Discovery of (4-Pyrazolyl)-2-aminopyrimidines as Potent and Selective Inhibitors of Cyclin-Dependent Kinase 2.

CDK2 is a critical regulator of the cell cycle. For a variety of human cancers, the dysregulation of CDK2/cyclin E1 can lead to tumor growth and proliferation. Historically, early efforts to develop CDK2 inhibitors with clinical applications proved unsuccessful due to challenges in achieving selectivity over off-target CDK isoforms with associated toxicity. In this report, we describe the discovery of (4-pyrazolyl)-2-aminopyrimidines as a potent class of CDK2 inhibitors that display selectivity over CDKs 1, 4, 6, 7, and 9. SAR studies led to the identification of compound 17, a kinase selective and highly potent CDK2 inhibitor (IC50 = 0.29 nM). The evaluation of 17 in CCNE1-amplified mouse models shows the pharmacodynamic inhibition of CDK2, measured by reduced Rb phosphorylation, and antitumor activity.

Discovery of 5,7-Dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-ones as Highly Selective CDK2 Inhibitors.

A series of exceptionally selective CDK2 inhibitors are described. Starting from an HTS hit, we successfully scaffold hopped to a 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one core structure, which imparted a promising initial selectivity within the CDK family. Extensive further SAR identified additional factors that drove selectivity to above 200× for CDKs 1/4/6/7/9. General kinome selectivity was also greatly improved. Finally, use of in vivo metabolite identification allowed us to pinpoint sulfonamide dealkylation as the primary metabolite, which was ameliorated through the deuterium effect.

Identification of pAKT as a pharmacodynamic marker for MER kinase in human melanoma G361 cells.

BACKGROUND: The MER signaling pathway represents an attractive therapeutic target for human cancers. Growth arrest-specific protein 6 (GAS6)-induced MER phosphorylation is often unstable and difficult to detect without pervanadate pretreatment in human cancer cells, posing a challenge for the development of selective MER kinase inhibitors. Here, we identified phosphorylated AKT (pAKT) as a specific pharmacodynamic marker for MER kinase inhibitors in human melanoma G361 cells. METHODS: The expression of MER, TYRO3, and AXL were profiled among multiple human cancer cells. To determine whether they play a role in the activation of pAKT, MER and TYRO3 were selectively depleted by small, interfering RNA knockdown. In addition, using AKT phosphorylation as a readout, a high-throughput cell-based assay was established in G361 cells for evaluation of the potency of potential inhibitors of MER pathway activation. RESULTS: We demonstrated that high levels of MER and TYRO3, but not AXL, were expressed in G361 cells. In these cells, pAKT was induced by GAS6 treatment, which could be reversed by AXL/MER inhibitors. We showed that GAS6-induced pAKT is only dependent on MER kinase, but not TYRO3, in G361 cells. Furthermore, we observed a correlation in potency between inhibition of pAKT in G361 cells and pMER in MER-overexpressing Ba/F3 cells by these inhibitors. CONCLUSIONS: In summary, we have demonstrated that GAS6-induced pAKT is a possible pharmacodynamic marker for the inhibition of MER kinase, and we have successfully developed a cell-based functional assay for screening small-molecule inhibitors of MER kinase for potential therapeutic utility in treating GAS6/MER-deregulated human cancers.

A Potent and Selective Dual Inhibitor of AXL and MERTK Possesses Both Immunomodulatory and Tumor-Targeted Activity.

TYRO3, AXL, and MERTK constitute the TAM family of receptor tyrosine kinases, which play important roles in tumor growth, survival, cell adhesion, as well as innate immunity, phagocytosis, and immune-suppressive activity. Therefore, targeting both AXL and MERTK kinases may directly impact tumor growth and relieve immunosuppression. We describe here the discovery of INCB081776, a potent and selective dual inhibitor of AXL and MERTK that is currently in phase 1 clinical trials. In cellular assays, INCB081776 effectively blocked autophosphorylation of AXL or MERTK with low nanomolar half maximal inhibitory concentration values in tumor cells and Ba/F3 cells transfected with constitutively active AXL or MERTK. INCB081776 inhibited activation of MERTK in primary human macrophages and partially reversed M2 macrophage-mediated suppression of T-cell proliferation, which was associated with increased interferon-γ production. In vivo, the antitumor activity of INCB081776 was enhanced in combination with checkpoint blockade in syngeneic models, and resulted in increased proliferation of intratumoral CD4+ and CD8+ T cells. Finally, antitumor activity of INCB081776 was observed in a subset of sarcoma patient-derived xenograft models, which was linked with inhibition of phospho-AKT. These data support the potential therapeutic utility of INCB081776 as an immunotherapeutic agent capable of both enhancing tumor immune surveillance and blocking tumor cell survival mechanisms.

Knowledge, practices and expectations of preventive care: a qualitative study of patients attending government general outpatient clinics in Hong Kong.

BACKGROUND: Evidence-based preventive care recommendations have been well established, but studies have persistently reported gaps between these recommendations and general practitioners' practices in providing preventive care. Many studies have explored factors that affect the delivery of preventive care from the perspectives of the practitioners, but relatively few have evaluated the patients' point of view. The purpose of this study was to explore patients' understanding of preventive care, the actions they were taking in terms of preventive health and their expectations from family doctors in providing preventive care. METHODS: A qualitative study was conducted based on one-on-one in-depth interviews. Twenty-eight patients without chronic illnesses were purposively recruited from government general outpatient clinics in Hong Kong. The interviews took place between November 2013 and February 2014. RESULTS: The participants' knowledge of preventive care was limited, and their preventive practices were mostly restricted to healthy lifestyle practices. They rarely obtained individualised preventive care advice from doctors. Screening investigations were initiated after symptoms had already occurred, and the decision of what to check was arbitrary. Few of the participants knew what they wanted from their doctors in terms of preventive care. CONCLUSIONS: These findings show significant gaps between evidence-based preventive recommendations and patients' current knowledge and practice, and show the need for a wider spectrum of preventive care education and reliable sources to provide individualised and affordable preventive assessment and screening services. Most importantly, primary care providers must take a more proactive role to provide preventive services.

Cost-Effectiveness of a Short Message Service Intervention to Prevent Type 2 Diabetes from Impaired Glucose Tolerance.

Aims. To investigate the costs and cost-effectiveness of a short message service (SMS) intervention to prevent the onset of type 2 diabetes mellitus (T2DM) in subjects with impaired glucose tolerance (IGT). Methods. A Markov model was developed to simulate the cost and effectiveness outcomes of the SMS intervention and usual clinical practice from the health provider's perspective. The direct programme costs and the two-year SMS intervention costs were evaluated in subjects with IGT. All costs were expressed in 2011 US dollars. The incremental cost-effectiveness ratio was calculated as cost per T2DM onset prevented, cost per life year gained, and cost per quality adjusted life year (QALY) gained. Results. Within the two-year trial period, the net intervention cost of the SMS group was $42.03 per subject. The SMS intervention managed to reduce 5.05% onset of diabetes, resulting in saving $118.39 per subject over two years. In the lifetime model, the SMS intervention dominated the control by gaining an additional 0.071 QALY and saving $1020.35 per person. The SMS intervention remained dominant in all sensitivity analyses. Conclusions. The SMS intervention for IGT subjects had the superiority of lower monetary cost and a considerable improvement in preventing or delaying the T2DM onset. This trial is registered with ClinicalTrials.gov NCT01556880.

The pharmacokinetics, pharmacodynamics, and safety of baricitinib, an oral JAK 1/2 inhibitor, in healthy volunteers.

Baricitinib (also known as LY3009104 or INCB028050), a novel and potent small molecule inhibitor of Janus kinase family of enzymes (JAKs) with selectivity for JAK1 and JAK2, is currently in clinical development for the treatment of rheumatoid arthritis (RA) and other inflammatory disorders. Two double-blind, randomized, and placebo-controlled studies were conducted to evaluate single ascending doses of 1-20 mg and multiple ascending doses of 2-20 mg QD and 5 mg BID for 10 or 28 days in healthy volunteers. Following oral administration, baricitinib plasma concentration typically attains its peak value within 1.5 hours postdose and subsequently declines in a bi-exponential fashion. Baricitinib demonstrates dose-linear and time-invariant pharmacokinetics, with low oral-dose clearance (17 L/h) and minimal systemic accumulation observed following repeat dosing. The mean renal clearance of baricitinib was determined to be ∼2 L/h. The effect of a high-fat meal on baricitinib pharmacokinetics was insignificant. The pharmacodynamics of baricitinib, evaluated by the inhibition of STAT3 phosphorylation following cytokine stimulation in the whole blood ex vivo, was well correlated with baricitinib plasma concentrations. Baricitinib was generally safe and well tolerated, with no serious treatment-related adverse events (AEs) reported from either of the studies. An expected rapidly reversible, dose-related decline in absolute neutrophil count was seen with baricitinib.

Detection and management of depression in adult primary care patients in Hong Kong: a cross-sectional survey conducted by a primary care practice-based research network.

BACKGROUND: This study aimed to examine the prevalence, risk factors, detection rates and management of primary care depression in Hong Kong. METHODS: A cross-sectional survey containing the PHQ-9 instrument was conducted on waiting room patients of 59 primary care doctors. Doctors blinded to the PHQ-9 scores reported whether they thought their patients had depression and their management. RESULTS: 10,179 patients completed the survey (response rate 81%). The prevalence of PHQ-9 positive screening was 10.7% (95% CI: 9.7%-11.7%). Using multivariate analysis, risk factors for being PHQ-9 positive included: being female; aged ≤34 years; being unmarried; unemployed, a student or a homemaker; having a monthly household income < HKD$30,000 (USD$3,800); being a current smoker; having no regular exercise; consulted a doctor or Chinese medical practitioner within the last month; having ≥ two co-morbidities; having a family history of mental illness; and having a past history of depression or other mental illness. Overall, 23.1% of patients who screened PHQ-9 positive received a diagnosis of depression by the doctor. Predictors for receiving a diagnosis of depression included: having higher PHQ-9 scores; a past history of depression or other mental health problem; being female; aged ≥35 years; being retired or a homemaker; being non-Chinese; having no regular exercise; consulted a doctor within the last month; having a family history of mental health problems; and consulted a doctor in private practice.In patients diagnosed with depression, 43% were prescribed antidepressants, 11% were prescribed benzodiazepines, 42% were provided with counseling and 9% were referred, most commonly to a counselor. CONCLUSION: About one in ten primary care patients screen positive for depression, of which doctors diagnose depression in approximately one in four. At greatest risk for depression are patients with a past history of depression, who are unemployed, or who have multiple illnesses. Patients most likely to receive a diagnosis of depression by a doctor are those with a past history of depression or who have severe symptoms of depression. Chinese patients are half as likely to be diagnosed with depression as non-Chinese patients. Over half of all patients diagnosed with depression are treated with medications.

Having a Family Doctor is Associated with Some Better Patient-Reported Outcomes of Primary Care Consultations.

BACKGROUND: Hong Kong (HK) has pluralistic primary care that is provided by a variety of doctors. The aim of our study was to assess patient-reported outcomes of primary care consultations in HK and whether having a family doctor (FD) made any difference. METHODS: We interviewed by telephone 3148 subjects from 5174 contacted households (response rate 60.8%) randomly selected from the general population of HK about the experience of their last primary care consultations in September 2007 and April 2008. We compared the patient-reported outcomes (PRO) and patient-centered process of care in those with a FD, those with other types of regular primary care doctors (ORD) and those without any regular primary care doctor (NRD). PRO included patient enablement, global improvement in health, overall satisfaction, and likelihood of recommending their doctors to family and friends. Patient-centered process of care indicators was explanations about the illness, and address of patient's concerns. RESULTS: One thousand one hundred fifty, 746, and 1157 reported to have FD, ORD, and NRD, respectively. Over 80% of those with FD consulted their usual primary care doctors in the last consultation compared with 27% of those with NRD. Compared with subjects having ORD or NRD, subjects with FD reported being more enabled after the consultation and were more likely to recommend their doctors to family and friends. Subjects with FD and ORD were more likely than those having NRD to report a global improvement in health and satisfaction. FD group was more likely than the other two groups to report receiving an explanation on the diagnosis, nature, and expected course of the illness, and having their concerns addressed. Patient enablement was associated with explanation of diagnosis, nature, and expected course of illness, and address of patient's concerns. CONCLUSION: People with a regular FD were more likely to feel being enabled and to experience patient-centered care in consultations.

Pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in renal and hepatic impairment patients.

Hepatic and renal impairment studies were conducted with ruxolitinib, a JAK1&2 inhibitor that is cleared predominantly by metabolism. Both studies were open label, single-dose studies. Ruxolitinib area under the curve (AUC) was increased by 87%, 28%, and 65%, respectively, in subjects with mild, moderate, and severe hepatic impairment compared to healthy subjects with no correlation between exposure of ruxolitinib and the degree of hepatic impairment. The pharmacodynamics (PD) data were consistent with ruxolitinib pharmacokinetics (PK). The renal impairment study showed a surprising finding. While there was no change in ruxolitinib PK with varying degrees of renal impairment, the PD showed increasing pharmacological activity with increased severity of renal impairment. Analysis of the metabolite exposures revealed that active metabolites contributed to the observed incremental increase in PD activity. The recovery of ruxolitinib in dialysate was negligible. The starting dose of ruxolitinib in subjects with any hepatic impairment or moderate or severe renal impairment should be decreased to 10 mg twice daily (BID) if their platelet counts are between 100 × 10(9) /L and 150 × 10(9) /L. Subjects on dialysis should initiate dosing with a single dose of 15 or 20 mg, based on platelet counts, with dosing only on the days of dialysis.

The associations of body mass index with physical and mental aspects of health-related quality of life in Chinese patients with type 2 diabetes mellitus: results from a cross-sectional survey.

BACKGROUND: This study aimed to determine the associations of various clinical factors with generic health-related quality of life (HRQOL) scores among Hong Kong Chinese patients with type 2 diabetes mellitus (T2DM) in the outpatient primary care setting using the short-form 12 (SF-12). METHODS: A cross-sectional survey of 488 Chinese adults with T2DM recruited from a primary care outpatient clinic was conducted from May to August 2008. Data on the standard Chinese (HK) SF-12 Health Survey and patients' socio-demographics were collected from face-to-face interviews. Glycaemic control, body mass index (BMI), chronic co-morbidities, diabetic complications and treatment modalities were determined for each patient through medical records. Associations of socio-demographic and clinical factors with physical component summary (PCS-12) and mental component summary scores (MCS-12) were evaluated using multiple linear regression. RESULTS: The socio-demographic correlates of PCS-12 and MCS-12 were age, gender and BMI. After adjustment for socio-demographic variables, the BMI was negatively associated with PCS-12 but positively associated with MCS-12. The presence of diabetic complications was associated with lower PCS-12 (regression coefficient:-3.0 points, p < 0.05) while being on insulin treatment was associated with lower MCS-12 (regression coefficient:-5.8 points, p < 0.05). In contrast, glycaemic control, duration of T2DM and treatment with oral hypoglycaemic drugs were not significantly associated with PCS-12 or MCS-12. CONCLUSIONS: Among T2DM subjects in the primary care setting, impairments in the physical aspect of HRQOL were evident in subjects who were obese or had diabetic complications whereas defects in the mental aspect of HRQOL were observed in patients with lower BMI or receiving insulin injections.

A short message service (SMS) intervention to prevent diabetes in Chinese professional drivers with pre-diabetes: a pilot single-blinded randomized controlled trial.

AIM: To determine the efficacy of delivering short-message service (SMS) to provide diabetes-related information in reducing the risk of developing diabetes in Chinese professional drivers with pre-diabetes. METHODS: A pilot single-blinded randomized controlled trial was conducted in Hong Kong between 05/2009 and 04/2012. Professional drivers with impaired glucose tolerance (IGT) were randomly allocated to either a SMS group receiving messages comprising knowledge and lifestyle modification on diabetes or to a control group with usual care. Primary outcomes were the incidence rate of diabetes mellitus over 12 and 24 months period. RESULTS: Fifty-four, out of 104 professional drivers recruited, were randomly allocated to intervention group. Fewer subjects developed diabetes at 12 months in intervention group (5.56%) compared to control group (16.00%). Relative risk (RR) of diabetes onset was 0.35 (95%CI: 0.10­1.24) and the number needed to treat (NNT) for preventing one diabetes was 9.57. At 24 months, RR increased to 0.62 (95%CI: 0.24­1.61) with a NNT of 10.58. Logistic regression showed a significant odds ratio of 0.04 (P = 0.021) for intervention group compared to control group at 12-month follow-up for completers and a non-significant odds ratio of 0.34 (P = 0.303) at 24-month follow-up. CONCLUSIONS: The SMS program proved to have potential to reduce the risk of developing diabetes at 12 months but additional measures should be integrated to prevent or delay disease progression.

Benzimidazoles as benzamide replacements within cyclohexane-based CC chemokine receptor 2 (CCR2) antagonists.

We describe the design, synthesis, and evaluation of benzimidazoles as benzamide replacements within a series of trisubstituted cyclohexane CCR2 antagonists. 7-Trifluoromethylbenzimidazoles displayed potent binding and functional antagonism of CCR2 while being selective over CCR3. These benzimidazoles were also incorporated into lactam-containing antagonists, thus completely eliminating the customary bis-amide.

The impact of work nature, lifestyle, and obesity on health-related quality of life in Chinese professional drivers.

OBJECTIVE: To assess the association of work nature, lifestyle and obesity with health-related quality of life (HRQOL) in professional drivers. METHODS: A total of 3376 Chinese professional drivers aged 18 to 70 years were recruited to assess the HRQOL by SF-12 summary scores (Physical Component Summary [PCS]; Mental Component Summary [MCS]), and collect data for work nature, lifestyle, and body mass index. Factors associated with HRQOL were examined by multiphase regression analyses. RESULTS: Professional drivers reported poorer physical and mental HRQOL than the general population. Shift work and lorry driving had significant negative effect on HRQOL. Obesity was associated with lower PCS but higher MCS. CONCLUSIONS: HRQOL of professional drivers tended to be low, especially among lorry drivers and shift drivers. Health intervention programs should promote regular exercise, healthy eating, no smoking, and weight control, which are modifiable factors improving HRQOL.

Discovery of an orally-bioavailable CC Chemokine Receptor 2 antagonist derived from an acyclic diaminoalcohol backbone.

We describe an isostere-driven approach to improve upon a previously-described series of capped dipeptide antagonists of CC Chemokine Receptor 2 (CCR2). Modification of the substitution around the isostere was combined with additional changes in a distal aromatic substituent to provide single-digit nanomolar antagonists of CCR2. These studies led to the identification of 18, a compound that was suitable for studies in murine models of CCR2 activity.

The importance of transcultural nursing in cancer care.

All patients around the time of cancer diagnosis are emotionally vulnerable. This sense of anxiety is further heightened for patients who are not fully integrated into the society in which they are receiving care because of the cultural shock and language barriers they may face. This article explores the author's experience of caring for a patient from China who was studying in the UK and was admitted with acute promyelocytic leukaemia. The patient had a limited grasp of English and was used to very different cultural norms. Bridging the cultural gap as outlined by Narayanasamy in the ACCESS model (2002) enabled the author to provide the important holistic nursing care that could be easily overlooked in these situations. There is a need for nurses to actively seek to understand cultural differences and take the opportunity to experience transcultural nursing.

The effect of CYP3A4 inhibition or induction on the pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in healthy volunteers.

Ruxolitinib, a selective Janus kinase (JAK) 1&2 inhibitor in development for the treatment of myeloproliferative neoplasms, is primarily metabolized by CYP3A4. The effects of inhibition or induction of CYP3A4 on single oral dose ruxolitinib pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated in healthy volunteers. Coadministration of ketoconazole (a potent CYP3A4 inhibitor) and erythromycin (a moderate CYP3A4 inhibitor) increased total ruxolitinib plasma exposure (AUC(0-∞)) by 91% and 27%, respectively, and ruxolitinib PD, as measured by the inhibition of interleukin (IL)-6-stimulated STAT3 phosphorylation in whole blood, was generally consistent with the PK observed. Pretreatment with rifampin, a potent CYP3A4 inducer, decreased ruxolitinib AUC(0-∞) by 71% while resulting in only a 10% decrease in the overall PD activity. This apparent PK/PD discrepancy may be explained, in part, by an increase in the relative abundance of ruxolitinib active metabolites with the rifampin coadministration. The collective PK/PD data suggest that starting doses of ruxolitinib should be reduced by 50% if coadministered with a potent CYP3A4 inhibitor, whereas adjustments in ruxolitinib starting doses may not be needed when coadministered with inducers or mild/moderate inhibitors of CYP3A4. All study doses of ruxolitinib were generally safe and well tolerated when given alone and in combination with ketoconazole, erythromycin, or rifampin.

The epidemiology and natural history of depressive disorders in Hong Kong's primary care.

BACKGROUND: Depressive disorders are commonly managed in primary care and family physicians are ideally placed to serve as central providers to these patients. Around the world, the prevalence of depressive disorders in patients presenting to primary care is between 10-20%, of which around 50% remain undiagnosed. In Hong Kong, many barriers exist preventing the optimal treatment and management of patients with depressive disorders. The pathways of care, the long term outcomes and the factors affecting prognosis of these patients requires closer examination. METHODS/DESIGN: The aim of this study is to examine the prevalence, incidence and natural history of depressive disorders in primary care and the factors influencing diagnosis, management and outcomes using a cross-sectional study followed by a longitudinal cohort study.Doctors working in primary care settings across Hong Kong have been invited to participate in this study. On one day each month over twelve months, patients in the doctor's waiting room are invited to complete a questionnaire containing items on socio-demography, co-morbidity, family history, previous doctor-diagnosed mental illness, recent mental and other health care utilization, symptoms of depression and health-related quality of life. Following the consultation, the doctors provide information regarding presenting problem, whether they think the patient has depression, and if so, whether the diagnosis is new or old, and the duration of the depressive illness if not a new diagnosis. If the doctor detects a depressive disorder, they are asked to provide information regarding patient management. Patients who consent are followed up by telephone at 2, 12, 26 and 52 weeks. DISCUSSION: The study will provide information regarding cross-sectional prevalence, 12 month incidence, remission rate, outcomes and factors affecting outcomes of patients with depressive disorders in primary care. The epidemiology, outcomes, pathways of care, predictors for prognosis and service needs for primary care patients with depressive disorders will be described and recommendations made for policy and service planning.

The pharmacokinetics, pharmacodynamics, and safety of orally dosed INCB018424 phosphate in healthy volunteers.

INCB018424 phosphate, a potent inhibitor of JAK enzymes with selectivity for JAK1&2, is in development for the treatment of myelofibrosis (MF). The oral dose pharmacokinetics, pharmacodynamics, safety, and tolerability of INCB018424 were evaluated in healthy volunteers in 2 double-blind, randomized, and placebo-controlled studies. The first study evaluated single ascending doses of 5 to 200 mg INCB018424 and the effect of food, whereas the second study evaluated multiple ascending doses, including both once- and twice-daily dosing for 10 days. As a Biopharma-ceutical Classification System class I drug, INCB018424 exhibited good oral bioavailability and dose-proportional systemic exposures. INCB018424 showed low oral dose clearance and a small volume of distribution, with an approximate 3-hour plasma half-life and insignificant accumulation following repeat dosing. A high-fat meal reduced INCB018424 C(max) by 24% but had little effect on INCB018424 AUC. INCB018424 was cleared primarily by metabolism with negligible renal excretion. The pharmacodynamics of INCB018424, evaluated by the inhibition of phosphorylated STAT3 following cytokine stimulation in whole blood, showed good correlation with INCB018424 plasma concentrations. INCB018424 was generally safe and well tolerated, with 25 mg bid and 100 mg qd established as the maximum tolerated doses in healthy volunteers.

Does vocational training in family medicine have an impact on antibiotic prescribing pattern?

BACKGROUND: Antibiotics overuse is common and is the major cause of antibiotic resistance. Rational use of antibiotics by GPs is essential as most health problems are exclusively dealt within primary care. Postgraduate family medicine (FM) training has become established in various countries over the last few decades but little is known about the effect of FM training on antibiotic prescribing. OBJECTIVE: To determine whether GPs with FM training prescribe less antibiotics than those without training. METHODS: GPs working in a pluralistic primary health care system took part in the 2007-08 primary care morbidity and management survey in Hong Kong and collected information of all consecutive patient encounters during predetermined weeks of data collection. Characteristics of GPs, training status, patient morbidity and antibiotic prescribing pattern were compared using multivariate regression analyses. RESULTS: One hundred and nine GPs, of whom 67 had FM training, participated in the study and recorded 69 973 health problems. The overall antibiotic prescribing rate was 8.5% and that of GPs with FM training was 5.4% compared with the 13.3% among those without. Multivariate logistic regression showed that GPs with FM training were less likely to prescribe antibiotics (odds ratio 0.68, P < 0.05). They had lower antibiotic prescribing rates when managing upper respiratory tract infections, acute bronchitis and cough but higher in treating infective conjunctivitis and acute laryngitis. CONCLUSIONS: Postgraduate FM training in Hong Kong is associated with significantly lower antibiotic prescribing rates. This supports the importance of FM training in rationalizing the use of antibiotics in Hong Kong.