidelines should be increased, and equipment for the appropriate interventional procedures should be provided in every clinic to obtain optimal and standard management of bone metastases.
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http://dx.doi.org/10.1007/s00520-014-2253-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153980PMC
October 2014

Bevacizumab + capecitabine as maintenance therapy after initial bevacizumab + XELOX treatment in previously untreated patients with metastatic colorectal cancer: phase III 'Stop and Go' study results--a Turkish Oncology Group Trial.

Oncology 2013 12;85(6):328-35. Epub 2013 Nov 12.

Institute of Cancer, Hacettepe University, Ankara, Turkey.

Objective: It was the aim of this study to evaluate maintenance therapy with bevacizumab + capecitabine following induction with bevacizumab + capecitabine + oxaliplatin (XELOX) versus bevacizumab + XELOX until progression as first-line therapy in metastatic colorectal cancer (mCRC).

Methods: Patients received either bevacizumab (7.5 mg/kg) + XELOX (capecitabine 1,000 mg/m(2) twice daily on days 1-14 + oxaliplatin 130 mg/m(2) on day 1 every 3 weeks) until disease progression (arm A) or the same doses of bevacizumab + XELOX for 6 cycles followed by bevacizumab + capecitabine until disease progression (arm B). The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR) and safety.

Results: One hundred and twenty-three patients were randomized. Treatment compliance was similar in both groups. Median PFS was significantly longer for arm B than for arm A (11.0 vs. 8.3 months; p = 0.002). There was no significant difference between the two arms for ORR (66.7 vs. 59.0%; p = 0.861) or median OS (23.8 vs. 20.2 months; p = 0.100). Tolerability was acceptable in both treatment arms; the most frequent grade 3/4 treatment-related adverse events (arm B vs. arm A) were fatigue (6.6 vs. 16.1%), diarrhoea (3.3 vs. 11.3%), anorexia (3.3 vs. 11.3%), and neuropathy (1.6 vs. 8.1%).

Conclusions: Maintenance therapy with bevacizumab + capecitabine can be considered an appropriate option following induction bevacizumab + XELOX in patients with mCRC instead of continuation of bevacizumab + XELOX.
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http://dx.doi.org/10.1159/000355914DOI Listing
March 2014

Association of insulin resistance, viral load, and adipokine levels with liver histology in patients with chronic hepatitis C: an observational, multicenter study in Turkey.

Eur J Gastroenterol Hepatol 2012 Dec;24(12):1393-9

Department of Infectious Diseases and Clinical Microbiology, University School of Medicine, Adana, Turkey.

Objective: To evaluate the association of insulin resistance (IR), viral load, and adipokine levels with liver histology in patients with chronic hepatitis C (CHC).

Patients And Methods: In this noninterventional, multicenter study carried out at 11 infectious diseases clinics in Turkey, 103 CHC patients [mean (SD) age: 50.2 (11.0) years, 60 (58.3%) women] planned to be treated by ribavirin and peginterferon-α2a were included. Data on hepatic fibrosis and steatosis, IR, viral load, and hepatitis C virus-RNA genotyping, adipokine, and cytokine levels were collected.

Results: The mean (SD) Knodell score was 8.1 (3.6); grade I steatosis was evident in 46 (44.7%) patients and IR was identified in 56 (54.9%). There was a significant positive correlation of the homeostasis model assessment-IR index with Knodell fibrosis (r=0.235; P=0.027) and hepatic steatosis (r=0.435; P<0.001). There was a significant positive correlation of leptin levels with Knodell fibrosis (r=0.265; P=0.013) and hepatic activity index (r=0.218; P=0.041). Hepatic steatosis was correlated negatively with adiponectin (r=-0.320; P=0.001) and positively with leptin (r=-0.368; P<0.001) levels. Logistic regression analysis showed that increase in age [odds ratio (OR), 1.056; 95% confidence interval (CI), 1.005-1.110; P=0.030] was the only significant predictor of hepatic fibrosis (OR, 1.056; 95% CI, 1.005-1.110; P=0.030), whereas increase in age (OR, 1.066; 95% CI, 1.006-1.130; P=0.030), the presence of IR (OR, 5.621; 95% CI, 1.547-20.425; P=0.009), and decrease in adiponectin levels (OR, 0.808; 95% CI, 0.682-0.957; P=0.013) were the significant predictors of hepatic steatosis.

Conclusion: Our findings indicate a significant relationship of hepatic fibrosis and hepatic steatosis with IR and leptin levels, but not with the viral load in Turkish patients with CHC.
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http://dx.doi.org/10.1097/MEG.0b013e3283585863DOI Listing
December 2012

Fasidotril Eli Lilly.

Curr Opin Investig Drugs 2003 Sep;4(9):1113-9

Department of Pharmacology, Faculty of Medicine, Osmangazi University, Eskisehir 26480, Turkey.

Lilly is developing fasidotril, a diester prodrug of the active metabolite fasidotrilat, for the potential treatment of hypertension and congestive heart failure (CHF). Phase II trials to investigate the potential of fasidotril for the treatment of hypertension and CHF had commenced by the late 1990s, and were ongoing in July 2003 in the US and Europe.
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September 2003

Expression of enzymatically-active phospholipase Cgamma2 in E. coli.

J Biochem Mol Biol 2002 Sep;35(5):508-12

Department of Pharmacology, Temple University Medical School, Philadelphia, PA, USA.

Phospholipase C-gamma-2 (PLCgamma2) activation is a key signaling event for many cell functions. In order to delineate the pathways that lead to PLCgamma2 activation, we devised a quick method for obtaining sufficient PLCgamma2. We obtained the full-length cDNA for human PLCgamma2 and expressed it in E. coli using the expression vector pT5T. To enhance the protein expression, tandem AGG-AGG arginine codons at the amino acid positions 1204-1205 were replaced by CGG-CGG arginine codons. The protein expression was detected in a Western blot analysis by both anti-PLCgamma2 antibodies and the antibodies that are raised against the tripeptide epitope (Glu-Glu-Phe) tag that are genetically-engineered to its carboxyl terminal. Crude lysates that were prepared from bacteria that express PLCgamma2 were found to catalyze the hydrolysis of phosphatidylinositol 4,5 bisphosphate. Similar to previous reports on PLCgamma2 that is isolated from mammalian tissue, the recombinant enzyme was Ca2+ dependent with optimal activity at 1-10 microM Ca2+.
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http://dx.doi.org/10.5483/bmbrep.2002.35.5.508DOI Listing
September 2002

Activation of phospholipase Cgamma2 by tyrosine phosphorylation.

Mol Pharmacol 2002 Sep;62(3):672-9

Department of Pharmacology, Temple University Medical School, Philadelphia, Pennsylvania 19140, USA.

Phospholipase Cgamma2 (PLCgamma2) has been implicated in collagen-induced signal transduction in platelets and antigen-dependent signaling in B-lymphocytes. It has been suggested that tyrosine kinases activate PLCgamma2. We expressed the full-length cDNA for human PLCgamma2 in bacteria and purified the recombinant enzyme. The recombinant enzyme was Ca(2+)-dependent with optimal activity in the range of 1 to 10 microM Ca(2+). In vitro phosphorylation experiments with recombinant PLCgamma2 and recombinant Lck, Fyn, and Lyn tyrosine kinases showed that phosphorylation of PLCgamma2 led to activation of the recombinant enzyme. Using site-directed mutagenesis, we investigated the role of specific tyrosine residues in activation of PLCgamma2. A mutant form of PLCgamma2, in which all three tyrosines at positions 743, 753, and 759 in the SH2-SH3 linker region were replaced by phenylalanines, exhibited decreased Lck-induced phosphorylation and completely abolished the Lck-dependent activation of PLCgamma2. Individual mutations of these tyrosine residues demonstrated that tyrosines 753 and 759, but not 743, were responsible for Lck-induced activation of PLCgamma2. To confirm these results, we procured a phosphospecific antibody to a peptide containing phosphorylated tyrosines corresponding to residues 753 and 759. This antibody recognized phosphorylated wild-type PLCgamma2 on Western blots but did not interact with unphosphorylated PLCgamma2 or with PLCgamma2 containing mutated tyrosine residues at 753 and 759. Using this antibody, we showed in intact platelets that collagen, a PLCgamma2-dependent agonist, induces phosphorylation of PLCgamma2 at Y753 and Y759. These studies demonstrate the importance of these two tyrosine residues in regulating the activity of PLCgamma2.
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http://dx.doi.org/10.1124/mol.62.3.672DOI Listing
September 2002

Aripiprazole (Otsuka Pharmaceutical Co).

Curr Opin Investig Drugs 2002 Jan;3(1):113-20

Department of Pharmacology, University of Toronto, Ontario, Canada.

Otsuka Pharmaceuticals in collaboration with Bristol-Myers Squibb is developing aripiprazole, a dual dopamine autoreceptor agonist and postsynaptic D2 receptor antagonist, for the potential treatment of psychoses including schizophrenia [281327], [340364]. A regulatory filing for schizophrenia in the US was submitted at the end of 2001 [340364]. The compound entered phase III trials in Japan in 1995 [192966]. Although presynaptic dopamine autoreceptor agonists may be efficacious in the treatment of schizophrenia, they may also potentially increase the risk for exacerbation of psychosis through stimulation of postsynaptic dopaminergic receptors [245791], [350478], [350479]. However, earlier neuropharmacology studies have shown that aripiprazole can act as a presynaptic D2 agonist while displaying an antagonistic effect at the postsynaptic D2 receptors [281327], [337126], [350479], [424587], [424588]. In animal models, aripiprazole inhibits the apomorphine-induced stereotypy, without causing catalepsy [281327], [337126]. Moreover, in contrast to classical antipsychotics that produce disabling movement disorders, aripiprazole does not cause an upregulation of D2 receptors or an increase in expression of the c-fos mRNA in the striatum, in agreement with the low risk for extrapyramidal side effects (EPS) during aripiprazole treatment [245781], [262096], [350481], [350483]. Collectively, aripiprazole is an important atypical antipsychotic candidate with a favorable safety profile. Moreover, the mechanism of action of aripiprazole differentiates it from both typical and atypical antipsychotics and hence, may provide important leads for pharmacotherapy of schizophrenia and other psychotic disorders. In January 2000, Lehman Brothers predicted peak sales of aripiprazole could reach US $500 million [357788]. In February 2001, Credit Suisse First Boston predicted sales of US $403 million in 2005 [399484].
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January 2002

Glycoprotein VI-mediated platelet fibrinogen receptor activation occurs through calcium-sensitive and PKC-sensitive pathways without a requirement for secreted ADP.

Blood 2002 May;99(9):3228-34

Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.

Collagen activates platelets by transducing signals through glycoprotein VI (GPVI). It is not clear whether collagen can directly activate fibrinogen receptors on the adherent platelets without a role for positive feedback agonists. We investigated the contribution of secondary G protein signaling to the mechanism of GPVI-stimulated platelet aggregation using the GPVI-selective agonists, convulxin and collagen-related peptide (CRP) as well as collagen. Adenosine diphosphate (ADP) scavengers or ADP receptor antagonists shifted the concentration-response curve slightly to the right at low concentrations of convulxin, whereas platelet aggregation at higher concentrations of convulxin was unaffected by these agents. ADP receptor antagonists shifted the concentration-response curve of collagen- or CRP-induced platelet aggregation to the right at all the concentrations. Protein kinase C inhibitor, Ro 31-8220, or a calcium chelator 5,5'-dimethyl-BAPTA shifted the concentration-response curve of convulxin-induced platelet aggregation to the right. In addition, pretreatment with both Ro 31-8220 and dimethyl-BAPTA resulted in total inhibition of convulxin-mediated aggregation. Blockade of either the calcium- or protein kinase C-regulated pathway leads to inhibition of fibrinogen receptor activation on platelets adherent to collagen, but inhibition of both pathways leads to abolished fibrinogen receptor activation. We conclude that collagen-induced activation of fibrinogen receptor on adherent platelets through GPVI signaling occurs without any significant role for secreted ADP or thromboxane A(2). Furthermore, protein kinase C- and calcium-regulated pathways independently contribute to GPVI-mediated platelet aggregation.
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http://dx.doi.org/10.1182/blood.v99.9.3228DOI Listing
May 2002