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Background: The use of statins to lower high serum cholesterol levels may be associated with a number of adverse reactions, including severe myopathy. The solute carrier organic anion transporter 1B1 (SLCO1B1) gene, which encodes the organic anion-transporting polypeptide OATP1B1, is related to the intracellular transport of statins. The aim of this research was to study the association of rs2306283 and rs4149056 genetic polymorphism of the SLCO1B1 gene with the development of statin-induced myopathy in Jordanian diabetics receiving statins. Methods: We included 413 patients attending the Diabetes Clinics of the National Center for Diabetes, Endocrinology and Genetics, Amman, Jordan. The study was approved by the Institutional Review Board of NCDEG. Myopathy was defined as the elevation of creatine kinase more than 3 times the upper limit of normal. Every subject signed an informed consent form and donated 3-5 mL of venous blood. Genome DNA was extracted from lymphocytes of peripheral blood. Genotypes were identified using the Tetra Amplification Refractory Mutation System of SLCO1B1. Results: The minor allele frequencies of rs2306283 [G] and rs4149056 [C] were 0.38 and 0.23, respectively. The two SNPs followed the Hardy-Weinberg equilibrium. The development of SIM was significantly associated with the homozygous and heterozygous minor allele genotype of rs4149056 (CC and CT), and the homozygous wild type allele genotype of rs2306283 (AA). There was no linkage disequilibrium between the two SNPs in the studied subgroups. Conclusions: Genetic polymorphism in the SLCO1B1 Gene is a risk factor for the development of SIM in Jordanian patients.

Background:: Food-drug interactions may lead to suppression or induction of drug metabolizing enzymes. Pomegranate is a commonly used fruit in folk medicine all over the world. Data concerning the effect of pomegranate on the activity of UDP-glucuronosyltransferases (UGTs) is scarce. Objective:: The purpose of this work was to investigate the effect of pomegranate juice ingestion on the transcription of ugt2b1, ugt2a3, and ugt1a9 in the liver and small intestine of male mice. Methods:: Pomegranate juice was administered to 10 male mice for 14 days in drinking bottles instead of water. Ten control mice received water in the drinking bottles. On the 15th day, the mice were sacrificed and the liver and the small intestine were removed. The small intestine was divided into 3 parts. Total mRNA was extracted from samples of these specimens, and cDNA was synthesized by quantitative real-time polymerase chain reaction (RT-PCR) using specific primers for each ugt gene. Results:: The ugt1a9 mRNA level was reduced by 2.25-fold in the liver and by 6-, 1.5-, and 3-folds in the first, second and third part of the small intestine, respectively. The ugt2b1 mRNA level in the liver and the third part of the small intestine was not affected, while it was reduced by 3.7- and 3-folds in the first and second parts of the small intestine, respectively. The ugt2a3 mRNA level was not affected in the liver and the 3 parts of the small intestine. Conclusions:: Some ugt mRNA levels may be reduced by the ingestion of pomegranate juice, which may reduce the metabolism of their drug substrates. The consequences may be an accumulation of such drugs in the body and enhanced toxicity.

Several severe asthma comorbidities have been identified: an emerging one is bronchiectasis. We evaluated the frequency of bronchiectasis on severe asthma in a real-life setting, through the 'Severe Asthma Network Italy' (SANI) registry.SANI registry encompasses demographic, clinical, functional and inflammatory data of Italian severe asthmatics. Data obtained by the enrolled patients were analyzed, focusing the attention on those patients with concomitant clinically relevant bronchiectasis.About 15.5% patients have bronchiectasis. Bronchiectasis diagnosis was associated with a higher prevalence of chronic rhinosinusitis with nasal polyps (54.6% vs. 38%, p = 0.001) and higher serum IgE levels (673.4 vs. 412.1 kUI/L, p = 0.013). Patients with bronchiectasis had worse asthma control (ACT: 16.7 vs 18.2, p = 0.013), worse quality of life (AQLQ: 4.08 vs. 4.60, p = 0.02) and lower lung function (FEVsevere asthma associated with bronchiectasis represents a particularly severe asthma variant, possibly driven by an eosinophilic endotype. We, therefore, suggest that bronchiectasis should necessarily be assessed in severe asthmatic patients.

Although the documentation of data about the Libyan vegetation began since ancient time and modern studies started at the beginning of the eighteenth century, the Libyan flora is not fully ...

Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m−2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day−1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day−1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.

The effect of licorice drink, a widely used herb in the Middle East, on hepatic and intestinal cytochrome P3A6 (CYP3A6) and P-glycoprotein (P-gp) gene transcription using rabbit as an animal model was assessed. This article reports that licorice treated groups showed a significant induction of hepatic CYP3A6 expression by 17.6-folds, and an inhibition of intestinal CYP3A6 expression by 7.6-folds. Licorice administration did not affect P-gp expression neither in hepatic nor in intestinal tissues. It is concluded that licorice can affect the metabolism of drugs that are CYP3A6 substrates, but it might not affect the transport of drugs dependent on P-gp. [Med-Science 2017; 6(1.000): 35-40]

Pomelo fruit juice and pomelo ethylacetate extract have been shown to increase the bioavailability of some CYP3A substrates. The purpose of this study was to investigate if this effect might be contributed to by changes in CYP3A and p-glycoprotein mRNAs levels in the liver and proximal small intestine. The ethyl acetate extract of pomelo mix was administered for 7 days to 10 rabbits. Nine rabbits were administered tap water for 7 days. The administration was through oral intubation to the stomach. On the 8(th) day, the rabbits were sacrificed, and the liver and the proximal 15 cm of the small intestine were dissected. Total RNA was extracted from the specimens and cDNA was prepared by quantitative real-time-polymerase chain reaction (RT-PCR) using specific primers. The ethyl acetate extract of pomelo mix reduced the mRNA expression of CYP3A6 almost 5-folds in the intestine and 2-folds in the liver. In contrast, a 1-fold increase to the p-glycoprotein mRNA expression was observed under the same experimental conditions. In conclusion, the ethyl acetate extract of pomelo mix reduced the mRNA expression of CYP3A6 in both intestine and liver but to different degrees, while the p-glycoprotein mRNA expression was not reduced.

There is no agreement on the involvement of angiotensin II type 1 receptor (AT1R) gene A(1166)C variant and essential hypertension. The purpose of this study was to investigate the association between angiotensin II type 1 receptor (AT1R) gene A(1166)C variants with essential hypertension and some related parameters in a sample of Jordanian hypertensive patients. DNA samples from 108 hypertensive individuals and 102 age- and gender-matched non-hypertensive controls of the Jordanian population were analyzed by polymerase chain reaction followed by restriction fragment length polymorphism assay (PCR-RFLP) methods to determine the frequency of A(1166)C variants alleles. No statistically significant differences were found in the distribution of alleles and genotypes between hypertensive and non-hypertensive individuals, not even after gender segregation. The frequency of the variant allele (C(1166)) was significantly higher in the early-onset compared to the late-onset group of hypertensive males, in subjects with positive family history of hypertension, and in subjects with high waist circumference. In conclusion, the A(1166)C polymorphism is not associated with essential hypertension in Jordanian hypertensive individuals. However, it was associated with an early onset of hypertension in males, with positive family history of hypertension, and with high waist circumference irrespective of blood pressure status.

Background: There are incon- sistent reports concerning N-acetyltransfer- ase 2 (NAT2) genotypes in diabetes mellitus (DM). Objective: The objective of the study was to explore any association between NAT2 genotypes and Type 1 and Type 2 DM in Jordanians. Methods: 106 Type 1 and 110 Type 2 DM patients attending the "National Center for Diabetes, Endocrinology and Ge- netics", Amman, Jordan, were included in the study. DNA was extracted from venous blood using a commercial DNA extraction kit. NAT2 genotyping was performed using polymerase chain reaction-restriction frag- ment length polymorphism (PCR-RFLP). Results: The frequency of the genotype that encodes rapid acetylation (the wild-type genotype NAT2*4/4) was similar in the two types of diabetes mellitus. Those which en- code intermediate acetylation (NAT2*4/5, NAT2*4/6, and NAT2*4/7) were higher in Type 2 diabetes (0.482) compared to Type 1 diabetes (0.339), while the frequency of genotypes which encode slow acetyla- tion (NAT2*5/5, NAT2*5/6, NAT2*5/7, NAT2*6/6, NAT2*6/7, and NAT2*7/7) were higher in Type 1 diabetes (0.547) compared to Type 2 diabetes (0.418). Conclusion: There is excess of genotypes encoding intermedi- ate acetylation in Type 2 DM and an excess of slow acetylator genotypes in Type 1 DM. Furthermore, NAT2*4/6 genotype (which encodes intermediate acetylation) was more prevalent in Type 2 DM. Type 1 DM behaved similar to non-diabetic controls in regard to acetylation status.

This study is intended to facilitate damage detection in concrete bridge girders without the need for visual inspection while minimizing field measurements. Beams with different material and cracking parameters were modeled using ABAQUS finite-element analysis software to obtain stiffness values at specified nodes. The resulting database was then used to train an artificial neural network (ANN) model to inversely predict the most probable cracking pattern. The aim is to use the ANN approach to solve an inverse problem where a unique analytical solution is not attainable. Accordingly, simple span beams with three, five, seven, and nine stiffness nodes and a single crack were modeled in this work. To confirm that the ANN approach can characterize the logic within the databases, networks with geometric, material, and cracking parameters as inputs and stiffness values as outputs were created. These networks provided excellent prediction accuracy measures (R2 values>99%). For the inverse problem, the n...

Background and Aims Thiopurine S-methyltransferase (TPMT) is responsible for inactivation of thiopurine drugs which are commonly used in leukemia, organ transplantation and autoimmune diseases. The gene encoding TPMT is polymorphic, and both phenotyping and genotyping studies have shown ethnic variations in gene sequence and enzyme activity worldwide. The aim of this study is to identify the most common genetic polymorphisms of TPMT in healthy Jordanian volunteers and patients with rheumatoid arthritis (RA). Methods A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to identify the frequency of TPMT ( *2, *3A, *3B, and *3C ) polymorphisms in 250 healthy Jordanian volunteers and 110 RA patients. Results Only four healthy subjects (1.6%) and one RA patient (0.9%) with variant alleles were identified in this study. Two healthy subjects had the TPMT*3A allele and the other two had the TPMT*3B allele, whereas the one RA patient had the TPMT*3A allele. No homozygous polymorphisms were detected and all genotypes detected were heterozygous ( *1/*3A ) ( *1/*3B ). None of the subjects had TPMT*2 or TPMT*3C variant alleles. Conclusions Mutant alleles identified in this study have a low frequency. TPMT ( *3A and *3B ) were the only detected heterozygous alleles. No homozygous variant allele was detected. Further studies are necessary to identify other variant alleles that might uniquely occur in Jordanians.

Aim: To determine the frequency of major N-acetyltransferase (NAT2) alleles and genotypes among Jordanian patients with rheumatoid arthritis (RA). Methods: The study was approved by the IRB of the Jordan University Hospital. An informed consent was signed by every patient. DNA samples from 150 healthy volunteers and 108 patients with RA were analyzed by polymerase chain reaction followed by a restriction fragment length polymorphism assay (PCR-RFLP) to determine the frequency of four major alleles: NAT2*4, NAT2*5, NAT2*6, and NAT2*7. Results: The most prevalent genotypes are those that encode the slow acetylation phenotype. About 59.3% of the patients with RA carried the slow, 33.3% the intermediate, and 7.4% the fast-encoding genotypes. The frequency of NAT2 alleles was 0.241 (95% confidence interval [CI] 0.184–0.298) for NAT2*4, 0.449 (95% CI 0.383–0.515) for NAT2*5, 0.273 (95% CI 0.214–0.332) for NAT2*6, and 0.037 (95% CI 0.012–0.062) for NAT2*7 allele. The overall frequency of the slow acetylation genotype in patients with RA is similar to that in healthy Jordanian volunteers. However, the NAT2*5/7 genotype was found in seven patients (6.5%) with RA and was absent in Jordanian volunteers, and the z test revealed that the difference was statistically significant. This genotype constituted 10.9% of the genotypes encoding slow acetylation. Conclusion: The overall acetylator genotype in RA is similar to that in healthy volunteers. The overall slow acetylator genotypes do not seem to be a genetic risk factor for RA among Jordanians. However, the NAT2*5/7 genotype seems to be related to RA. The nature of this relationship needs further clarification.

Scand J Caring Sci; 2013; 27; 131–138 Discrepancies between elderly patient’s self-reported and prescribed medications: a social investigation Aims: To study some characteristics of the elderly people attending the family practice clinic at the Jordan University Hospital (JUH) and to evaluate their knowledge of the prescribed drugs. Methods: A total of 400 elderly people (180 men and 220 women) aged 71 ± 5.8 years were studied regarding sociodemographic characteristics and the use of medicinal and nonmedicinal remedies. In addition, agreement between self-reported drug information and information taken from the medical records was also evaluated. Findings: Almost one-third of the patients had full agreement between their knowledge of total number of drugs they take and the numbers found in the medical records, whereas 43.4% underestimated and 21.8% overestimated these numbers. Five drugs/classes were accurately estimated by the patient (methyldopa, ezetimibe, warfarin, statins and antigout drugs). Underestimation was noticed in 17 drugs/classes and overestimation in 14. The significantly underestimated drug classes were biphoshponates, proton pump inhibitors, sulfonylureas and antiepileptic drugs. Conclusion: Some aspects of elderly people were evaluated regarding their medication knowledge. Almost two-third of the patients did not take their drugs in the proper way. The results of the study highlight the importance of taking several actions by all healthcare workers and by the community to optimise health care provided for elderly people.

This study aims to facilitate damage detection in concrete bridge girders without the need for visual inspection while minimizing field measurements. Beams with different material parameters and cracking patterns are modeled using mechanics-based ABAQUS finite element analysis software program in order to obtain stiffness values at specified nodes. The resulting database is then used to train an Artificial Neural Network (ANN) model to inversely predict the most probable cracking pattern. The aim is to use ANN approach to solve an inverse problem where a unique analytical solution is not attainable. Accordingly, simple span beams with 3, 5, 7 and 9 stiffness nodes and a single crack were modeled in this work. To confirm that the ANN approach can characterize the logic within the databases, networks with geometric material and cracking parameters as inputs and stiffness values as outputs were created. These networks provided excellent prediction accuracy measures (R2 values > 99%). For the inverse problem, the noted trend shows that better prediction accuracy measures are achieved when more stiffness nodes are utilized in the ANN modeling process. It was observed that decreasing the number of required outputs immensely improves the quality of predictions provided by the ANN.

The effect of ethyl acetate extract of pomelo fruit on systemic exposure of verapamil was explored in rabbits. Two groups each of 8 locally-inbred New Zealand male rabbits were used. The first group was used for single-dose treatment (both verapamil and pomelo extract). The second group was used for multiple-dose treatment, pomelo extract (once daily for 14 days) and verapamil single doses (at days 7 and 14). A verapamil dose of 30 mg/kg and a pomelo extract dose of 45 mg/kg were used. Single-dose treatment with pomelo extract resulted in a minor change in mean C(max) of verapamil in plasma, while a decrease of 37.8% in AUC(0-24) and 28.3% in AUC(0-∞) was observed but did not reach statistical significance. After the first period of multiple dose treatment (pomelo extract for 7 days), the combination increased the concentration of verapamil in plasma with a significant increase in mean C(max), AUC(0-24) and AUC(0-∞) by 461.9%, 299.7%, and 261.1%, respectively (p values were 0.005, 0.002, and 0.006, respectively). In contrast, after the second period (day 14 of pomelo extract use), the combination decreased the concentration of verapamil in the plasma with a substantial decrease in mean C(max), AUC(0-24), and AUC(0-∞), by 68.2%, 69.7% and 58.3%, respectively. This decrease did not reach statistical significance (p values were 0.073, 0.081 and 0.083, respectively). The T(max) was not affected significantly in both studies. The study illustrates a complex time-dependent interaction between verapamil and the ethyl acetate extract of pomelo mix. More intensive studies are needed to further understand the nature of the interaction.

INTRODUCTION Variation in nicotine metabolism may be due to genetic alterations in CYP 2A6, environmental factors, and diet. The purpose of this research was to evaluate mint drink effect on nicotine metabolism as judged by nicotine/cotinine ratio in urine of Jordanian smokers. METHODS Twenty-four Jordanian smoker volunteers were allocated randomly into two groups. They either received mint drink 3 times a day for 1 week during the mint drink period or avoided menthol-containing products and mint drink for 1 week during the off-menthol period. One group treatment sequence was mint drink, off-menthol, while the other group treatment was off-menthol, mint drink. Early morning urine samples were collected at baseline and at the end of each period. Samples were analyzed by liquid chromatography-mass spectrometry for the nicotine and cotinine concentrations. Nicotine/cotinine ratio was calculated and compared among the different periods for each participant using the paired t test. RESULTS All participants showed a consistent pattern of higher nicotine/cotinine ratios during mint drink compared with off-menthol periods, although to a variable extent. Mean nicotine/cotinine ratio during mint drink for all participants (1.327 ± 0.707) was higher than that during off-menthol (0.993 ± 0.547). Paired t test statistical analysis revealed a p < .0001. The mean difference in nicotine/cotinine ratio between the two periods was (-0.335), and the 95% confidence interval of the mean difference was (-0.451) - (-0.219). CONCLUSION Mint drink increased nicotine/cotinine ratio in urine, suggesting a reduction in conversion of nicotine to cotinine.

The effect of licorice root drink (aqueous extract of Glycyrrhiza glabra Fabaceae) on plasma concentration of verapamil, using rabbits as animal model, was investigated. Two groups of locally inbred New Zealand male rabbits were used. The first group was given a single dose of licorice drink (4 ml/kg body weight) concomitantly with 30 mg/kg verapamil, and the second group was given a daily dose of licorice drink (4 ml/kg body weight) for two weeks, with single doses of verapamil on days, 7 and 14. Single dose treatment resulted in a nonsignificant decrease in mean C(max) by 33.2% (P = 0.41), but in a significant decrease of AUC(0-24) and AUC(0-infinity) by 60.5% and 63.6%, respectively (P = 0.01). First period of multiple dose treatment study (7 days), resulted in a significant reduction in mean C(max), AUC(0-24) and AUC(0-infinity) by 55.0%, 47.0% and 45.7%, respectively (P = 0.02, 0.03 and 0.03, respectively). A more pronounced effect was seen at second period of multiple dose treatment study (14 days), where the corresponding decrease was, 85.4%, 76.8% and 73.3%, respectively (P0.01). Mean T(max) was significantly increased 4.2-fold over control period at day 14 of multiple dose study (P = 0.02). In conclusion, licorice root drink decreased verapamil systemic exposure both after single dose and after daily doses for 14 days.

Diabetic nephropathy is one of the leading causes of end-stage renal disease (ESRD). There is some evidence that differences in extracellular fluid volume and capillary permeability do exist between diabetic and non-diabetic patients. This may have an impact on the gentamicin volume of distribution and clearance and thus dosing regimen. The pharmacokinetic parameters of gentamicin [volume of distribution (Vd), clearance (CL), elimination rate constant (K), and half life of elimination (t((1/2)))] were studied before hemodialysis in 20 non-diabetic patients (controls) and 20 diabetic patients, in addition to its hemodialysis clearance.There were no statistically significant differences in Vd, CL, K, and t((1/2)) of gentamicin between the control and diabetic group. Therefore, a composite Vd of 0.25 l/kg and clearance of 0.063 ml/min/kg are suggested for dose calculation for both groups of patients. The mean hemodialysis clearance of gentamicin was higher in the diabetic (87.3 ml/min) than the control group (68.5 ml/min), comparing means by the unpaired t-test (P = 0.018).In conclusion, the same method can be used to calculate the loading dose of gentamicin in ESRD patients between dialysis sessions in both controls and diabetics, whereas, diabetics are expected to receive a higher replacement dose after the end of dialysis.

Summary A rapid, specific and a one-stage protein precipitation method for simultaneous estimation of dapsone (DDS) and monoacetyldapsone (MAD) concentration in plasma and urine using high performance liquid chromatography (HPLC) is described. The applicability of the method for monitoring DDS and MAD blood levels in two different acetylator phenotype volunteers following the administration of 100-mg oral dose of DDS was shown. Cumulative urinary excretion of DDS and MAD were studied in the same volunteers.

Previous studies have shown a high prevalence of vitamin D deficiency among Jordanians despite adequate exposure to sunlight, suggesting the presence of other causes for this deficiency. The aim of this study was to identify the relationship between 25-hydroxyvitamin D [25-(OH) VD] status and the nonsynonymous single-nucleotide polymorphisms (SNPs) (rs7041 and rs4588) of the GC gene, which encodes the vitamin D binding protein, and one SNP (rs10741657) near the CYP2R1 gene.Blood samples from 381 subjects (74 males and 307 females, 18-60 years of age) were obtained from the "National Center for Diabetes, Endocrinology and Genetics" (Amman, Jordan). The subjects were classified as "apparently healthy" if they did not suffer from chronic diseases and as "unhealthy" if they suffered from certain chronic diseases. Subjects' genotypes for GC; rs7041 and rs4588; CYP2R1; rs10741657 were determined by the polymerase chain reaction-restriction fragment length polymorphism assay method.Apparently, healthy subjects had significantly higher 25-(OH) VD levels than unhealthy patients. In apparently healthy subjects, the rs10743657 genotypes containing the variant allele A (AA, GA) were associated with higher 25-(OH) VD levels than the homozygous wild-type genotype (GG). The genotypes containing the variant allele of rs7041 (TT, TG) and rs4588 (AA, AC) were associated with lower 25-(OH) VD levels than the wild-type genotypes (GG and CC, respectively). Haplotype analysis of rs7041 and rs4588 revealed that the haplotypes GC1S and GC1S/S were associated with 25-(OH) VD sufficiency, whereas haplotypes GC1F/S, GC1F/2, GC1S/2, GC2, and GC2/2 were associated with 25-(OH) VD deficiency. In unhealthy patients, only the homozygous genotype of the variant allele of rs7041 (TT) was associated with higher 25-(OH) VD levels, which is the reverse of what had been observed in apparently healthy subjects.The rs70141657G/A of CYP2R1 and rs7041T/G and rs4588C/A of vitamin D binding protein genetic polymorphisms were associated with increased risk of vitamin D deficiency among apparently healthy Jordanians.

OBJECTIVES The purpose of this study was to determine the genotype/allele frequencies of C677T and A1298C polymorphisms of methylenetetrahydrofolate (MTHFR) gene in Jordanian rheumatoid arthritis (RA) patients. In addition, the association between MTHFR gene C677T and A1298C polymorphisms and response to and toxicity of methotrexate (MTX) was evaluated. METHODS 159 adult rheumatoid arthritis ent Rheumatology Clinic at The Jordan University Hospital, between December, 2011 and April, 2012 were recruited into the study. Genomic DNA was extracted from leukocytes using Wizard Genomic DNA extraction Kit. The DNA extracts were amplified by polymerase chain reaction (PCR), and the PCR products were subjected to restriction enzymes to identify the C677T and A1298C genotypes. Genotype frequencies were identified and their relationship to some measures of MTX response and toxicity were evaluated. RESULTS The 677 TT genotype frequency was higher in RA patients (15.1%) compared to the healthy control group (5.9%) (odds ratio 3.09, 95% confidence interval (CI) 1.39-6.87, p-value=0.0056). No such differences were seen with the A1298C genotypes. The frequencies of 677T and 1298C variant alleles were 0.346 and 0.296, respectively. None of the change-in-disease-activity measurements in MTX-treated patients has a significant association with the various genotypes. There was no significant association between A1298C genotypes and "œany MTX toxicity", but there was an association between C677T polymorphism and "œany MTX toxicity" (p=0.037). In addition, there was no association between both SNPs and specific MTX adverse effects. However, some haplotypes or combinations of the C677T and A1298C genotypes were associated with certain MTX side effects. CONCLUSIONS More data from a larger number of RA patients are needed to evaluate the role of pharmacogenetic studies of MTHFR gene in predicting MTX response and toxicity.

OBJECTIVES Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). Genetic polymorphisms of reduced folate carrier (RFC1 G80A) and multi-drug resistance-1 (MDR1 C3435T) might affect MTX response and/or toxicity. The aim of this study was to find out if there is an association between those polymorphisms and MTX toxicity and/or response in Jordanian RA patients. METHOD A genotyping approach was used to determine the studied polymorphisms in 159 RA patients. RESULTS There was an association between RFC1 G80A and MDR1 C3435T polymorphisms with MTX toxicity. Patients with RFC1 80GG genotype were at higher risk for gastrointestinal toxicity (p = 0.036). Patients carrying at least one MDR1 3435T variant allele were at higher risk for MTX overall toxicity (p = 0.04), especially hepatotoxicity (p = 0.028). Furthermore, the distribution of RFC1 G80A polymorphism between males and females was significantly different. The variant genotype 80AA was found to be more in males than in females (60% vs. 31%) (p = 0.011). CONCLUSIONS Our results suggest that genetic polymorphisms in methotrexate transporters affect the toxicity but not the response of MTX treatment. Further studies should be performed to have more conclusive results.

Reliable and economical design of portland cement concrete (PCC) pavement structural systems relies on various factors, among which is the proper characterization of the expected permeability response of the concrete mixes. Permeability is a highly important factor that strongly relates the durability of concrete structures and pavement systems to changing environmental conditions. One of the most common environmental attacks that causes the deterioration of concrete structures is the corrosion of reinforcing steel due to chloride penetration. On an annual basis, corrosion-related structural repairs typically cost millions of dollars. To properly characterize the permeability response of a PCC pavement structure, the Kansas DOT (KDOT) generally runs the rapid chloride permeability test (RCPT) to determine the resistance of concrete to penetration of chloride ions. RCPT typically measures the number of coulombs passing through a concrete sample over a period of 6 h at a concrete age of 7, 28, and 56 days. In this study, back-propagation artificial neural network (ANN) and regression-based permeability response prediction models for rapid chloride penetration test were developed by using the database provided by KDOT to reduce the duration of the testing period or ultimately eliminate the need to conduct the RCPT. The back-propagation ANN learning technique proved to be an efficient methodology to produce relatively accurate permeability response-prediction models. Comparison of the prediction accuracy of the developed models proved that ANN models have outperformed their counterpart regression-based models. The sensitivity analysis also was performed on randomly selected data sets to evaluate the reliability of developed models. The developed ANN models proved effective in characterizing the permeability (RCPT results) response of concrete mixes used in PCC pavements.

Determination of the swell potential of a troublesome soil can only be made possible through the use of systematic methods for identifying, testing, and evaluating that potential. For proper evaluation of the severity of swelling for such soils, an accurate soil swell potential assessment method is warranted. To address this key issue, a two-phase research study was performed to develop combined artificial neural network and reliability-based soil swell prediction models. In Phase 1, a reasonable-sized database representing 514 swell soil tests retrieved from over 51 different projects in Kansas was used to develop both neural network–based (NNB) and statistical-based (SB) swell potential prediction models. Direct comparison of results obtained showed that NNB models provide significant improvements in prediction accuracy over their SB counterparts. In the second phase, predictions obtained using the developed NNB models along with the available experimental database were used to produce reliability (probability) factor matrices, which are used to assign a specific confidence level to predictions obtained via NNB models in order to classify the soil under consideration as a swelling or nonswelling type.

To find out whether any of a preset battery of clinical and laboratory parameters has significant correlation with blood loss caused by transurethral prostatectomy (TURP).All new patients undergoing a TURP over a 1-year period were included in the study. For each patient the following parameters were documented: (1) Pre-operatively: Age, mode of presentation, blood pressure, complete blood count, coagulation screening, calcification of abdominal blood vessels on plain X-ray, prostate size on digital rectal examination (DRE), pre-operative urine culture, presence of haematuria, ECG changes and drugs taken. (2) Intraoperatively: prostate morphology at cystoscopy, type of anaesthesia, operating surgeon, operating time, weight of resected prostate tissue and any blood transfusions. (3) Postoperatively: Length of irrigation time and prostate histology. All the intra-operative and postoperative blood loss was calculated. Their sum constituted total blood loss which constituted the dependent variable of the study. Statistical methods used included bivariate correlation, Students t test or the chi(2) test as appropriate.Of 140 TURPs, 121 were eligible for final analysis. The mean total blood loss was 552 ml (34 ml per gram of tissue) and the mean resected prostate weight was 18 g. Of the continuous variables, the one with strongest correlation with total blood loss was resected prostate weight (r = 0.47, p = 0.000) followed by prostate size on DRE (r = 0.45, p = 0.000) then operating time (r = 0.39, p = 0.000). Of the categorical variables, the one with the strongest correlation with total blood loss was preoperative urine culture (p = 0.01).The only reversible factor associated with blood loss caused by TURP is pre-operative urinary infection. Operating time is partly controllable, as it may improve (i.e. decrease) with experience of the operator.

The pharmacokinetic parameters (AUC, Cmax, Tmax, and t1/2) of nifedipine following single oral administration of a 10 mg capsule of test product were compared to those of the same amount of a reference product. The two products in capsule form were administered according to a randomized two-way crossover design in 22 healthy male volunteers. Nifedipine plasma concentrations were determined using a rapid, sensitive and precise high performance liquid chromatography (HPLC) method with ultraviolet (UV) detection at 235 nm. The parametric 90% confidence intervals of the mean value of the ratio [Myogard (test product) /Adalat (reference product)] for pharmacokinetic parameters were 0.90-1.08, 0.80-1.07, and 0.93-1.12 for AUC0--infinity, Cmax and t1/2, respectively. In each case, values were within the acceptable bioequivalence range of 0.8-1.25. Distribution free point estimate for the difference in expected medians of Tmax of the two products (Myogard-Adalat) was 0.00 h with a 90% confidence interval of 0.00-0.13 which is greater than the accepted bioequivalence of +/- 0.12. The kinetic parameters were comparable to those reported for nifedipine, and no statistically significant differences were found in any of them when comparing the two products by analysis of variance (ANOVA) on log-transformed data. Thus, the two products could be considered bioequivalent regarding absorption rate (Cmax and Tmax), extent of absorption (Cmax and AUC) and elimination (t1/2).

The aim of the study was to determine the allele and genotype frequencies of rs1532624 SNP of the cholesteryl ester transfer protein gene (CETP) among 116 Jordanian patients taking statins, and to study the impact of the genotypes on response to statin therapy. The study was approved by the Institutional review Board (IRB) of The Jordan University Hospital. An informed consent was signed by every participant. A single fragment encoding a 307 bp sequence of the CETP gene, including the SNP of interest at position 14645 in intron 7, was amplified using a polymerase chain reaction (PCR) technique directly from whole blood. The PCR product was then subjected to DNA sequencing. The frequencies of the genotypes of the homozygous minor allele (AA), the homozygous major allele (CC), and the heterozygous allele (CA) were 0.121, 0.405, and 0.474, respectively. The minor allele (A) frequency was 0.358. The frequencies did not deviate from Hardy-Weinberg equilibrium. The lipid profile before the start of statin therapy was similar for all genotypes regarding total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and triglycerides, while high density lipoprotein cholesterol (HDL-C) was significantly higher in the AA genotype. The AA genotype was also associated with significantly lower CETP activity than the other genotypes. The response to statin therapy was less in the AA genotype than the other genotypes for TC and LDL-C. In conclusion, the homozygous minor allele subjects have higher base line HDL-C, and lower CETP activity than the other genotypes (CA and CC). They also have less reduction in TC and LDL-C after statin therapy.

We tested the ability of 194 unrelated, healthy Jordanian volunteers to metabolize S-mephenytoin. Mephenytoin (100 mg) was coadministered with debrisoquin (10 mg) orally and urine was collected for 8 hours. Mephenytoin metabolism was tested according to three measures: the amount of 4-hydroxymephenytoin, the S/R enantiomeric ratio, and the presence of a polar, acid-labile metabolite in urine collected for 8 hours after the dose. The S/R ratio and the presence of the acid-labile metabolite were determined in the urine of 16 patients who had low amounts of 4-hydroxymephenytoin (log hydroxylation index ≥1). On examination of these three parameters of oxidation status, nine subjects were found to be poor metabolizers of mephenytoin by all three parameters. Thus 4.6% (95% confidence interval of 1.6% to 7.6%) of Jordanian subjects studied were poor metabolizers of mephenytoin. According to the Hardy-Weinberg Law, the frequency of the recessive autosomal gene controlling the poor metabolizer status of mephenytoin was predicted to be 0.215% (95% confidence interval of 0.146% to 0.283%). These results are on the same order of magnitude as those determined in European white populations and constitute the first report in Arab populations. Clinical Pharmacology & Therapeutics (1995) 58, 542–547; doi

BACKGROUND Vancomycin is used in neonatal intensive care units to treat nosocomial infections caused by methicillin-resistant Staphylococcus aureus (MRSA) or coagulase-negative staphylococci. Current dosing regimens are not adequate, producing trough concentrations below the target range. PATIENTS AND METHODS 151 neonates who received vancomycin and had vancomycin peak and trough concentration measurements as part of regular therapeutic drug monitoring were utilized. The patients were divided into three groups according to gestational age; less than 28 weeks, 28 to less than 34 weeks and 34 weeks to term. Neonates were given vancomycin doses as per guidelines. The pharmacokinetic parameters, elimination rate constant (K), elimination half-life (t1/2), volume of distribution (VD) and clearance (CL), were calculated. RESULTS Peak vancomycin concentrations ranged from 9.4 to 52.8 mg/l, while troughs ranged from 0.0 to 16.6 mg/l. One third of the trough concentrations were below 5 mg/l and are thus, subtherapeutic. There were no statistically significant differences between the three groups in regard to elimination rate constant and half-life. However, there was a statistically significant difference in volume of distribution between the three groups (p < 0.05), and in clearance between the first group and the other two (p < 0.05), using Kruskal-Wallis statistical test. CONCLUSIONS The empirical dosing method used was inadequate in one third of patients. Individualization of vancomycin dosing in the neonatal critical care unit at The Jordan University Hospital seems necessary.

The pharmacokinetic parameters of digoxin given intravenously (0.075 mg/kg) alone and following treatment with oral cholestyramine (8 gm in 50 ml water) were studied in rabbits. Pretreatment with cholestyramine produced a significant decrease in the serum concentration of digoxin and significantly enhances its systemic clearance as indicated by a statistically significant decrease in the area under the concentration-time curve (AUC), half time of elimination (t1/2), and mean residence time (MRT). These findings indicate that the idea of gastrointestinal dialysis, known with activated charcoal, could be extended to ion-exchange resins that could be a potentially useful adjunctive measure in the management of drug overdose especially with commonly used drugs with a low therapeutic index like digoxin.

1. The N-acetylation of dapsone (DDS) was studied in 160 unrelated healthy Jordanian volunteers. 2. The frequency of slow acetylators determined using the plasma monoacetyldapsone (MADDS) to DDS ratio (MADDS/DDS), was 67.5% with a 95% confidence interval of 59 to 76%. Slow acetylators had an acetylation ratio of less than 0.42. 3. Applying the Hardy-Weinberg Law, the frequency of the recessive allele controlling slow acetylation was found to be 0.82 +/- 0.02. 4. The frequency distribution histogram of the plasma MADDS/DDS ratio showed an apparent trimodal pattern. The number of homozygous (n = 16) and heterozygous (n = 36) rapid acetylators derived from the observed data did not agree with those predicted for the respective rapid acetylators (n = 5 and n = 47) according to the Hardy-Weinberg Law. The suggested antimode used to discriminate the two groups was 0.82. 5. The mean plasma concentration of MADDS and the mean plasma acetylation ratio were about three times lower in slow than in rapid acetylators. However, there was no difference in mean plasma DDS concentration between slow and rapid acetylators. 6. There was a significant correlation (r = 0.853, P less than 0.001) between plasma MADDS concentration and the acetylation ratio. For DDS such a correlation was absent (r = 0.059, P = 0.23).

Glucuronidation of 7-hydroxy-4-methylcoumarin (7-OH-4-MC) was comparable in three of the four human liver samples studied. In liver sample IV the glucuronidation rate of 7-OH-4-MC was almost 40% of that in the other samples. That might be due to interindividual variation in the capacity to glucuronidate. Glucuronidation rates were not reduced in the one human liver sample which displayed mild centrilobular cholestasis on histopathology. Furosemide (FR), salicylic acid (SA), lorazepam (Z) and menthol (MT) inhibited the glucuronidation of 7-OH-4-MC to varying degrees (30-90%). Paracetamol (PA) and 5-hydroxytryptamine (HT) were not inhibitors of the glucuronidation of 7-OH-4-MC. These findings suggest the presence of other UDP-glucuronosyltransferase (UDPGT) isozymes in the human liver microsomes which are responsible for the glucuronidation of PA and HT than those which glucuronidate 7-OH-4-MC.

The O-demethylation of dextromethorphan (DMT) to dextrorphan (DRP) was studied in 241 unrelated, healthy Jordanian volunteers (171 males, 70 females). Urine was collected for 8 h following a single oral dose of DMT bromhydrate 30 mg. A thin-layer chromatographic (TLC) technique was used to identify the metaboliser phenotype. The frequency of the poor metaboliser phenotype was found to be 2.9% (approximate 95% confidence interval 0.8-5.0%). Applying the Hardy-Weinberg Law, the frequency of the recessive autosomal gene controlling poor metabolism was 0.17 (95% confidence interval 0.108-0.232).

Contrary to the general belief that cimetidine and ranitidine spare glucuronidation of drugs, some authors have indicated that both cimetidine and ranitidine could inhibit the glucuronidation of paracetamol (acetaminophen) by cultured rat hepatocytes. Thus, we tested the effect of three histamine H2-receptor blockers (cimetidine, ranitidine and famotidine) on the glucuronidation of 7-hydroxy-4-methylcoumarin (7-OH-4-MC) by human liver microsomes. None of the drugs studied produced significant inhibition of the glucuronidation of 7-OH-4-MC when used at concentrations up to 1.5 mM. Thus, even the new H2-receptor blocker, famotidine, spares glucuronidation. These findings further support the previous reports which suggest that glucuronide conjugation in humans is spared by H2-receptor blockers.

Glucuronidation of 7-hydroxy-4-methylcoumarin (7-H-4-MC) by microsomal UDP-glucuronosyltransferases from 12 human liver biopsy samples was studied. Glucuronidation rates were highest for livers with mild cholestasis while those for livers with mild fatty changes were similar to normal livers. The lowest rates were exhibited by livers showing primary or metastatic carcinoma on histological examination. Thus, glucuronidation of not only bile acids but also of other substrates such as 7-H-4-MC may be elevated in cholestasis. These results are also consistent with other studies stating that glucuronidation might be spared in certain mild hepatic diseases.

The present study represents the current prescribing trend for antihypertensive drugs in family medicine clinics at Jordan University Hospital in Jordan. The study sample involved 416 male and female hypertensive Jordanian patients. Our results demonstrate that 2 hypertensive patients were not receiving any antihypertensive therapy at the time of evaluation, 192 patients were on a single antihypertensive therapy, 157 patients were on two antihypertensive drugs, 52 patients were on triple antihypertensive therapy and 13 patients were on four or more drugs. The most frequent classes of antihypertensive drugs used or prescribed to patients either as a single therapy or in combinations include angiotensin converting enzyme inhibitors, β-blockers, calcium channel blockers, diuretics and angiotensin receptor blockers. Among the mono-therapy prescriptions, angiotensin converting enzyme inhibitors were the most commonly prescribed and diuretics were least used. In combined therapy, diuretics were the most prescribed antihypertensive drugs, followed by β-blockers. Combinations consisting of diuretics and β-blockers were the most commonly seen. With respect to overall use, angiotensin converting enzyme inhibitors were the most prescribed agents. Despite an observed significant reduction in blood pressure between first and last visits to the family clinics, most of the patients did not achieve recommended blood pressure control according to the international guidelines. [Med-Science 2013; 2(1.000): 469-88]

The frequency distribution of the 8-h urinary ratio of log metoprolol/alpha-hydroxymetoprolol was assessed in 65 healthy, unrelated Jordanian volunteers. There was no apparent bimodality in the frequency distribution of this ratio among the subjects studied. The frequency of the poor metabolizer phenotype of metoprolol alpha-hydroxylation was 1.5% (one subject). There was a significant correlation (r = 0.61, P < 0.05, n = 39) between the log metoprolol/alpha-hydroxymetoprolol and the log debrisoquine/4-hydroxydebrisoquine ratios. However, the frequency of poor metabolizer status of debrisoquine among the 39 subjects was 7.7% (three subjects). Only one of the poor metabolizer of metoprolol alpha-hydroxylation. These findings indicate that metoprolol alpha-hydroxylation by CYP2D6 represents a poor probe for studying debrisoquine polymorphism in Jordanians.

A 33-year-old female with severe diffuse coronary artery disease and left ventricular outflow tract obstruction secondary to homozygous familial hypercholesterolaemia underwent liver and heart transplantation. During a post-operative follow-up period of 13 months, apart from one episode of cardiac rejection at 3 weeks, she has remained well and without evidence of accelerated coronary disease on angiography. By 3 months after transplantation serum total cholesterol, low density lipoprotein cholesterol, apolipoprotein B and lipoprotein(a) levels had decreased and apolipoprotein in A-I and high density lipoprotein cholesterol levels had increased, all to within the normal range. These changes were accompanied by marked regression of xanthomata and were maintained at 13 months. Liver transplantation provides an effective means of correcting serum lipids in patients with homozygous familial hypercholesterolaemia and is an important adjunct to cardiac transplantation.

The acetylator phenotype was determined in 31 insulin-dependent (IDDM) and 110 noninsulin-dependent (NIDDM) Jordanian diabetics, and was compared to that of 160 healthy volunteers of the same ethnic group. Dapsone was used as the test drug. The rapid acetylator phenotype was slightly less frequent in IDDM and slightly more frequent in NIDDM. Neither of the differences was significant. When acetylator status in the two types of diabetes mellitus was compared, there was a significant difference among the two groups. Patients with IDDM had a higher percentage of the slow acetylator phenotype when compared to NIDDM patients. The association between acetylator status and IDDM in Jordanians, which agrees with that reported for the Saudi Arabian population, is the reverse of what is found in European populations. The results demonstrate ethnic differences in acetylator status among IDDM patients.

Hydatid cyst of the heart is an uncommon lesion which usually develops in the left ventricle. Diagnosis should be considered in patients coming from an area where hydatid cyst is endemic and who present with an abnormal heart shadow on chest X-ray, frequently associated with T wave changes on the electrocardiogram. The cyst tends to grow and thus compress the neighboring myocardium. It causes displacement of the coronary vessels, rhythm disturbances and mechanical interference with the AV valves and ventricular function. Spontaneous involution of the cyst with calcification of its wall as well as rupture with anaphylactic shock may occur. Early excision with standby cardiopulmonary bypass is advisable. Three patients with hydatid cyst of the left ventricle, 2 of whom were operated on by using cardiopulmonary bypass, are presented. Results of the surgical treatment, both early and late, are rewarding, with relief of symptoms, regression of electrocardiographic abnormalities and very low incidence of recurrence.

Anomalous origin of the right coronary artery (RCA) from the pulmonary artery (PA) is very rare, and may be an isolated defect, or associated with other congenital cardiac or non-cardiac defects. The anomalous right coronary artery may appear grossly normal if it arises near an aorto-pulmonary window, and will be perfused by oxygenated blood. However, it may be vein-like and perfused in a retrograde fashion from the left coronary artery (LCA). This was once thought to be a benign lesion, and an incidental finding during cardiac catheterization or surgical repair of the associated congenital cardiac anomaly, but, sudden cardiac deaths have been reported. Associated congenital cardiac defects reported include tetralogy of Fallot (2 cases), aorto-pulmonary window (3 cases), and atrial septal defect (1 case). Another case associated with tetralogy of Fallot is described. Surgical correction of these associated lesions should include anatomical correction of the anomalous right coronary artery.

The glucuronidation of 6-hydroxylated bile acids by human liver microsomes has been studied in vitro; for comparison, several major bile acids lacking a 6-hydroxyl group were also investigated. Glucuronidation rates for 6 alpha-hydroxylated bile acids were 10-20 times higher than those of substrates lacking a hydroxyl group in position 6. The highest rates measured were for hyodeoxy- and hyocholic acids, and kinetic analyses were carried out using these substrates. Rigorous product identification by high-field proton nuclear magnetic resonance and by electron impact mass spectrometry of methyl ester/peracetate derivatives revealed that 6-O-beta-D-glucuronides were the exclusive products formed in these enzymatic reactions. These results, together with literature data, indicate that 6 alpha-hydroxylation followed by 6-O-glucuronidation constitutes an alternative route of excretion of toxic hydrophobic bile acids.