A review and assessment of potential sources of ethnic differences in drug responsiveness

The International Conference on Harmonization (ICH) E5 guidelines were developed to provide a general framework for evaluating the potential impact of ethnic factors on the acceptability of foreign clinical data, with the underlying objective to facilitate global drug development and registration. It is well recognized that all drugs exhibit significant inter-subject variability in pharmacokinetics and pharmacologic response and that such differences vary considerably among individual drugs and depend on a variety of factors. One such potential factor involves ethnicity. The objective of the present work was to perform an extensive review of the world literature on ethnic differences in drug disposition and responsiveness to determine their general significance in relation to drug development and registration. A few examples of suspected ethnic differences in pharmacokinetics or pharmacodynamics were identified. The available literature, however, was found to be heterologous, including a variety of study designs and research methodologies, and most of the publications were on drugs that were approved a long time ago.     

A review of exemestane in the management of breast cancer

Breast cancer is a major health problem in developed countries. Endocrine therapy is a key component in the management of hormone receptor-positive disease. Although tamoxifen has historically been the gold standard in the first-line management of early and advanced breast cancer, the rise of third-generation aromatase inhibitors in the past decade has resulted in a major shift in endocrine therapy. Clinical trials of aromatase inhibitors including exemestane, an orally active steroidal aromatase inactivator, have demonstrated significant improvements in outcome measures compared with tamoxifen. In early breast cancer, key questions remain regarding the optimal sequence, duration and type of aromatase inhibitors, as well as their long-term safety.     

A review of exemestane in the management of breast cancer

Breast cancer is a major health problem in developed countries. Endocrine therapy is a key component in the management of hormone receptor-positive disease. Although tamoxifen has historically been the gold standard in the first-line management of early and advanced breast cancer, the rise of third-generation aromatase inhibitors in the past decade has resulted in a major shift in endocrine therapy. Clinical trials of aromatase inhibitors including exemestane, an orally active steroidal aromatase inactivator, have demonstrated significant improvements in outcome measures compared with tamoxifen. In early breast cancer, key questions remain regarding the optimal sequence, duration and type of aromatase inhibitors, as well as their long-term safety.     

Population differences in breast cancer severity

Breast cancer incidence and mortality vary among different populations. African-American, Hispanic, Asian and Native American women have lower incidence but higher mortality compared with non-Hispanic white women. Explanations for the observed variation include social and economic factors such as education, income level, health insurance coverage, use of mammography, parity, breastfeeding and diet. Breast cancer may be a heterogeneous disease with different subtypes of tumors having different genetic and environmental risk factors. The difference in frequency of particular tumor subtypes between populations may explain some of the differences in incidence and mortality. Known genetic variants explain a small fraction of breast cancer cases, and so far there are no susceptibility genes that explain population differences in incidence and mortality. Studies evaluating the risk for particular tumor subtypes combining genetic and environmental variables and analyzing cases from different populations are needed to understand population differences in the severity of breast cancer.     

Systematic review: geographical and ethnic differences in gastro-oesophageal reflux disease

BACKGROUND: Many observers believe that gastro-oesophageal reflux disease is more common among white individuals compared with Asians and Afro-Caribbean subjects. AIM: To perform a systematic review regarding geographical and ethnic factors in the prevalence of reflux symptoms, endoscopic oesophagitis, hiatus hernia and Barrett's oesophagus. RESULTS: Differences in definitions and methodology make comparison between studies difficult. Overall, however, the community prevalence of reflux symptoms, as well as the prevalence of endoscopic oesophagitis, hiatus hernia and Barrett's oesophagus among patients undergoing upper endoscopy, were lower among Asian and Afro-Caribbean subjects compared with white individuals. There may also be a north-south gradient in the prevalence of gastro-oesophageal reflux disease among western countries. Gastro-oesophageal reflux disease may be moderately common in the Middle East. There are suggestions that the prevalence of gastro-oesophageal reflux disease is increasing in the Far East. CONCLUSIONS: More data are required, especially from Africa, South America, the Middle East, and the Indian subcontinent. Suggestions are made regarding definitions and methodology to facilitate comparison between future studies from different countries.     

A review of coumarin derivatives in pharmacotherapy of breast cancer

The coumarin (benzopyran-2-one, or chromen-2-one) ring system, present in natural products (such as the anticoagulant warfarin) that display interesting pharmacological properties, has intrigued chemists and medicinal chemists for decades to explore the natural coumarins or synthetic analogs for their applicability as drugs. Many molecules based on the coumarin ring system have been synthesized utilizing innovative synthetic techniques. The diversity oriented synthetic routes have led to interesting derivatives including the furanocoumarins, pyranocoumarins, and coumarin sulfamates (COUMATES), which have been found to be useful in photochemotherapy, antitumor and anti-HIV therapy, and as stimulants for central nervous system, antibacterials, anti-inflammatory, anti-coagulants, and dyes. Of particular interest in breast cancer chemotherapy, some coumarins and their active metabolite 7-hydroxycoumarin analogs have shown sulfatase and aromatase inhibitory activities. Coumarin based selective estrogen receptor modulators (SERMs) and coumarin-estrogen conjugates have also been described as potential antibreast cancer agents. Since breast cancer is the second leading cause of death in American women behind lung cancer, there is a strong impetus to identify potential new drug treatments for breast cancer. Therefore, the objective of this review is to focus on important coumarin analogs with antibreast cancer activities, highlight their mechanisms of action and structure-activity relationships on selected receptors in breast tissues, and the different methods that have been applied in the construction of these pharmacologically important coumarin analogs.     

The enhanced bladder cancer susceptibility of NAT2 slow acetylators towards aromatic amines: a review considering ethnic differences

Human bladder cancer may be caused by exposure to aromatic amines. The polymorphic enzyme N-acetyltransferase 2 (NAT2) is involved in the metabolism of these compounds. Two classical studies on chemical workers in Europe, exposed in the past to aromatic amines like benzidine, unambiguously showed that the slow acetylator status is a genetic risk factor for arylamine-induced bladder cancer. In the former benzidine industry in Huddington, Great Britain, 22 of 23 exposed cases with bladder cancer, but only 57% of 95 local controls without bladder cancer were of the slow acetylator phenotype. In Leverkusen, Germany, 82% of 92 benzidine-exposed chemical workers with bladder cancer were of the slow acetylator phenotype, whereas only 48% of 331 chemical workers who had worked at that plant were of the slow acetylator phenotype. This is in line with several smaller studies, which also show an over-representation of the slow acetylator status in formerly arylamine-exposed subjects with bladder cancer. Some of these studies included also subjects that were exposed to aromatic amines by having applied dyes, paints and varnishes. These European findings are in contrast to a large study on Chinese workers occupationally exposed to aromatic amines. In this study, only five of 38 bladder cancer cases occupationally exposed to arylamines were of the slow acetylator genotype. This is much lower than the ratio of slow acetylators to the general population in China. This points to different mechanisms of susceptibility for bladder cancer upon exposure to aromatic amines between European (Caucasian) and Chinese populations.     

重新审视蒽环类药物在乳腺癌辅助化疗中的地位

蒽环类药物以其卓越的疗效成为乳腺癌术后辅助化疗的里程碑。多项随机临床试验结果表明:含蒽环类药物方案的辅助化疗可提高生存率,降低复发率和死亡率。近年研究还显示,蒽环类药物尤其使HER-2和Top-Ⅱ共同扩增的患者获益更大。蒽环类药物疗效确切,相关毒性可预测和预防,性价比更佳。蒽环类药物仍然是乳腺癌术后辅助化疗的基石,在辅助治疗中仍占有重要的地位。     

Diverticular disease of the colon: ethnic differences in frequency

BACKGROUND: Colonic diverticular disease is more common in Western populations than in developing countries. AIM: To determine whether the frequency of colonic diverticular disease is different in British patients of Indian-subcontinent Asian origin compared with other ethnic groups. METHODS: All colonoscopies performed over a 3-year period in a London hospital were studied. Patients of Indian-subcontinent Asian origin were identified by name. RESULTS: Five of 134 Indian-subcontinent Asian males (4%) had colonic diverticular disease, compared with 278 of 1268 patients of other ethnic groups (22%; P < 0.001). Five of 91 Indian-subcontinent Asian females (6%) had colonic diverticular disease, compared with 333 of 1486 patients of other ethnic groups (23%; P < 0.001). Although patients of Indian-subcontinent Asian origin (54.8 +/- 15.8 years) were younger than those of other ethnic groups (60.3 +/- 17.8 years; P < 0.0001), the ethnic difference in the frequency of diverticular disease persisted even when age was taken into account. CONCLUSION: There is a lower frequency of colonic diverticular disease in Indian-subcontinent Asians presenting for colonoscopy, compared with other ethnic groups. This cannot be explained by sex or age differences. Our findings require confirmation, but may provide opportunities for research into the aetiology of colonic diverticular disease.     

CYP3A5 polymorphism and the ethnic differences in cyclosporine pharmacokinetics in healthy subjects

To determine the relationship between CYP3A5 polymorphism and cyclosporine pharmacokinetic parameters among healthy volunteers, an oral cyclosporine (CsA) pharmacokinetic study was performed in 16 healthy subjects. Blood CsA concentrations were measured by high-performance liquid chromatography. Concentration-versus-time data were analyzed by a noncompartmental method using WinNonLin, and the blood samples were genotyped for the CYP3A5 using the polymerase chain reaction and pyrosequencing. CsA pharmacokinetic parameters were dichotomized and compared using the 1-way ANOVA test according to the CYP3A5*3C genotype. There were 6 homozygous A/A (wild type), 6 homozygous G/G (variant), and 4 heterozygous A/G genotypes for CYP3A5*3 C in these 16 healthy volunteers. All whites were G/G group, and all African Americans except 1 were either A/A or A/G group. The mean AUC (ng x h/mL) of CsA for the 3 genotype groups were 4962 +/- 1074 (A/A), 6677 +/- 1153 (G/G), and 5416 +/- 1817 (A/G), (A/A versus G/G, P = 0.03), and the mean CL/F (mL/min/kg) were 15.6 +/- 3.1 (A/A), 12.0 +/- 2.3 (G/G), and 14.7 +/- 5.9 (A/G), (A/A versus G/G, P = 0.04). None of the other parameters were significantly different among the 3 genotypes. In conclusion, the CYP3A5*3C polymorphism appears to affect AUC and CL/F of oral CsA significantly in healthy subjects, which may partly explain some of the differences of pharmacokinetics in CsA between African Americans and whites.     

Inter-subject and ethnic differences in paracetamol metabolism.

The 24 h urinary excretion of paracetamol and its metabolites following a single oral dose of 1.5 g was compared in 111 Caucasians (Scotland), 67 West Africans (Ghana) and 20 East Africans (Kenya). The fractional recovery of the mercapturic acid and cysteine conjugates of paracetamol was 9.3% in the Caucasians compared with only 5.2% and 4.4% in the Ghanaians and Kenyans respectively (P = less than 0.0005). This probably indicates markedly reduced metabolic activation of paracetamol in the Africans. There were no ethnic differences in the sulphate conjugation of paracetamol, but the mean fractional recovery of the glucuronide conjugate in Caucasians (54%) was significantly less than in the Africans (58%). The sulphate conjugation of paracetamol was increased and glucuronide conjugation reduced in Caucasian females compared with males. A similar trend was seen in the Ghanaians but there were no other significant sex differences. The range of intersubject variation in the metabolic activation of paracetamol was sixty fold compared with only a three fold variation in glucuronide and sulphate conjugation. This has important implications for susceptibility to paracetamol hepatotoxicity following overdosage especially in a small subgroup showing extensive metabolic activation. These ethnic differences in paracetamol metabolism may be related to genetic or environmental factors including differences in diet and protein intake.     

Docetaxel. A pharmacoeconomic review of its use in the treatment of metastatic breast cancer.

Advanced breast cancer has a poor prognosis (median duration of survival about 2 years); thus, treatment options are largely palliative. Recent studies with the taxoids docetaxel and paclitaxel suggest that these agents are effective second-line therapy in patients with metastatic breast cancer. Objective response rates range from 30 to 57% with docetaxel monotherapy in clinical trials in patients with advanced disease who had failed to respond to previous therapy, and the median time to disease progression ranges from 17 to 20 weeks. Currently available pharmacoeconomic data relating to docetaxel in the treatment of women with metastatic breast cancer include a cost-minimisation study and 3 cost-utility studies which relate to the UK, French and US healthcare systems. All analyses compared docetaxel with paclitaxel. Since no direct clinical comparisons of these 2 agents have been performed, model assumptions were based on available, rather than comparative, clinical data. The French model also considered vinorelbine monotherapy as a comparator. Considering direct costs only, costs associated with docetaxel ranged from < 0.3% less to 13% more than those of paclitaxel. When utilities were evaluated, docetaxel was associated with incremental gains versus paclitaxel of 33 and 75 additional days of quality-adjusted health in the UK and US studies, respectively, and 22 additional days of quality-adjusted progression-free survival (QPFS) in the French analysis. Thus, the incremental cost utility of docetaxel versus paclitaxel was an estimated Pounds 2431 per quality-adjusted life-year (QALY) in the UK analysis (1994 values) and US$8615 per QALY in the US analysis (1997 values). The French model found that docetaxel cost 700 French francs less for the extra days of QPFS (1993 costs). CONCLUSIONS: Cost-utility analyses, compiled in the absence of direct comparative data, show that docetaxel offers utility gains versus paclitaxel in the treatment of metastatic breast cancer. The incremental cost for these gains is within the accepted range for healthcare interventions.     

Racial and ethnic differences in predictors of smoking cessation

Racial/ethnic differences in the determinants of smoking cessation could have important treatment implications. The current study examined racial/ethnic differences in smoking cessation, prospective predictors of cessation, and whether the predictive ability of these factors differed by race/ethnicity. Participants were 709 employed adults recruited through the National Rural Electric Co-op Association or through natural gas pipeline corporations. Data were collected in 1990 and 1994. Although race/ethnicity was not predictive of abstinence, Hispanic, African American, and White smokers displayed differential on tobacco-, alcohol-, and work-related variables. These racial/ethnic differences highlight the specific factors that should be considered when providing smoking cessation treatment to specific populations. Limitations are noted.     

Lethal malformations and perinatal mortality: a 10 year review with comparison of ethnic differences.

During 1976 to 1985 perinatal mortality in Leicestershire decreased from 21 to 9.5 per 1000 births. Throughout this period the incidence of lethal malformations, excluding neural tube defects, remained relatively constant at around 1.8 per 1000 births. Analysis of the malformations present in 201 lethally malformed babies showed that 147 (73%) had a disorder carrying a recurrence risk of 1% or greater. Only 7% of these malformations might have been predicted from the family history or advanced maternal age. The incidence of lethal malformations was significantly increased in the Asian population, largely because of an excess of autosomal recessive disorders. The contribution of lethal malformations to perinatal mortality has almost doubled over the past 10 years and is likely to increase despite prenatal diagnosis and improvements in obstetric and paediatric services.     

Nab-paclitaxel in the treatment of metastatic breast cancer: a comprehensive review

The novel paclitaxel formulation (nanoparticle albumin-bound [nab] paclitaxel (Abraxane^®) has recently been approved by the US FDA for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months after adjuvant chemotherapy. Apart from its superior efficacy, as demonstrated in the pivotal Phase III study, less toxicity compared with the traditional solvent-containing paclitaxel (Taxol^®) seems to contribute to its favorable therapeutic index. While approved as a single agent, nab-paclitaxel may prove more effective in combination with either biologic agents and/or other cytotoxic chemotherapeutic agents, as summarized in this article.     

Nab-paclitaxel in the treatment of metastatic breast cancer: a comprehensive review

The novel paclitaxel formulation (nanoparticle albumin-bound [nab] paclitaxel (Abraxane(?)) has recently been approved by the US FDA for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months after adjuvant chemotherapy. Apart from its superior efficacy, as demonstrated in the pivotal Phase III study, less toxicity compared with the traditional solvent-containing paclitaxel (Taxol(?)) seems to contribute to its favorable therapeutic index. While approved as a single agent, nab-paclitaxel may prove more effective in combination with either biologic agents and/or other cytotoxic chemotherapeutic agents, as summarized in this article.     

Racial and ethnic differences in preference-based health status measure

ABSTRACT

Objective: To document the racial and ethnic differences in individuals' perception of their general health status assessed by preferencebased measures.

Methods: Using the 2003 Medical Expenditure Panel Survey (MEPS), a nationally representative sample of 20?428 people with reported concurrent EuroQol (EQ‐5D) US scores were included in the study. Given the upper-bound of preference-based scores at 1.0, a two-part model was derived to identify the relationship between race/ethnicity and the preference-based score after controlling for individual demographic covariates, comorbidity profile, and functional and activity limitations. In order to generalize the results to the whole US population, the complex survey sampling design of the MEPS was taken into account using the specified sample weight, variance estimation stratum, and primary sampling unit.

Results: In the fully adjusted model, Asians were more likely to report being in full health (score of 1.0) than Whites by 4.2 percentage points (?p < 0.05), whereas no differences were identified for Blacks and Hispanics compared to Whites. Beyond health and disease conditions, education and income explained the racial/ethnic difference for EQ‐5D score for Blacks and Hispanics relative to Whites, but this was not the case between Asians and Whites. No clinically important differences were identified between racial/ethnic groups for individuals not reporting full health.

Conclusions: This study adds to the literature of health-related quality of life (HRQoL) by providing additional empirical evidence at the US national level to demonstrate racial/ethnic differences assessed by preference-based measures. Healthcare researchers and clinicians need to be aware that Asians are more likely to perceive a higher preference-based score than Whites, given the same health and disease conditions. Subgroup analysis may be considered regarding the optimal decision making and conclusions based on cost-effectiveness analysis.