Objective: To investigate the use of and expenditure on 17 of the most popular forms of complementary and alternative medicine (CAM) by adult Australians, sociodemographic characteristics of CAM users, and communication between CAM users and their doctors. Methods: In May–June 2005, a sample of 1067 adults, 18 years and older, from all Australian states and territories, was recruited by random-digit telephone dialing and interviewed about their CAM use in the previous 12 months. Results: In the 12-month period, 68.9% (95% CI: 66.1%–71.7%) of those interviewed used at least one of the 17 forms of CAM and 44.1% (95% confidence interval: 41.1%–47.1%) visited a CAM practitioner. The estimated number of visits to CAM practitioners by adult Australians in the 12-month period (69.2 million) was almost identical to the estimated number of visits to medical practitioners (69.3 million). The annual “out of pocket” expenditure on CAM, nationally, was estimated as 4.13 billion Australian dollars (US $3.12 billion). Less than half of the users always informed their medical practitioners about their use of CAM. The most common characteristics of CAM users were: age, 18–34; female; employed; well-educated; private health insurance coverage; and higher-than-average incomes. Conclusions: CAM use nationally in Australia appears to be considerably higher than estimated from previous Australian studies. This may reflect an increasing popularity of CAM; however, regional variations in CAM use and the broader range of CAM included in the current study may contribute to the difference. Most frequently, doctors would not appear to be aware of their patient use of CAM.

Pain is a distressing symptom experienced by more than 70% of patients with cancer but inadequately controlled in nearly 50% of these patients.^1,2 Although the World Health Organization analgesic ladder provides effectual approaches to relieve cancer pain,³ addiction to analgesics and the adverse effects of pharmacological interventions pose critical challenges to pain management.^4,5 Because pain is multidimensional, a multidisciplinary, comprehensive approach is needed to control pain successfully.^6,7

Cytochrome P450 (CYP) 3A4 is the most abundant enzyme of CYPs in the liver and gut that metabolizes approximately 50% currently available drugs. A number of important drugs have been identified as substrates, inducers, and/or inhibitors of CYP3A4. The substrates of CYP3A4 considerably overlap with those of P-glycoprotein. Both CYP3A4 and P-glycoprotein are subject to inhibition and induction by a number of factors. Mechanism-based inhibition of CYP3A4 is characterized by NADPH-, time-, and concentration-dependent enzyme inactivation occurring when some xenobiotics or drugs are converted by CYPs to reactive metabolites. Such an inhibition of CYP3A4 is caused by chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. To date, the identified clinically important mechanism-based CYP3A4 inhibitors mainly include macrolide antibiotics (eg, clarithromycin and erythromycin), anti-HIV agents (eg, ritonavir and delavirdine), antidepressants (eg, fluoxetine and fluvoxamine), calcium channel blockers (eg, verapamil and diltiazem), steroids and their modulators (eg, gestodene and mifepristone), and several herbal and dietary components. The inactivation of CYP3A4 by drugs often causes unfavorable and long-lasting drug-drug interactions and probably fatal toxicity, depending on many factors associated with the enzyme, drugs, and the patients. Clinicians are encouraged to have a sound knowledge of drug-induced, mechanism-based CYP3A4 inhibition; take proper cautions, and perform close monitoring for possible drug interactions when using drugs that are mechanism-based CYP3A4 inhibitors. To minimize drug-drug interactions involving mechanism-based CYP3A4 inhibition, it is necessary to choose safe drug combination regimens, adjust drug dosages appropriately, and conduct therapeutic drug monitoring for drugs with narrow therapeutic indices.

Human contains 49 ATP-binding cassette (ABC) transporter genes and the multidrug resistance associated proteins (MRP1/ABCC1, MRP2/ABCC2, MRP3/ABCC3, MRP4/ABCC4, MRP5/ABCC5, MRP6/ABCC6, MRP7/ABCC10, MRP8/ABCC11 and MRP9/ABCC12) belong to the ABCC family which contains 13 members. ABCC7 is cystic fibrosis transmembrane conductance regulator; ABCC8 and ABCC9 are the sulfonylurea receptors which constitute the ATPsensing subunits of a complex potassium channel. MRP10/ABCC13 is clearly a pseudo-gene which encodes a truncated protein that is highly expressed in fetal human liver with the highest similarity to MRP2/ABCC2 but without transporting activity. These transporters are localized to the apical and/or basolateral membrane of the hepatocytes, enterocytes, renal proximal tubule cells and endothelial cells of the blood-brain barrier. MRP/ABCC members transport a structurally diverse array of important endogenous substances and xenobiotics and their metabolites (in particular conjugates) with different substrate specificity and transport kinetics. The human MRP/ABCC transporters except MRP9/ABCC12 are all able to transport organic anions, such as drugs conjugated to glutathione, sulphate or glucuronate. In addition, selected MRP/ABCC members may transport a variety of endogenous compounds, such as leukotriene C4 (LTC4 by MRP1/ABCC1), bilirubin glucuronides (MRP2/ABCC2, and MRP3/ABCC3), prostaglandins E1 and E2 (MRP4/ABCC4), cGMP (MRP4/ABCC4, MRP5/ABCC5, and MRP8/ABCC11), and several glucuronosyl-, or sulfatidyl steroids. In vitro, the MRP/ABCC transporters can collectively confer resistance to natural product anticancer drugs and their conjugated metabolites, platinum compounds, folate antimetabolites, nucleoside and nucleotide analogs, arsenical and antimonial oxyanions, peptide-based agents, and in concert with alterations in phase II conjugating or biosynthetic enzymes, classical alkylating agents, alkylating agents. Several MRP/ABCC members (MRPs 1-3) are associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. Drug targeting of these transporters to overcome MRP/ABCC-mediated multidrug resistance may play a role in cancer chemotherapy. Most MRP/ABCC transporters are subject to inhibition by a variety of compounds. Based on currently available preclinical and limited clinical data, it can be expected that modulation of MRP members may represent a useful approach in the management of anticancer and antimicrobial drug resistance and possibly of inflammatory diseases and other diseases. A better understanding of their substrates and inhibitors has important implications in development of drugs for treatment of cancer and inflammation.

The current ‘fixed-dosage strategy’ approach to medicine, means there is much inter-individual variation in drug response. Pharmacogenetics is the study of how inter-individual variations in the DNA sequence of specific genes affect drug responses. This article will highlight current pharmacogenetic knowledge on important drug metabolizing enzymes, drug transporters and drug targets to understand interindividual variability in drug clearance and responses in clinical practice and potential use in personalized medicine. Polymorphisms in the cytochrome P450 (CYP) family may have had the most impact on the fate of pharmaceutical drugs. CYP2D6, CYP2C19 and CYP2C9 gene polymorphisms and gene duplications account for the most frequent variations in phase I metabolism of drugs since nearly 80% of drugs in use today are metabolised by these enzymes. Approximately 5% of Europeans and 1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers. CYP2C9 is another clinically significant drug metabolising enzyme that demonstrates genetic variants. Studies into CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and CYP2C9*3 alleles. Extensive polymorphism also occurs in a majority of Phase II drug metabolizing enzymes. One of the most important polymorphisms is thiopurine S-methyl transferases (TPMT) that catalyzes the S-methylation of thiopurine drugs. With respect to drug transport polymorphism, the most extensively studied drug transporter is P-glycoprotein (P-gp/MDR1), but the current data on the clinical impact is limited. Polymorphisms in drug transporters may change drugs distribution, excretion and response. Recent advances in molecular research have revealed many of the genes that encode drug targets demonstrate genetic polymorphism. These variations, in many cases, have altered the targets sensitivity to the specific drug molecule and thus have a profound effect on drug efficacy and toxicity. For example, the β2-adrenoreceptor, which is encoded by the ADRB2 gene, illustrates a clinically significant genetic variation in drug targets. The variable number tandem repeat polymorphisms in serotonin transporter (SERT/SLC6A4) gene are associated with response to antidepressants. The distribution of the common variant alleles of genes that encode drug metabolizing enzymes, drug transporters and drug targets has been found to vary among different populations. The promise of pharmacogenetics lies in its potential to identify the right drug at the right dose for the right individual. Drugs with a narrow therapeutic index are thought to benefit more from pharmacogenetic studies. For example, warfarin serves as a good practical example of how pharmacogenetics can be utilized prior to commencement of therapy in order to achieve maximum efficacy and minimum toxicity. As such, pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and licensed drugs.