Shu-Chuen Li

Factors affecting therapeutic compliance: A review from the patient’s perspective

Objective To explore and evaluate the most common factors causing therapeutic non-compliance. Methods A qualitative review was undertaken by a literature search of the Medline database from 1970 to 2005 to identify studies evaluating the factors contributing to therapeutic non-compliance. Results A total of 102 articles was retrieved and used in the review from the 2095 articles identified by the literature review process. From the literature review, it would appear that the definition of therapeutic compliance is adequately resolved. The preliminary evaluation revealed a number of factors that contributed to therapeutic non-compliance. These factors could be categorized to patient-centered factors, therapy-related factors, social and economic factors, healthcare system factors, and disease factors. For some of these factors, the impact on compliance was not unequivocal, but for other factors, the impact was inconsistent and contradictory. Conclusion There are numerous studies on therapeutic noncompliance over the years. The factors related to compliance may be better categorized as “soft” and “hard” factors as the approach in countering their effects may differ. The review also highlights that the interaction of the various factors has not been studied systematically. Future studies need to address this interaction issue, as this may be crucial to reducing the level of non-compliance in general, and to enhancing the possibility of achieving the desired healthcare outcomes.

The impact of diabetes mellitus and other chronic medical conditions on health-related Quality of Life: Is the whole greater than the sum of its parts?

BackgroundDiabetes mellitus (DM) is an important public health concern, the impact of which is increased by the high prevalence of co-existing chronic medical conditions among subjects with DM. The aims of this study were therefore to (1) evaluate the impact of DM and co-existing chronic medical conditions on health-related quality of life (HRQoL) (which could be additive, synergistic or subtractive); (2) to determine the extent to which the SF-6D (a single-index preference measure) captures the multidimensional information provided by the SF-36 (a profile measure).MethodsUsing data from a cross-sectional, population-based survey of Chinese, Malay and Indians in Singapore, we developed 9 separate multiple linear regression models, with each SF-36 scale or SF-6D index score being the dependent variable for one model. The influence of DM and a second chronic medical condition (hypertension (HTN), heart disease (HD), musculoskeletal illnesses (MS)) and their interactions were studied after adjusting for the influence of potential confounding variables.ResultsAmong 5,224 subjects, the prevalence of DM, HTN, HD and MS were 5.9%, 10.7%, 2.4% and 26.6% respectively. DM lowered SF-36 scores by more than 2 points on 3 SF-36 scales and lowered SF-6D scores by 0.03 points. Subjects with DM and HTN, DM and HD or DM and MS experienced further lowering of SF-36 scores exceeding 2 points on at least 6 scales and further lowering of SF-6D scores by 0.05, 0.08 and 0.10 points respectively. Generally, DM and co-existing medical conditions exerted additive effects on HRQoL, with the exception of DM and heart disease, where a subtractive effect was noted. SF-6D index scores generally reflected the patterns of influence of DM and chronic medical conditions on SF-36 scores.ConclusionDM and chronic medical conditions generally reduced HRQoL in this multiethnic general population in an additive, rather than synergistic or subtractive fashion. In this study, the SF-6D was a reasonably good summary measure for the SF-36.

Therapeutic Drugs that Behave as Mechanism-Based Inhibitors of Cytochrome P450 3A4

Cytochrome P450 (CYP) 3A4 is not only the most abundant isoform in human liver but also metabolizes approximately 60% of the therapeutic drugs. This feature renders CYP3A4 highly susceptible to both reversible and irreversible (mechanism-based) inhibition. The latter is characterized by NADPH-, time- and concentration-dependent enzyme inactivation, occurring when some drugs are converted by CYPs to reactive metabolites. Mechanism-based inactivation of CYP3A4 by drugs can be due to the chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. The clinical pharmacokinetic effect of a CYP3A4 inactivator is a function of its KI, kinact and partition ratio and the synthesis rate of new or replacement enzyme. Predicting drug-drug interactions involving CYP3A4 inactivation is possible when proper pharmacokinetic principles are followed. However, the prediction may become difficult, since the clinical outcomes due to CYP3A4 inactivation depend on many factors associated with the enzyme, drugs and the patients. A number of clinically important drugs have been identified to be mechanism-based CYP3A4 inhibitors. These include antibiotics (e.g. erythromycin and isoniazid), anticancer drugs (e.g. tamoxifen), antidepressants (e.g. fluoxetine and midazolam), anti-HIV agents (e.g. ritonavir and delavirdine), antihypertensives (e.g. dihydralazine and verapamil), steroids and their receptor modulators (e.g. gestodene and raloxifene), and some herbal constituents (e.g. bergamottin and glabridin). Compared to reversible inhibition, mechanism-based inhibitors of CYP3A4 more frequently cause unfavorable drug-drug interactions, as the inactivated CYP3A4 has to be replaced by newly synthesized CYP3A4 protein. Most CYP3A4 inactivators are also PgP substrates/inhibitors, confounding the in vitro-in vivo extrapolation. Clinicians should have good knowledge on these CYP3A4 inactivators and avoid their combination use.

Metabolism and transport of oxazaphosphorines and the clinical implications.

The oxazaphosphorines including cyclophosphamide (CPA), ifosfamide (IFO), and trofosfamide represent an important group of therapeutic agents due to their substantial antitumor and immuno-modulating activity. CPA is widely used as an anticancer drug, an immunosuppressant, and for the mobilization of hematopoetic progenitor cells from the bone marrow into peripheral blood prior to bone marrow transplantation for aplastic anemia, leukemia, and other malignancies. New oxazaphosphorines derivatives have been developed in an attempt to improve selectivity and response with reduced toxicity. These derivatives include mafosfamide (NSC 345842), glufosfamide (D19575, β-D-glucosylisophosphoramide mustard), NSC 612567 (aldophosphamide perhydrothiazine), and NSC 613060 (aldophosphamide thiazolidine). This review highlights the metabolism and transport of these oxazaphosphorines (mainly CPA and IFO, as these two oxazaphosphorine drugs are the most widely used alkylating agents) and the clinical implications. Both CPA and IFO are prodrugs that require activation by hepatic cytochrome P450 (CYP)-catalyzed 4-hydroxylation, yielding cytotoxic nitrogen mustards capable of reacting with DNA molecules to form crosslinks and lead to cell apoptosis and/or necrosis. Such prodrug activation can be enhanced within tumor cells by the CYP-based gene directed-enzyme prodrug therapy (GDEPT) approach. However, those newly synthesized oxazaphosphorine derivatives such as glufosfamide, NSC 612567 and NSC 613060, do not need hepatic activation. They are activated through other enzymatic and/or non-enzymatic pathways. For example, both NSC 612567 and NSC 613060 can be activated by plain phosphodiesterase (PDEs) in plasma and other tissues or by the high-affinity nuclear 3′-5′ exonucleases associated with DNA polymerases, such as DNA polymerases and ε. The alternative CYP-catalyzed inactivation pathway by N-dechloroethylation generates the neurotoxic and nephrotoxic byproduct chloroacetaldehyde (CAA). Various aldehyde dehydrogenases (ALDHs) and glutathione S-transferases (GSTs) are involved in the detoxification of oxazaphosphorine metabolites. The metabolism of oxazaphosphorines is auto-inducible, with the activation of the orphan nuclear receptor pregnane X receptor (PXR) being the major mechanism. Oxazaphosphorine metabolism is affected by a number of factors associated with the drugs (e.g., dosage, route of administration, chirality, and drug combination) and patients (e.g., age, gender, renal and hepatic function). Several drug transporters, such as breast cancer resistance protein (BCRP), multidrug resistance associated proteins (MRP1, MRP2, and MRP4) are involved in the active uptake and efflux of parental oxazaphosphorines, their cytotoxic mustards and conjugates in hepatocytes and tumor cells. Oxazaphosphorine metabolism and transport have a major impact on pharmacokinetic variability, pharmacokinetic-pharmacodynamic relationship, toxicity, resistance, and drug interactions since the drug-metabolizing enzymes and drug transporters involved are key determinants of the pharmacokinetics and pharmacodynamics of oxazaphosphorines. A better understanding of the factors that affect the metabolism and transport of oxazaphosphorines is important for their optional use in cancer chemotherapy.

Validity and reliability of the EQ-5D self-report questionnaire in Chinese-speaking patients with rheumatic diseases in Singapore

Validity and reliability of a Singaporean English EQ-5D self-report questionnaire (EQ-5D) were evaluated among consecutive outpatients with rheumatic diseases attending a tertiary referral hospital in Singapore (a multi-ethnic, urban Asian country). Subjects were interviewed twice within a 2-week period using a standardized questionnaire containing the EQ-5D, Short Form 36 Health Survey (SF-36) and assessing demographic and psychosocial characteristics. To assess validity of the EQ-5D, 13 hypotheses relating responses to EQ-5D dimension/Visual Analogue Scale (EQ-VAS) to SF-36 scores or other variables were examined using the Mann–Whitney test, Kruskal–Wallis test, or Spearmans correlation coefficient. Test–retest reliability was assessed using Cohens κ. Sixty-six subjects were studied (osteoarthritis: 9, rheumatoid arthritis: 26, systemic lupus erythematosus: 23, spondyloarthropathy: 8; female: 72.7%; mean age: 44.3 years). Ten of 13 a-priori hypotheses relating EQ-5D responses to external variables were fulfilled, supporting the validity of the EQ-5D. Cohens κ for test–retest reliability (n = 52) ranged from 0.29 to 0.61. The Singaporean English EQ-5D appears to be valid in measuring quality of life in Singaporeans with rheumatic diseases; however, its reliability requires further investigation. These data provide a basis for further studies assessing the validity of the EQ-5D in Singapore.

Does the 12-item General Health Questionnaire contain multiple factors and do we need them?

BackgroundThe 12-item General Health Questionnaire (GHQ-12) is widely used as a unidimensional instrument, but factor analyses tended to suggest that it contains two or three factors. Not much is known about the usefulness of the GHQ-12 factors, if they exist, in revealing between-patient differences in clinical states and health-related quality of life.MethodsWe addressed this issue in a cross-sectional survey of out-patients with psychological disorders in Singapore. The participants (n = 120) completed the GHQ-12, the Beck Anxiety Inventory, and the Short-Form 36 Health Survey. Confirmatory factor analysis was used to compare six previously proposed factor structures for the GHQ-12. Factor scores of the best-fitting model, as well as the overall GHQ-12 score, were assessed in relation to clinical and health-related quality of life variables.ResultsThe 3-factor model proposed by Graetz fitted the data better than a unidimensional model, two 2-factor models, and two other 3-factor models. However, the three factors were strongly correlated. Their values varied in a similar fashion in relation to clinical and health-related quality of life variables.ConclusionsThe 12-item General Health Questionnaire contains three factors, namely Anxiety and Depression, Social Dysfunction, and Loss of Confidence. Nevertheless, using them separately does not offer many practical advantages in differentiating clinical groups or identifying association with clinical or health-related quality of life variables.

Health‐related quality of life in chronic hepatitis B patients

The relationship between stages of chronic hepatitis B liver disease and health‐related quality of life (HRQoL) is an important aspect of the overall management of hepatitis B virus (HBV) infection, yet is not well characterized. Consequently we sought to examine HRQoL in HBV patients, stratified by disease severity, compared with normal controls and hypertensive patients, using the Short Form 36 Health Survey (SF‐36) and the EQ‐5D self‐report questionnaire. Univariate and multivariate analyses were then performed. A total of 432 HBV (156 asymptomatic carriers, 142 chronic hepatitis B, 66 compensated cirrhosis, 24 decompensated cirrhosis, 22 hepatocellular carcinoma, and 22 post–liver transplant) patients, 93 hypertensive patients, and 108 normal controls participated in the study. Multivariate analysis showed that normal controls and asymptomatic carriers had similar SF‐36 scores, which were better than those for hypertensive patients, but with development of chronic hepatitis B and compensated cirrhosis, showed a significant decrease in general health and the mental dimension, whereas those with advanced liver disease (decompensated cirrhosis and hepatocellular carcinoma) had significantly lower scores in all components (P < 0.05), indicating that the physical component deteriorates only with advanced liver disease. Similar results were obtained with EQ5D. Post–liver transplant patients had similar HRQoL to patients with decompensated cirrhosis and hepatocellular carcinoma, although there was a trend toward improvement. Conclusion: Our results showed that HRQoL in asymptomatic carriers is comparable to those of normal controls and better than hypertensive patients, but deteriorates with disease progression, initially in general health and mental dimensions, but with advanced disease all dimensions are affected. (HEPATOLOGY 2008.)

Usefulness of the Audit of Diabetes-Dependent Quality-of-Life (ADDQoL) Questionnaire in Patients with Diabetes in a Multi-Ethnic Asian Country

AbstractIntroduction: Asia will be at the forefront of the current epidemic of diabetes mellitus. Quality of life (QOL) is an important outcome measure in the assessment of diabetes care. However, few QOL instruments are culturally suitable for use in Asian countries. The Audit of Diabetes-Dependent Quality-of-Life (ADDQoL) questionnaire is a third-generation individualised QOL instrument. Individualised instruments such as the ADDQoL have the potential to be useful and less costly alternatives to computerised adaptive testing (CAT), which may not be practical in developing countries. Objective: To evaluate and validate the ADDQoL questionnaire in Englishspeaking patients with diabetes in Singapore, a multi-ethnic Asian country. Methods: The ADDQoL and EQ-5D were administered to English-speaking respondents with type 1 or 2 diabetes (aged ≥18 years) recruited from a tertiary acute-care referral hospital by convenience sampling. The usefulness of the key design features of the ADDQoL were assessed by measuring the number of zeroimportance responses, the change in item ranking with and without weighting for importance, and the frequency of utilisation of the ‘not applicable’ (NA) options. The acceptability, factor structure and internal consistency (Cronbach’s α) of the ADDQoL were also assessed. Data were subjected to unforced factor analysis with oblimin rotation and then the condition was set to force a one-factor solution.The validity of the ADDQoL was tested with the following hypotheses: those with moderate or severe problems on the EQ-5D would have worse ADDQoL average weighted impact (AWI) scores than those with a perfect health rating on the EQ-5D; those with better Present QOL scores on the ADDQoL would have better EQ-5D utility and visual analogue scale (VAS) scores; on the ADDQoL, AWI scores would correlate better with diabetes-dependent QOL than with Present QOL scores; and female respondents, those who required insulin or had longer duration of known diabetes would have worse ADDQoL AWI scores (known-group validity). Results: We analysed data from 152 respondents (49% Chinese, 34% Indian; 45% female; mean age 52 years, range 18–80; mean duration of known diabetes 10 years, range 0–62). There were few missing data. Weighted scoring and NA options were shown to be necessary, thus supporting the usefulness of individualised health-related QOL measures. Factor structure of the ADDQoL was supported and internal consistency was high (α = 0.94). All hypotheses were fulfilled except for one that was partially fulfilled; respondents with longer duration of known diabetes did not report worse ADDQoL AWI scores. Conclusions: The ADDQoL is culturally appropriate, valid, reliable and well accepted among Singaporean patients with diabetes. Individualised measures such as the ADDQoL allow one to obtain precise score estimates and may offer developing countries a useful alternative to CAT.

Progression of Parkinson's disease as evaluated by Hoehn and Yahr stage transition times

This study was carried out to evaluate progression in Parkinsons disease (PD) by analyzing time taken to transit from one Hoehn and Yahr (H&Y) stage to the next stage and to investigate the variables that would be associated with H&Y transition times using a large PD database that contained prospectively collected information. Data were obtained from the movement disorder database of the National Neuroscience Institute in Singapore. Kaplan‐Meier (KM) survival analysis was adopted to investigate the time taken to progress through various H&Y stages. Cox regression analysis was used to examine the association between the baseline variables at the entry point of each H&Y stage and the progression to the next stage. A total of 695 patients (mean age: 65.2, male: 57.3%) were studied. Using KM analysis, the median time taken to transit from H&Y stage 1 to 2, 2 to 2.5, 2.5 to 3 were 20, 62, and 25 months, respectively; whereas the median time taken to progress from stage 3 to 4 and 4 to 5 were 24 and 26 months, respectively. Cox regression analysis revealed that older age‐at‐diagnosis, longer PD duration, and higher Unified Parkinsons Disease Rating Scale (UPDRS) motor scores at baseline were associated with a significantly faster progression through various H&Y stages. Gender and ethnicity were not associated with disease progression. In conclusion, H&Y transition time is a useful measure of disease progression in PD and may be utilized in clinical studies evaluating therapeutic interventions and prognostic factors in PD.

The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-c30): validation of English version in Singapore.

Objective: This study aimed to validate the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30, English version 3.0) in Singaporean cancer patients. Methods: In a cross-sectional study, a heterogeneous sample of cancer patients (n = 57) self-administered a questionnaire containing the QLQ-C30, the Short Form 36 Health Survey (SF-36) and assessing health and sociodemographic status. Construct validity was assessed by testing a priori hypotheses that QLQ-C30 scales would be moderately or strongly correlated with SF-36 scales measuring similar dimensions of health-related quality of life (HRQoL) and that subjects reporting mild symptoms would have better HRQoL scores than those reporting severe symptoms. Internal consistency reliability was assessed using Cronbach’s α. Results: Strength of Spearman’s correlations between the QLQ-C30 and SF-36 scales assessing similar dimensions of HRQoL ranged from 0.35 to 0.67. Subjects with mild symptoms had better scores than those with severe symptoms for all six QLQ-C30 HRQoL scales (p < 0.05 for five scales, Mann–Whitney U tests). Cronbach’s α ranged from 0.19 for the cognitive functioning scale to 0.91 for the global QoL scale. Conclusion: This study provides preliminary evidence for the validity and reliability of the EORTC QLQ-C30 in English-speaking Singaporean cancer patients.