[Impact of baseline pulse pressure on new-onset cardio-and cerebrovascular events in diabetic population].

OBJECTIVE: To observe the association between baseline pulse pressure (PP) level and new-onset cardio-cerebrovascular events in diabetic population. METHODS: Physical examination data between July 2006 to October 2007 from a total of 101 510 employees of Kailuan Group were reviewed, 8306 subjects with a fasting plasma glucose level of ≥ 7.0 mmol/L or with confirmed diabetes diagnosis and were enrolled in this prospective cohort study. Subjects were followed up for 38-53 (48.1 ± 3.1) months and the cardio-cerebrovascular events were obtained every six months, association between baseline PP and new-onset cardio-cerebrovascular events in the diabetic population were analyzed. RESULTS: (1) Incidences of total cardio-cerebrovascular events in the PP groups were 3.4%, 2.8%, 4.5%, 6.4%, respectively. Incidences of cerebral infarction events and myocardial infarction were 2.1%, 1.6%, 2.9%, 3.9% and 1.1%, 0.7%, 1.0%, 1.7%, respectively. (2) Multivariate Cox's proportional hazards regression analysis indicated that baseline PP group was the risk factor for total cardio-cerebrovascular events, cerebral infarction events and myocardial infarction, and the risk for all the events of the PP ≥ 60 mm Hg (1 mm Hg = 0.133 kPa) group was increasing. The values of RR(95%CI) were 1.88 (95%CI 1.34-2.65, P < 0.01), 1.92 (95%CI 1.23-2.99, P < 0.01) and 1.52 (95%CI 0.82-2.81, P > 0.05) after adjust the other factors.(3) In line with increasing level of baseline PP, age, BMI, SBP, DBP, HDL-C, and hs-CRP levels significantly increased in this diabetic population (P < 0.01 or P < 0.05). CONCLUSION: The level of high baseline PP is a risk factor for new-onset cardio-cerebrovascular events in diabetic population.

In-vitro metabolism of glycyrrhetinic acid by human and rat liver microsomes and its interactions with six CYP substrates.

OBJECTIVES: Glycyrrhetinic acid is the main metabolite of glycyrrhizin and the main active component of Licorice root. This study was designed to investigate the in-vitro metabolism of glycyrrhetinic acid by liver microsomes and to examine possible metabolic interactions that glycyrrhetinic acid may have with other cytochrome P450 (CYP) substrates. METHODS: Glycyrrhetinic acid was incubated with rat liver microsomes (RLM) and human liver microsomes (HLM). Liquid chromatography tandem mass spectrometry was used for glycyrrhetinic acid or substrates identification and quantification. KEY FINDINGS: The K(m) and V(max) values for HLM are 33.41 µm and 2.23 nmol/mg protein/min, respectively; for RLM the K(m) and V(max) were 24.24µm and 6.86 nmol/mg protein/min, respectively. CYP3A4 is likely to be the major enzyme responsible for glycyrrhetinic acid metabolism in HLM while CYP2C9 and CYP2C19 are considerably less active. Other human CYP isoforms have minimal or no activity toward glycyrrhetinic acid. The interactions of glycyrrhetinic acid and six CYP substrates, such as phenacetin, diclofenac, (S)-mephenytoin, dextromethorphan, chlorzoxazone and midazolam were also investigated. The inhibitory action of glycyrrhetinic acid was observed in CYP2C9 for 4-hydroxylation of diclofenac, CYP2C19 for 4'-hydroxylation of (S)-mephenytoin and CYP3A4 for 1'-hydroxylation of midazolam with half maximal inhibitory concentration (IC50) values of 4.3-fold, 3.8-fold and 9.6-fold higher than specific inhibitors in HLM, respectively. However, glycyrrhetinic acid showed relatively little inhibitory effect (IC50>400 µm) on phenacetin O-deethylation, dextromethorphan O-demethylation and chlorzoxazone 6-hydroxylation. CONCLUSIONS: The study indicated that CYP3A4 is likely to be the major enzyme responsible for glycyrrhetinic acid metabolism in HLM while CYP2C9 and CYP2C19 are considerably less active. The results suggest that glycyrrhetinic acid has the potential to interact with a wide range of xenobiotics or endogenous chemicals that are CYP2C9, CYP2C19 and CYP3A4 substrates.

[Impact of patient compliance on the outcomes in hypertensive patients receiving hydrochlorothiazide based combination therapy with spironolactone or captopril].

OBJECTIVE: To explore the impact of patient compliance on the long-term outcomes in hypertensive patients receiving hydrochlorothiazide (HCTZ) based combination therapy with spironolactone or captopril. METHODS: A total of 853 patients with mild to moderate hypertension were recruited and randomly divided into HCTZ group (HCTZ 12.5 mg q.d), spironolactone group (HCTZ 12.5 mg q.d and spironolactone 20 mg q.d), and captopril group (HCTZ 12.5 mg q.d and captopril 25 mg bid) after 2-week placebo washout period and 6-week loading period for HCTZ. Since the efficacy of combination therapy was proven to be better than monotherapy 1 year after therapy beginning, patients in HCTZ group were randomly assigned to spironolactone group or captopril group. The patients were followed up for 4 years. Patients were divided to compliance (n = 424) or non-compliance group (n = 429) according test drug taking questionnaire. During the follow-up time, the blood pressure and the outcomes were recorded monthly, and blood biochemical parameters were determined once a year. RESULTS: At the end of follow up, incidence of cardio-cerebral vascular events was significantly lower in compliance group (2 fatal, 8 non-fatal) than that in noncompliance group (7 fatal, 21 non-fatal, P < 0.05). Systolic blood pressure [-(19.4 +/- 20.6) mm Hg, 1 mm Hg = 0.133 kPa] and diastolic blood pressure [-(10.7 +/- 13.5) mm Hg] were significantly reduced compared values at baseline and noncompliance group (all P < 0.001) while the reduction did not reach statistically significance in noncompliance group [-(7.3 +/- 18.2) mm Hg and -(3.5 +/- 10.2) mm Hg, all P > 0.05 vs. baseline]. The serum BUN, Cr and UA levels in the compliance group were significantly higher and the serum K(+), CHO, LDL-C level were significantly lower than baseline values. The serum BUN, UA levels in the compliance group were significantly higher while the serum K(+), cholesterol levels were significantly lower than those in the noncompliance group (all P < 0.05). CONCLUSIONS: This study indicates that patient compliance could affect the long-term outcome and antihypertensive efficacy in hypertensive patients receiving HCTZ based combination therapy with spironolactone or captopril.