Validation of pharmacogenetic algorithms and warfarin dosing table in Egyptian patients

Background Warfarin remains a difficult drug to use due to the large variability in dose response. Clear understanding of the accuracy of warfarin pharmacogenetic dosing methods might lead to appropriate control of anticoagulation. Objective This study aims to evaluate the accuracy of warfarin dosing table and two pharmacogenetic algorithms, namely the algorithms of Gage et al. (Clin Pharmacol Ther 84:326?C331, 2008), and the International Warfarin Pharmacogenetics Consortium algorithm (IWPC) in a real Egyptian clinical setting. Additionally, three non-pharmacogenetic dosing methods (the Gage, IWPC clinical algorithms and the empiric 5?mg/day dosing) were evaluated. Setting Sixty-three Egyptian patients on a stable therapeutic warfarin dose were included. Patients were recruited from the outpatient clinic of the critical care medicine department. Methods CYP2C9 and VKORC1 polymorphisms were genotyped by real time PCR system. Predicted doses by all dosing methods were calculated and compared with the actual therapeutic warfarin doses. Results The Gage algorithm (adjusted R²?=?0.421, and mean absolute error (MAE)?=?3.3), and IWPC algorithm (adjusted R²?=?0.419, MAE?=?3.2) produced better accuracy than did the warfarin dosing table (adjusted R²?=?0.246, MAE?=?3.5), the two clinical algorithms (R²?=?0.24, MAE?=?3.7) and the fixed dose approach (MAE?=?3.9). However, all dosing models produced comparable clinical accuracy with respect to proportion of patients within 1?mg/day of actual dose (ideal dose). Non-pharmacogenetic methods severely over-predicted dose (defined as ??2?mg/day more than actual dose) compared to the three pharmacogenetic models. In comparison to non-pharmacogenetic methods, the three pharmacogenetic models performed better regarding the low dose group in terms of percentage of patients within ideal dose. In the high dose group, none of the dosing models predicted warfarin doses within ideal dose. Conclusion Our study showed that genotype-based dosing improved prediction of warfarin therapeutic dose beyond that available with the fixed-dose approach or the clinical algorithms, especially in the low-dose group. However, the two pharmacogenetic algorithms were the most accurate.     

Nanoparticulate Assembly of Mannuronic Acid-and Guluronic Acid-Rich Alginate: Oral Insulin Carrier and Glucose Binder

The relationship of high and low molecular weight mannuronic acid (M)- and guluronic acid (G)-rich alginate nanoparticles as oral insulin carrier was elucidated. Nanoparticles were prepared through ionotropic gelation using Ca^2 +, and then in vitro physicochemical attributes and in vivo antidiabetic characteristics were examined. The alginate nanoparticles had insulin release retarded when the matrices had high alginate-to-insulin ratio or strong alginate–insulin interaction via O-H moiety. High molecular weight M-rich alginate nanoparticles were characterized by assemblies of long polymer chains that enabled insulin encapsulation with weaker polymer–drug interaction than nanoparticles prepared from other alginate grades. They were able to encapsulate and yet release and have insulin absorbed into systemic circulation, thereby lowering rat blood glucose. High molecular weight G- and low molecular weight M-rich alginate nanoparticles showed remarkable polymer–insulin interaction. This retarded the drug release and negated its absorption. Blood glucose lowering was, however, demonstrated in vivo with insulin-free matrices of these nanoparticles because of the strong alginate–glucose binding that led to intestinal glucose retention. Alginate nanoparticles can be used as oral insulin carrier or glucose binder in the treatment of diabetes as a function of its chemical composition. High molecular weight M-rich alginate nanoparticles are a suitable vehicle for future development into oral insulin carrier. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:4353–4363,2013     

Adult discoid lupus erythematosus

BACKGROUND: Discoid lupus erythematosus is a particular form of systemic lupus in which manifestations are confined to the skin. AIM: Our purpose was to evaluate the epidemiology trends, presenting clinical manifestations, therapeutic features and outcome of patients with discoid lupus erythematosus (DLE). METHODS: It's a retrospective study, done in the dermatology department of Habib Thameur Hospital over an 8 years period. We included only the cases of DLE confirmed by the histology and/or the direct immunofluorescence. RESULTS: We identified 26 patients mean aged 46.19 years. All of them were adults. The lesions were localized on the face for 25 patients, neck (7 patients), scalp (6) and hands (6). Eleven patients presented a generalized DLE. The mean period of follow-up was 3 years raging from 1 month to 20 years. After a 15 year evolution, 1 patient presented degeneration in squamous cell carcinoma of 2 lesions. CONCLUSION: Unfortunately, there is still in our country a long delay before the first consultation, which, added to an absence of adequate photoprotection, can obscure the prognosis of DLE.     

Metastatic inguinal nodes from an unknown primary neoplasm. A review of 56 cases

Fifty-six cases of this uncommon neoplastic manifestation are presented. These cases represent 0.065% of 86,589 new cases of malignant disease seen at The Princess Margaret Hospital from 1968 to 1982. There were 29 men and 27 women. The median age at presentation was 58 years. Three major groups were identified: inguinal disease, 24 cases; unilateral inguinal plus iliac disease, 16 cases; local plus systemic disease, 16 cases. Pathologic subtypes were anaplastic, 24; squamous, 11; adenocarcinoma, nine; melanoma, nine; and others, three. Survival at 5 years for all patients was 27%. Among 40 patients who presented with inguinal and inguinal plus iliac disease, survival was 37.5% at 5 years. Initial treatment following biopsy was radiation in 35, lymph node dissection in eight, and chemotherapy in four. Excisional biopsy only was performed in nine cases. There were no treatment-related deaths. The findings observed in this study, in which radiation therapy was employed as initial management in the majority of cases, suggests that radiation therapy is a valid alternative to surgery in the management of this disease.     

Spinal tuberculosis: a five-year review of cases at the National Tuberculosis Centre.

We reviewed 31 cases (19 males and 12 females) of spinal tuberculosis seen at the National Tuberculosis Centre from 1985 to 1989. The mean age was 35.4 years. The predominant clinical feature was backache (90.3%), while neurological features were found in 30.9%. An elevated erythrocyte sedimentation rate (in 80.0%) and a positive Mantoux test (in 70.9%) served as useful investigations. Spinal x-ray was abnormal in all cases, the lumbar spine being most commonly involved. Bacteriological or histopathological confirmation was obtained in only 29.0% of cases. The mainstay of treatment was anti-tuberculous chemotherapy with surgery being performed in 41.9% of patients.     

Benign prostatic hyperplasia: Clinical benefits on Three-Dimensional ultrasound eXtended Imaging (3D-XI)

Objectives:   To prospectively evaluate whether trans -rectal Three-Dimensional eXtended Imaging (3D XI) allows characterization of the prostate gland in cases of isolated benign prostate hyperplasia (BPH) so as to elucidate the motive for discrepancy of postvoiding residual urine.
Methods:   The study was conducted according to the standards of the local ethics committee. Patients gave informed consent. Disclosing the 3D XI display of the prostatic urethra and prostatic gland zones was a preliminary essential. The study included 113 men with a clinical diagnosis of BPH in whom transurethral resection of the prostate was planned. Patients aged from 52 to 75 years (mean 63). Other causes of infravesical obstructive uropathy and prostate neoplastic involvement were excluded. All patients were evaluated by three-dimensional Trans-Rectal Ultrasound using 3D XI methods. Patients were grouped according to the postvoiding residual urine volume into three groups, less and more than 100 mL and urine retention.
Results:   3D XI provided excellent resolution and diagnostic authority of prostate gland anatomy and for the appraisal of BPH morphology. The balance and type of nodular eruption proved responsible for the severity of symptoms aspires by extra-axial nodular effect upon the prostate urethra. The 3D XI analysis regarding the nodular stromal to glandular ratio compared to the histopathological results proved effectual in 98.3% of stromal-dominant, 100% in glandular-dominant and 93.3% in mixed type hyperplasia.
Conclusions:   The severity of symptoms among men with BPH showed an association with the nodular credence, highlighted by 3D XI as a supportive tool in characterizing BPH.     

Urinary cystatin C as a specific marker of tubular dysfunction.

BACKGROUND: Cystatin C (CST3), a strong inhibitor of cysteine proteinases, is freely filtered by the kidney glomerulus and is reabsorbed by the tubules, where it is almost totally catabolized, with the remainder then eliminated in urine. In tubular diseases, it seems sensible to postulate that CST3 degradation would be reduced and consequently an increase in its urinary elimination would be observed. METHODS: We report here the development of an automatic quantitative assay to measure CST3 concentrations in urine using a Behring N-Latex Cystatin C kit on a BNII laser nephelometer. We tested its clinical relevance on several kidney disease patients. RESULTS: This assay is sensitive (limit of detection 0.008 mg/L) and precise (within- and between-day CVs < 4%). Reference values for freshly collected urine samples range from 0.03 to 0.18 mg/L. Mean urine CST3 concentrations obtained from 52 patients with kidney tubular disease (4.31 +/- 3.85 mg/L) were significantly higher than those for 60 controls (0.096 +/- 0.044 mg/L; p < 0.0001) and 47 glomerular disease patients (0.106 +/- 0.133 mg/L; p < 0.0001). CONCLUSION: Increased urinary CST3 concentrations allow the accurate detection of tubular dysfunction among pure and mixed nephropathies. Because of its ability to be processed on automated clinical chemistry analyzers, this assay could easily be used as an adjunct to the standard panel used to screen kidney pathologies, even in emergency situations.     

Propolis protects against 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxicity in rat hepatocytes

The present experiment was undertaken to determine the effectiveness of propolis in alleviating the toxicity of TCDD on cultured primary rat hepatocytes. Propolis (25, 50 and 100 μM) was added to plain culture or simultaneously with TCDD (5 and 10 μM). The hepatocytes were treated with TCDD and propolis for 48 h. Then cell viability was detected by [3-(4,5-dimethyl-thiazol-2-yl) 2,5-diphenyltetrazolium bromide] (MTT) assay and lactate dehydrogenase (LDH) release, while total antioxidant capacity (TAC) and total oxidative stress (TOS) levels were determined to evaluate the oxidative injury. The DNA damage was also analyzed by liver micronucleus assay (LMN) and 8-oxo-2-deoxyguanosine (8-OH-dG). The results of MTT and LDH assays showed that TCDD decreased cell viability. TCDD also increased TOS level and decreased TAC level in rat hepatocytes. On the basis of increasing doses, the TCDD caused significant increases of micronucleated hepatocytes (MNHEPs) and 8-OH-dG levels as compared to control culture. In cultures treated with propolis alone, cell viability and TOS level were not affected, while the level of TAC was significantly increased in dose-dependent fashion. The presence of propolis with TCDD modulated its toxic effects on primary hepatocytes cultures. Noteworthy, propolis has a protective effect against TCDD-mediated DNA damages.