Use of a Bayesian approach in the design and evaluation of NCE2s.

Taiwan's regulatory agency defines New Chemical Entity 2 (NCE2) as a compound drug that has been approved and marketed for ten years in a top-ten pharmaceutically-advanced country but which is new in Taiwan. To apply for registration of NCE2 in Taiwan, a clinical trial may be conducted in Taiwan to evaluate the efficacy and safety. Since the NCE2 has been approved in at least one of the top-ten pharmaceutically-advanced countries, we can borrow the information from all of the observed data from other countries to synthesize the data from both Taiwan and other countries to assess the NCE2 efficacy. In this paper, we propose a Bayesian approach that uses a mixture of prior information to help evaluate an NCE2's efficacy. Numerical examples illustrate applications of the proposed approach in different scenarios. A method for sample-size determination for such trials is also proposed.

Comparison of the effects of serotonin-norepinephrine reuptake inhibitors versus selective serotonin reuptake inhibitors on cerebrovascular events.

BACKGROUND: Use of selective serotonin reuptake inhibitors (SSRIs) has been associated with an increased risk of intracranial hemorrhage. However, little is known about cerebrovascular risk in users of serotonin-norepinephrine reuptake inhibitors (SNRIs). Our aim was to determine the differential risk of cerebrovascular events between SSRIs and SNRIs. METHOD: A nationwide population-based cohort study was conducted in adult patients who started taking SSRIs or SNRIs during the time period 2005 through 2009. The outcome of interest was defined by the first hospitalization diagnosis for ischemic stroke (ICD-9-CM codes 433, 434, 436) or intracranial hemorrhage (ICD-9-CM codes 430, 431, 432). We used a Cox regression model with time-varying medication use and adjusted for stroke risk factors to estimate the hazard ratios (HRs) of ischemic stroke and intracranial hemorrhage associated with SNRI use, using SSRI use as a reference. RESULTS: Among 582,650 SSRI and 76,920 SNRI initiators with an average follow-up period of 3.2 years, there was a nonsignificantly increased trend toward intracranial hemorrhage (adjusted HR = 1.24 [95% CI, 0.97-1.58]) in SNRI users compared to SSRI users. The risk of ischemic stroke was comparable between the 2 treatment groups (adjusted HR = 1.01 [0.90-1.12]). Similar results were obtained in sensitivity analyses, considering a dose-response relation, allowance of a 7-day grace period between study drug discontinuation and outcome occurrence, and restriction to exclusive users, who remained on the initial treatment. In the subgroup analysis, there was an increased incidence of intracranial hemorrhages in SNRI users compared to SSRI users in patients without prior depression (adjusted HR = 1.63 [1.14-2.32]). CONCLUSIONS: Use of SNRIs is not associated with an increased risk of either ischemic stroke or intracranial hemorrhage as compared to use of SSRIs in adult patients with depression or anxiety. However, SNRIs should be used cautiously in patients without depression.

Comparing individual angiotensin-converting enzyme inhibitors with losartan in the risk of hospitalization for pneumonia and related mortality: a nationwide cohort study.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors might decrease the risk of pneumonia, but head-to-head comparisons with angiotensin receptor blockers (ARBs) were seldom made. The objective of this study was to evaluate incidence of pneumonia and mortality for different ACE inhibitors as compared to losartan, an ARB that has similar indications. METHODS: Adult patients aged more than 20 years who initiated ACE inhibitors and losartan between 1 January 2004 and 31 December 2009 were identified from Taiwan's National Health Insurance Database. The outcomes of interest were hospitalization for pneumonia and pneumonia-related mortality. Participants were followed from treatment initiation to the earliest of outcome occurrence, death or disenrollment, treatment discontinuation, switching to other ACE inhibitors or ARBs, or study termination (31 December 31 2010). Proportional-hazards regression model was used to calculate the hazard ratios and their 95% confidence intervals (CIs), adjusted on baseline characteristics. RESULTS: A total of 1,192,082 ACE inhibitors and 175,668 losartan initiators were included. The risk of hospitalization for pneumonia was significantly higher for captopril (hazard ratio 1.94, 95% CI 1.82-2.07), enalapril (hazard ratio 1.14, 95% CI 1.07-1.22), fosinopril (hazard ratio 1.11, 95% CI 1.02-1.21), perindopril (hazard ratio 1.14, 95% CI 1.04-1.25), and ramipril (hazard ratio 1.11, 95% CI 1.02-1.22), as compared with losartan. Captopril was associated with a significantly increased risk of pneumonia mortality (hazard ratio 2.43, 95% CI 1.79-3.31). CONCLUSIONS: Treatment with ACE inhibitors is not associated with a lower risk of pneumonia incidence and mortality as compared with losartan.

Continuation of statin therapy and a decreased risk of atrial fibrillation/flutter in patients with and without chronic kidney disease.

BACKGROUND: To contain cost, Taiwan's previous National Health Insurance Reimbursement Policy requested that physicians discontinue their patients' statin therapy once the serum cholesterol had reached appropriate levels. This allowed us to evaluate the association between statin continuation and the occurrence of atrial fibrillation/flutter and whether it was modified by chronic kidney disease (CKD) status. METHODS: Patients who initiated statin therapy between January 1, 2001 and December 31, 2009 were identified from a random sample of one million subjects in the Taiwan National Health Insurance Research Database. The outcome was atrial fibrillation/flutter. A proportional hazard regression model with time-varying statin use was applied to estimate the hazard ratios (HR) and 95% confidence intervals (CIs) for atrial fibrillation/flutter according to current statin use versus treatment discontinuation, adjusted for baseline disease risk scores and time-varying covariates. RESULTS: A total of 6767 CKD and 63,678 non-CKD patients initiating statin therapy were included and followed for an average of 4.0 years. A total of 1118 participants experienced new-onset atrial fibrillation/flutter. The incidence of atrial fibrillation/flutter was approximately 2 fold higher in the CKD patients. Continuation of statin therapy was associated with a 22% (adjusted hazard ratio 0.78; 95% CI: 0.65-0.93) and 57% (adjusted HR 0.43; 95% CI: 0.27-0.68) decrease in atrial fibrillation/flutter hazard as compared with discontinuation in non-CKD and CKD patients, respectively. CONCLUSIONS: Continuation of statin therapy was associated with a decreased risk of atrial fibrillation/flutter among CKD and non-CKD patients. However, further randomized studies are still needed to assess the association.

Effects of selective serotonin reuptake inhibitors versus tricyclic antidepressants on cerebrovascular events: a nationwide population-based cohort study.

Depression is a common disorder worldwide and is strongly associated with stroke. Use of antidepressants could potentially decrease the risk of stroke in patients with depression. However, the role of selective serotonin reuptake inhibitors (SSRIs), the most frequently prescribed antidepressant in this era, in the risk of stroke showed inconsistent results. We aimed to assess the association between the use of different types of antidepressants, SSRIs and tricyclic antidepressants (TCAs), and the risk of cerebrovascular events in patients with depression or anxiety. A nationwide population-based cohort study was retrospectively conducted in patients with depression or anxiety who started to take SSRIs and TCAs identified from the Taiwan National Health Insurance claims database (2001-2009). We examined the association between the 2 types of antidepressants and incidence of stroke using a proportional hazard model adjusted for stroke risk factors. Among the 24,662 SSRI and 14,736 TCA initiators, the crude incidence rate for stroke was 10.03 and 13.77 per 100 person-years, respectively. Selective serotonin reuptake inhibitor use was not associated with risk of stroke as compared with TCAs in the time-fixed analysis. After adjusting for baseline propensity scores in the time-varying analysis, SSRI use significantly reduced risk of stroke as compared with TCAs with the adjusted hazard ratio of 0.67 (95% confidence interval, 0.47-0.96). The effect persisted even after considering the antidepressant dosage (hazard ratio, 0.65 [0.42 to 0.99]). In summary, use of SSRIs was associated with a reduced risk for stroke, as compared with TCAs, in this specific disease population.

Discontinuation of statin therapy associates with Parkinson disease: a population-based study.

OBJECTIVE: To evaluate the effect of discontinuing statin therapy on incidence of Parkinson disease (PD) in statin users. METHODS: Participants who were free of PD and initiated statin therapy were recruited between 2001 and 2008. We examined the association between discontinuing use of statins with different lipophilicity and the incidence of PD using the Cox regression model with time-varying statin use. RESULTS: Among the 43,810 statin initiators, the incidence rate for PD was 1.68 and 3.52 per 1,000,000 person-days for lipophilic and hydrophilic statins, respectively. Continuation of lipophilic statins was associated with a decreased risk of PD (hazard ratio [HR] 0.42 [95% confidence interval 0.27-0.64]) as compared with statin discontinuation, which was not modified by comorbidities or medications. There was no association between hydrophilic statins and occurrence of PD. Among lipophilic statins, a significant association was observed for simvastatin (HR 0.23 [0.07-0.73]) and atorvastatin (HR 0.33 [0.17-0.65]), especially in female users (HR 0.11 [0.02-0.80] for simvastatin; HR 0.24 [0.09-0.64] for atorvastatin). As for atorvastatin users, the beneficial effect was seen in the elderly subgroup (HR 0.42 [0.21-0.87]). However, long-term use of statins, either lipophilic or hydrophilic, was not significantly associated with PD in a dose/duration-response relation. CONCLUSIONS: Continuation of lipophilic statin therapy was associated with a decreased incidence of PD as compared to discontinuation in statin users, especially in subgroups of women and elderly. Long-term follow-up study is needed to clarify the potential beneficial role of lipophilic statins in PD.

Statins of high versus low cholesterol-lowering efficacy and the development of severe renal failure.

BACKGROUND: The objective of this nationwide retrospective cohort study was to examine the renal outcomes of HMG-CoA reductase inhibitor (statin) initiators. METHODS: The patients who started to take statins with high cholesterol-lowering efficacy (atorvastatin and rosuvastatin) and low efficacy (lovastatin, simvastatin, pravastatin, and fluvastatin) between 1 January 2001 and 31 December 2008 were identified from the Taiwan National Health Insurance claims database. The outcome of interest was severe renal failure, defined as the composite endpoint of hemodialysis, peritoneal dialysis, and kidney transplantation. A proportional hazard regression model was applied to estimate the incidence ratio between the two groups, adjusted for the propensity scores based upon baseline characteristics. RESULTS: Among of the 26,007 and 42,249 statin initiators, the crude incidence rate for developing severe renal failure was 0.65 and 0.46 per 100 person-years for the high-efficacy and low-efficacy groups, respectively. Despite that these two groups had comparable risk for myocardial infarction (hazard ratio: 1.06, 95%CI: 0.92­1.21), there was a 13% increased hazard for developing severe renal failure in the rosuvastatin and atorvastatin initiators (hazard ratio: 1.13, 95%CI: 1.02­1.26). The increased risk associated with these two statins was consistent across different risk groups (diabetes, chronic kidney disease, and ischemic heart disease). CONCLUSIONS: Statins with high cholesterol-lowering efficacy might increase the risk for developing severe renal failure. An alternative explanation is that the renal risk cannot be ameliorated as much as cardiovascular risk. Further follow-up studies or meta-analyses are needed to solve the controversy.

Antidepressant use and the risk of upper gastrointestinal bleeding in psychiatric patients: a nationwide cohort study in Taiwan.

The magnitude of risk between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding (UGIB) is still unknown in patients with psychiatric diseases. The aim of this study was to quantify the risk of UGIB induced by use of antidepressants with different affinities for serotonin transporters in psychiatric patients using Taiwan's nationwide health insurance claims database. We conducted a propensity score- matched retrospective cohort study and identified 304,606 psychiatric patients who initiated antidepressant treatment during the 2005-2006 period. Antidepressants were classified as high- (HA group), intermediate- (IA group), or low-affinity (LA group) serotonin reuptake inhibitors. Patients in the LA group were matched 1:1 to those in the HA and IA groups according to their propensity scores. Subjects who were successfully matched were followed up from the date of antidepressant initiation to first hospitalization for UGIB, drug discontinuation, transition to or addition of antidepressants in another group, or the study's end (whichever occurred first). A total of 153,486 psychiatric patients were successfully matched, and 498 first UGIB events were identified. Compared with the LA group, patients in the HA group had a higher risk for UGIB (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.11-1.71). The HR (95% CI) of the IA group was 1.11 (95% CI, 0.88-1.41). The trend for elevated UGIB risk with increasing affinity of serotonin transporters was statistically significant (P < 0.01). Elderly patients and those with prior UGIB history were more susceptible to the harmful effects. Our findings suggest that the use of high-affinity serotonin reuptake inhibitors may increase the risk for UGIB in psychiatric patients.

Non-steroidal anti-inflammatory drugs use and risk of upper gastrointestinal adverse events in cirrhotic patients.

BACKGROUND/AIMS: The upper gastrointestinal (GI) toxicity associated with non-steroidal anti-inflammatory drugs (NSAID) use among cirrhotic patients remains unclear. The objective of this study was to evaluate the risk of upper GI adverse events associated with celecoxib and oral and parenteral non-selective NSAIDs in cirrhotic patients. METHODS: All the patients aged ≥ 20 years with a diagnosis of cirrhosis hospitalized for variceal bleeding and non-variceal upper GI adverse events (oesophageal, gastric, duodenal ulcer, bleeding; gastritis and duodenitis) in 2006 were identified using ICD-9-CM diagnosis codes from inpatient claims from the Taiwan National Health Insurance Database. In the case-crossover study design, the case period was defined as 1-30 days and the control period as 31-60 days before the date of hospitalization. The information for individual NSAID use was obtained from the outpatient pharmacy prescription database. Adjusted self-matched odds ratios (OR) and their 95% confidence intervals (CI) were estimated with a conditional logistic regression model. RESULTS: A total of 4876 cirrhotic patients were included. The adjusted OR (95% CI) was 1.44 (0.89-2.31) for celecoxib, 1.87 (1.66-2.11) for oral non-selective NSAIDs and 1.90 (1.55-2.32) for parenteral NSAIDs overall. Risks were similar for variceal and non-variceal events. Concomitant use of proton pump inhibitors and histamine-2 receptor antagonists tended to decrease the upper GI toxicity associated with non-selective NSAIDs and celecoxib. CONCLUSION: The use of nsNSAIDs but not celecoxib was associated with a two-fold increased risk of variceal and non-variceal upper GI events among cirrhotic patients.

Value of preapproval safety data in predicting postapproval hepatic safety and assessing the legitimacy of class warning.

OBJECTIVE: The objective of this study was to systematically evaluate whether preapproval safety data for nonhepatotoxic drugs and hepatotoxic drugs can be compared to improve preapproval prediction of postapproval hepatic safety and to assess the legitimacy of applying class warnings. METHODS: Drugs within a therapeutic class that included at least one drug that had been withdrawn from the market because of liver toxicity or had a warning of potential liver toxicity issued by major regulatory agencies, and at least one drug free from such regulatory action, were identified and divided into two groups: drugs with and drugs without regulatory action. Preapproval clinical data [including the elevation rates of alanine aminotransferse (ALT) and withdrawal due to liver toxicity, the number of patients with combined elevation of ALT and bilirubin, and liver failure] and nonclinical data (including chemical structures, metabolic pathways, and other significant findings in animal studies) were compared between the two groups. RESULTS: Six drug classes were assessed in this study: thiazolidinediones, cyclooxygenase-2 inhibitors, fluoroquinolones, catechol-O-methyltransferase (COMT) inhibitors, leukotriene receptor inhibitors, and endothelin receptor antagonists. In two classes (COMT inhibitors and endothelin receptor antagonists), drugs with regulatory action had significantly higher rates of ALT elevation of more than threefold and greater numbers of patients with combined elevation of ALT and bilirubin than drugs without regulatory action. Drugs with regulatory action also had chemical structures or metabolic pathways associated with the toxicity. The legitimacy of class warnings was refuted in all six classes of drugs. CONCLUSION: Preapproval safety data may help predict postapproval hepatic safety and can be used to assess the legitimacy of applying class warnings.

Association of galactose single-point test levels and phenytoin metabolic polymorphisms with gingival hyperplasia in patients receiving long-term phenytoin therapy.

STUDY OBJECTIVE: To evaluate whether the occurrence or severity of gingival hyperplasia is associated with liver function test results or phenytoin metabolism. DESIGN: Prospective analysis. SETTING: University-affiliated medical center in Taipei, Taiwan. PATIENTS: Sixty-six patients (mean age 37.9 yrs) with epilepsy who were receiving phenytoin for more than 1 year. Intervention. Four blood samples were drawn from each patient for liver function testing, concentrations of phenytoin and its metabolites R-5-(4'-hydroxyphenyl)-5-phenylhydantoin (R-HPPH) and S-HPPH, and genotyping of cytochrome P450 (CYP) 2C9 and 2C19. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of phenytoin and its metabolites were determined by a high-performance liquid chromatography method. The CYP2C9 and CYP2C19 genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism analysis. Conventional liver function assays and a quantitative liver function test--galactose single-point (GSP) measurement--were performed. Statistical analyses were performed to evaluate the association between liver function test results as well as metabolic phenotype and the occurrence and severity of gingival hyperplasia. Among liver function tests, only GSP levels showed a significant difference between patients with and those without gingival hyperplasia. Patients with an elevated GSP level (> or = 280 microg/ml) had a significantly higher odds ratio (OR 4.51) for the occurrence of gingival hyperplasia. In addition, increased R-HPPH (OR 1.02) and phenytoin (OR 1.09) concentrations were associated with an increased occurrence of gingival hyperplasia. However, only increased GSP and R-HPPH concentrations had significantly higher ORs (2.84 and 1.02, respectively) associated with the severity of gingival hyperplasia. Although mean +/- SD plasma R-HPPH concentration was significantly lower in CYP2C19 poor metabolizers compared with CYP2C9 and CYP2C19 extensive metabolizers and CYP2C9 poor metabolizers (30.38 +/- 16.73 vs 68.22 +/- 44.75 and 78.95 +/- 51.67 microg/ml, respectively), no significant association between genotype and gingival hyperplasia was found. CONCLUSION: Increased GSP, phenytoin, and R-HPPH concentrations were associated with increased occurrence of phenytoin-induced gingival hyperplasia; only increased GSP and R-HPPH concentrations were associated with increased severity of this adverse effect.

Association of polymorphisms in NR1I2 and ABCB1 genes with epilepsy treatment responses.

OBJECTIVES: The aim of this study was to investigate whether the polymorphisms in the NR1I2 and ABCB1 genes were associated with epilepsy treatment responses. METHODS & RESULTS: NR1I2and ABCB1 polymorphisms were genotyped in 114 drug-resistant epileptic patients, 213 seizure-free patients and 287 normal controls. Highly specific real-time PCR was applied to detect the variants by using TaqMan allelic specific probe. For a single gene test, it was demonstrated that 3435C>T in the ABCB1 gene had a significant effect on epilepsy treatment responses, but polymorphisms in the NR1I2 gene did not. Further analysis using a logistic regression model revealed that only 2677G>T and 3435C>T in the ABCB1 gene and their interaction term were associated with drug-resistant epilepsy after adjustment for etiology and epilepsy classification. In the present study, the polymorphisms in the NR1I2 gene were not significantly associated with epilepsy treatment responses. CONCLUSION: Our results indicated that 2677G>T and 3435C > T in the ABCB1 gene contributed to drug-resistant epilepsy. Although biologically plausible, the polymorphisms in NR1I2 investigated in the present study did not play a role in epilepsy treatment responses. Other unveiled genetic variants in the NR1I2 gene that may have the potential to affect ABCB1 gene expression are worth further investigation in future studies.

Effects of variant UDP-glucuronosyltransferase 1A1 gene, glucose-6-phosphate dehydrogenase deficiency and thalassemia on cholelithiasis.

AIM: To test the hypothesis that the variant UDP-glucuronosyltransferase 1A1 (UGT1A1) gene, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and thalassemia influence bilirubin metabolism and play a role in the development of cholelithiasis. METHODS: A total of 372 Taiwan Chinese with cholelithiasis who had undergone cholecystectomy and 293 healthy individuals were divided into case and control groups, respectively. PCR and restriction fragment length polymorphism were used to analyze the promoter area and nucleotides 211, 686, 1,091, and 1,456 of the UGT1A1 gene for all subjects and the gene variants for thalassemia and G6PD deficiency. RESULTS: Variation frequencies for the cholelithiasis patients were 16.1%, 25.8%, 5.4%, and 4.3% for A(TA)(6) TAA/A(TA)(7)TAA (6/7), heterozygosity within the coding region, compound heterozygosity, and homozygosity of the UGT1A1 gene, respectively. Comparing the case and control groups, a statistically significant difference in frequency was demonstrated for the homozygous variation of the UGT1A1 gene (P = 0.012, chi(2) test), but not for the other variations. Further, no difference was demonstrated in a between-group comparison of the incidence of G6PD deficiency and thalassemia (2.7% vs 2.4% and 5.1% vs 5.1%, respectively). The bilirubin levels for the cholelithiasis patients with the homozygous variant-UGT1A1 gene were significantly different from the control analog (18.0+/-6.5 and 12.7+/-2.9 micromol/L, respectively; P<0.001, Student's t test). CONCLUSION: Our results show that the homozygous variation in the UGT1A1 gene is a risk factor for the development of cholelithiasis in Taiwan Chinese.

Screening CYP3A single nucleotide polymorphisms in a Han Chinese population with a genotyping chip.

Human cytochrome P450 (CYP)3A is a major P450 enzyme found in the liver and gastrointestinal tract. It plays an important role in the metabolism of a wide variety of drugs, some endogenous steroids and harmful environmental contaminants. It has been shown that CYP3A alleles encoding enzymes with little or no activity are largely created by single nucleotide polymorphisms (SNPs) in the sequences of these genes. The most prevalent of these SNPs are often of low allelic frequency, and many are specific to certain ethnic groups. Therefore, an accurate determination of their frequency in any given ethnic population requires investigations involving large sample sizes. A genotyping chip with enzyme-colorimetric detection was developed and used for simultaneous analysis of 22 known CYP3A SNPs in 451 Han Chinese subjects. Following multiplex polymerase chain reaction and allele-specific primer extension labeling, an enzymatic colorimetry detection system was employed to visualize genotype patterns on a nylon membrane. With this robust system, accurate discrimination ratios were obtained, and approximately 9,922 genotypes were determined. We found that the major CYP3A SNPs in the Chinese subjects were CYP3A4*4 (allele frequency 2.4%), CYP3A4*5 (0.7%), CYP3A4*18A (2.7%) and CYP3A5*3C (70.2%). Most of the major CYP3A4 SNPs found in other ethnicities were not found in this study. Using these SNPs, 11 haplotypes were identified. Comparison between present and previous studies shows that CYP3A4*4 and CYP3A4*5 alleles were Chinese-specific. The genotyping chip developed in this study is an efficient, economic and accurate system for screening multiple SNPs in a large population. Application of such technology is expected to be less labor intensive and easier to adapt to specific searches when compared with other methodologies.

Genetic factors related to unconjugated hyperbilirubinemia amongst adults.

Some variations in the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene are involved in the development of unconjugated hyperbilirubinemia. We hypothesize that other genetic factors may also be associated with this disease. A total of 227 adults with normal routine haematology and liver function (apart from bilirubin testing for which they revealed bilirubin > or = 25.7 micromol/l and unconjugated bilirubin/total bilirubin > or = 80%), and 235 sex- and age-matched controls, were recruited. All subjects were analysed for UGT1A1, glucose-6-phosphate dehydrogenase (G6PD) and organic anion transporter polypeptide 2 (OATP2) genotypes using polymerase chain reaction-restriction fragment length polymorphism. The results indicated that G6PD deficiency, variant UGT1A1 gene and variant OATP2 gene were risk factors for hyperbilirubinemia. The odds ratios (OR) (with 95% confidence interval) were 220.83 (34.68-1406.30), 73.61 (17.01-318.63), 45.15 (11.19-182.22), 15.46 (4.35-54.99) and 6.51 (1.83-23.09), respectively, for individuals featuring the common UGT1A1/OATP2 haplotypes homozygous/heterozygous, compound heterozygous/heterozygous, compound heterozygous/wild-type, heterozygous/heterozygous and heterozygous/wild-type variations amongst subjects with normal G6PD activity. Amongst the subjects with G6PD deficiency, the OR was 159.00 (24.57-1028.94) for individuals carrying variations in both UGT1A1 and OATP2 genes. The UGT1A1/OATP2 haplotypes homozygous/wild-type, homozygous/compound heterozygous and homozygous/homozygous for G6PD normal and variant/wild-type for G6PD deficient individuals were only observed in the case group, and not in the control group. Amongst hyperbilirubinemic adults, bilirubin values tended to parallel variation status of their haplotypes. Adults featuring certain haplotypes in UGT1A1, OATP2 and G6PD genes face a high risk of developing unconjugated hyperbilirubinemia.

Polymorphisms of uridine-diphosphoglucuronosyltransferase 1A7 gene in Taiwan Chinese.

AIM: Single nucleotide polymorphisms (SNPs) of uridine-diphosphoglucuro-nosyltransferase 1A7 (UGT1A7) gene are associated with the development of orolaryngeal cancer, hepatocellular carcinoma, and colorectal cancer. We performed this research to establish the techniques for determining UGT1A7 gene and basic data of this gene for Taiwan Chinese. METHODS: We collected blood samples from 112 healthy adults and 505 subjects carrying different genotypes of UGT1A1, and determined the promoter area and the entire sequence of UGT1A7 exon 1 by polymerase chain reaction. We designed appropriate primers and restriction enzymes to detect variant UGT1A7 genotypes found in the study subjects. RESULTS: Six SNPs at nucleotides 33, 387, 391, 392, 622, and 756 within the coding region of UGT1A7 exon 1 were found. The incidence of UGT1A7 *1/*2 (N129R131W208/K129K131W208) was predominant (35.7%) while that of UGT1A7 *3/*3 (K129K131R208/K129K131R208) was the least (2.7%). The allele frequency of UGT1A7*3, which exists in a considerable proportion of Caucasians (0.361) and Japanese (0.255), was identified only to be 0.152 in our study subjects. A novel variation at nucleotide -57 in the upstream was found, which was associated with SNPs at nucleotides 33, 387, 391, 392, and 622 in one of the variant haplotypes. The nucleotide changes at positions 387, 391, 392 and 756 were in linkage in another variant haplotype. The allele frequency of UGT1A7*3 was 0.018, 0.158, 0.242, 0.433, and 0.920 in subjects carrying wild, A(TA) (6)TAA/A(TA)(7)TAA, A(TA)(7)TAA/A(TA)(7)TAA, 211G/211A, and 211A/211A variants of UGT1A1 gene, respectively. By using natural or mutagenesis primers, we successfully detected the variations at nucleotides -57, 33, 387, and 622 with the restriction enzymes HpyCH4 IV, Taq I, Afl II, and Rsa I, respectively. CONCLUSION: The results indicate that the allele frequencies of UGT1A7 gene in Taiwan Chinese are different from those in Caucasians and Japanese. Carriage of the nucleotide 211- variant UGT1A gene is highly associated with UGT1A7*3. The restriction-enzyme-digestion method for the determination of nucleotides -57 (or 33, or 622) and 387 can rapidly identify genotypes of UGT1A7 in an individual.

Quality of life in Taiwanese adults with chronic rhino-sinusitis.

BACKGROUND AND PURPOSE: Chronic rhino-sinusitis (CRS) is a disease in prevalence. This study evaluates the impact of this disorder to Taiwanese patients' general and sinus-related health status among Taiwanese patients with CRS. METHODS: A total of 201 consecutive CRS patients (male:female: 107:94, mean age: 40.1 +/- 14.6 years) seeking otolaryngological care at a tertiary referral medical center were recruited. Quality of life was measured by a Taiwan Standard Version of the Medical Outcome Study 36-Item Short Form Health Survey (SF-36) and a Chinese version Chronic Sinusitis Survey (CCSS). Patients were administered with the SF-36 and CCSS preoperatively. RESULTS: CRS has a significant impact on patients in seven of the eight domains of SF-36: role-physical (88.9 +/- 24.7), bodily pain (70.3 +/- 22.6), general health (56.1 +/- 11.6), social functioning (79.3 +/- 21.6), vitality (56.4 +/- 19.1), role-emotional (57.7 +/- 42.1), and mental health (48.4 +/- 17.2) subscores of CRS patients are all in significant decrement (p < 0.05) as compared with the data derived from Taiwanese general population. Physical functioning is the only domain without impact. Significant decrements (p < 0.05) are also observed in symptom subscale (43.3 +/- 27.8), medication subscale (80.3 +/- 26.4), and total survey score (63 +/- 20.3) of the CCSS as compared to the healthy subjects. The severity of CRS is significantly predictive (p < 0.05, R2 = 0.34) of CCSS. CONCLUSIONS: CRS has considerable impacts on a patient's sinus-related quality of life, as well as on their general health status.

Dose-response relationships of propranolol in Chinese subjects with different CYP2D6 genotypes.

BACKGROUND: For clinical treatment, a smaller dosage of propranolol is often used among Chinese people. Propranolol is metabolized by polymorphic CYP2D6. We postulate that the lower propranolol dosage in Chinese is due to a slower CYP2D6 metabolism. A majority of the Chinese population has the nucleotide T188 in the CYP2D6 gene (CYP2D6*10) instead of C188 (CYP2D6*1), which most white subjects have. Chinese subjects of different CYP2D6*1/CYP2D6*10 genotypes have been shown to have different propranolol pharmacokinetic characteristics. In this study, we compared the beta-blockade effects of propranolol in Chinese subjects of the two different CYP2D6 genotypes. METHODS: Based on the nucleotide 188 genotypes, two groups of 10 healthy subjects each were selected. Each subject was given a 10-, 20-, or 40-mg rac-propranolol tablet three times a day for 3 days in 3 different phases. Heart rate and blood pressure were measured in both supine and upright positions. The heart rate was also determined during treadmill exercise test. Plasma concentration of S-propranolol at 2 hrs after the last-dose administration was measured. RESULTS: Despite therebeing higher S-propranolol plasma concentration in CYP2D6*10 subjects than in CYP2D6*1 subjects at 10- and 20-mg dosage, the dose-response relationship was not significantly different in these subjects. CONCLUSIONS: Our results do not support the hypothesis that CYP2D6*1/CYP2D6*10 polymorphism may affect the beta-blockade effect of propranolol in Chinese subjects.

Coinheritance of variant UDP-glucuronosyl transferase 1A1 gene and glucose-6-phosphate dehydrogenase deficiency in adults with hyperbilirubinemia.

A total of 115 male adults with unconjugated hyperbilirubinemia were divided into six subgroups according to their glucose-6-phosphate dehydrogenase (G6PD) status (normal and deficient) and UDP-glucuronosyl transferase 1 (UGT1) A1 genotypes (heterozygous variation, compound heterozygous variation and homozygous variation). The mean (SD) value of serum bilirubin in the subjects with G6PD deficiency and homozygous variation in UGT1A1 gene was 51.3 (17.8) micromol/l, which was significantly higher compared to that in the other five subgroups. Among the 115 study subjects, five patients had bilirubin values greater than 51.3 micromol/l. All five of these subjects had a homozygous variant UGT1A1 genotype and four of them were G6PD deficient. Our data suggest that pronounced hyperbilirubinemia in G6PD-deficient male adults is attributable to the coinheritance of homozygous variation in the UGT1A1 gene.