An Updated Classification of Primary Lymphedema Based on Age of Onset, Lymphatic Anomalies, and Genetics.

Primary lymphedema (PLE) is a chronic disease caused by lymphatic dysplasia and progresses to irreversible tissue edema and hypertrophy. Understanding of PLE has been hitherto limited. The aim of this study is to devise an updated classification system for PLE of 1013 patients with PLE of lower limb were enrolled. Sex, age of onset, location, family history and morbidity were documented. The lymphatic imaging findings of magnetic reso-nance lymphography (MRL), indocyanine green lymphography (ICGL) and lymphoscin-tigraphy (LSG), skin tissue immunohisto-chemical staining, whole exome sequencing and the correlation of genotype-phenotype were evaluated. Patients were divided into a congenital onset category and a late onset category. The late onset category was further divided according to developmental age. The ratio of congenital-onset to late-onset PLE was 1:4 and that the highest incidence was in adolescence. The sex ratio was 1.04:1 and 1.5:1 in congenital-onset and late-onset groups, respectively. Three major lymphatic anomalies were identified, in which segmental lymphatic dysfunction, characterized by delayed or partial demonstration of lymph vessels, is the most common and associated with FLT4, GJC2, CELSR1, and PTPN14 mutations. The next most common type is lymphatic hyperplasia, which is associated with FOXC2 and GATA2 variants, followed by initial lymphatic aplasia or dysfunction, which is more common in pa-tients with congenital PLE and associated with FLT4 mutation. A functional and structural combined classification of lymphatic anomalies is proposed, which includes segmental lymphatic dysfunction, lymphatic hyperplasia and initial lymphatic aplasia or dysfunction.

Treatment of secondary lower limb lymphedema after gynecologic cancer with complex decongestive therapy.

Secondary lower extremity lymphedema is a common complication of treatment for gynecological cancers. Conservative therapy plays an important role in the treatment of patients with secondary lower extremity lymphedema; in particular, complex decongestive therapy (CDT) has been recognized as an effective nonoperative technique for these patients. But CDT therapy for secondary lower extremity lymphedema remains a problem in China because this technique and its effectiveness have not achieved widespread use and popularity. Our goal was to assess effects of CDT in patients with secondary lower limb lymphedema after treatment for gynecological cancers. The retrospective study consisted of 60 patients who were treated with 20 sessions of CDT. Assessments included objective changes in limb circumference, degree of LE, imaging features, and incidence of erysipelas before and after CDT treatment. We found that CDT can effectively improve lymph stasis and promote backflow, and decrease circumference, interstitial fluid content, and incidence of erysipelas of lymphedematous lower limb. Our results demonstrate that CDT is an effective treatment method for patients with secondary lower limb lymphedema following treatment for gynecologic cancers. This technique should be more widely utilized and popularized in China to improve the quality of life of millions of patients with secondary lower limb lymphedema.

Effects of the Traditional Chinese Medical Prescription Linba Fang as a Treatment for Lymphedema.

Lymphedema can lead to a series of complicated and irreversible chronic pathological changes, including lymphatic fluid retention, infiltration of inflammatory cells, lipid deposition, and fibrosis of the surrounding tissues. Typically, compression physiotherapy is recommended for early lymphedema. However, the chronic fluid compartments will lead to fat deposition, skin fibrosis, and hyperkeratosis. Few treatment methods are available for patients with lymphedema. Previous studies have attempted to apply diuretics, diosmin, and sodium ß-aescinate to treatment for venous edema, but the curative effect was unsatisfactory. There is currently no established effective treatment for lymphedema. In this paper, we investigated the effects of the traditional Chinese medical prescription Linba Fang as a treatment for lymphedema using a mouse model. A lymphedema model was established in C57BL/6 mice through lymphatic ablation at the base of tails. Negative controls were administered with 0.5% sodium carboxymethyl cellulose solution by gavage twice daily, positive controls with aescuvenforte, and test mice with Linba Fang. Aescuvenforte and Linba Fang were dissolved in 0.5% sodium carboxymethyl cellulose solution to produce a homogeneous mixture. After treatment for 2-4 weeks, tail diameter and weight, inflammatory cytokine levels (IL-1, IL-6, and TNF-α), lipid deposition, and fibrosis were evaluated. The results showed that none of the mice died during the treatment with Linba Fang. The levels of tail swelling, inflammation, lipid deposition, and fibrosis in mice treated with Linba Fang were significantly decreased compared with negative and positive controls. Among mice treated with the same dose of Linba Fang, the levels of tail swelling, inflammation, lipid deposition, and fibrosis in mice treated for 4 weeks were significantly lower than those treated for 2 weeks. Among mice treated for the same duration of time, the levels of tail swelling, inflammation, lipid deposition, and fibrosis showed a decreasing tendency following increasing doses. Notably, the inflammation in tail tissues decreased to the similar level of normal group after treatment for 4 weeks using the high dose of Linba Fang. In conclusion, the traditional Chinese medical prescription Linba Fang could inhibit the pathological changes caused by lymphedema, including swelling, inflammation, lipid deposition, and fibrosis.

Lymphatic system malformations in Noonan syndrome: Two case reports and imaging analysis.

L ymphedema is a well-known complication of Noonan syndrome (NS) but the lymphatic malformations in NS are poorly understood. We report clinical, genetic, and imaging information about a boy and girl with NS and late-onset lower extremity lymphedema. A de novo missense mutation of RIT1 (NM_006912.5) c.246T>A, p.Phe82Leu was identified in the girl, who also showed systemic lymphatic hyperplasia and dysfunction. Magnetic resonance lymphangiography (MRL) of the boy clearly demonstrated segmental dilated and hyperplastic lymphatics with impaired transport function in an affected limb and pelvic region. Indocyanine green lymphography (ICGL) showed delayed and partial enhancement of the lymph vessels in the affected limb but no lymph reflux was detected. No causative mutation was identified in the second case. Lymphoscintigraphy (LSG) failed to show lymph vessels in either of the children. Our study showed that MRL is a reliable and accurate test that can be used to demonstrate morpho-logical and functional defects of the lymphatic system. Moreover, ICGL is sufficiently sensitive to determine the functional condition of peripheral lymph vessels. The combined use of imaging modalities can give an accurate diagnosis of complex lymphatic system anomalies in NS and other syndromic diseases.

Does body mass index truly affect mortality and cardiovascular outcomes in patients after coronary revascularization with percutaneous coronary intervention or coronary artery bypass graft? A systematic review and network meta-analysis.

BACKGROUND: Obesity, a comorbid medical condition, is usually observed in patients with established coronary artery disease. Paradoxically, patients with a higher body mass index (BMI) usually have better clinical outcomes after coronary revascularization. METHODS: We searched five online databases through December 2017. We identified studies reporting the rate of all-cause mortality or cardiovascular-related outcomes among patients after coronary revascularization with percutaneous coronary intervention or coronary artery bypass graft based on various BMI categories. Network meta-analysis was performed using Bayesian methods. RESULTS: Sixty-five records involving 865,774 participants were included in our study. A U-shaped association was observed across BMI categories for all-cause mortality. Using normal weight as the reference, all-cause mortality was increased for (relative risk [RR]: 2.4; 95% credibility interval [CrI]: 2.1-2.7) patients with underweight, whereas it was lowered in patients with overweight, obese, and severely obese. This association remained significant in many subgroups. We also observed that the risk of major adverse cardiovascular events (MACE) was lowest among patients with overweight. Furthermore, patients with underweight were associated with greater risks of myocardial infarction (RR: 1.9; 95% CrI: 1.4-2.5), cardiovascular-related mortality (RR: 2.8; 95% CrI: 1.6-4.7), stroke (RR: 2.0; 95% CrI: 1.3-3.3) and heart failure (RR: 1.7; 95% CrI: 1.1-2.7) compared with normal weight patients; no significant association was observed among individuals with higher BMI. CONCLUSIONS: The 'obesity paradox' does exist in patients after coronary revascularization, especially for patients with post-percutaneous coronary intervention. All-cause mortality in patients with high BMI is significantly lower compared with patients with normal weight. Furthermore, patients with underweight experience higher rates of cardiovascular outcomes compared with patients with normal weight.

[A randomized study of intensity-modulated radiation therapy versus three dimensional conformal radiation therapy for pelvic radiation in patients of post-operative treatment with gynecologic malignant tumor].

Objective: To study the difference between intensity-modulated radiation therapy (IMRT) and three dimensional conformal radiation therapy (3D-CRT) for pelvic radiation of post-operative treatment with gynecologic malignant tumor. Methods: A prospective investigation study was conducted on 183 patients of post-operative patients with whole pelvic radiation therapy of cervical cancer or endometrial cancer in Zhejiang Cancer Hospital [IMRT group (n=85) and 3D-CRT group (n=98)] from Oct. 2015 to Oct. 2016. The two groups received same dose (45 Gy in 25 fractions). Comparison of two groups with radiation dosimetry:the score according to the Radiation Therapy Oncology Group (RTOG) acute radiation injury grading standards before and after radiotherapy reaction, the score from functional assessment of cancer therapy scale-cervix (FACT-Cx) scale and expanded prostate cancer index composite for clinical practice (EPIC-CP) scale were also analyzed. Results: (1) There were no significant effect with age, culture level, family economic condition and ratio of radiochemotherapy between two groups (all P>0.05). (2) Dosimetric comparison for IMRT vs 3D-CRT: the average dose of planning target volume (PTV) decreased (46.1±0.4) vs (46.4±0.5) Gy, V(45) dose percentage increased (95.2±1.0) % vs (93.3±2.0) %, intestinal bag dose of V(4)0 decreased (24.4±6.8) % vs (36.5±15.9) %, rectal V(40) dose percentage decreased (73.9±12.3) % vs (85.4±8.4) %, and lower rectal V(45) dose percentage (32.8±13.4) % vs (71.5±13.7) %, bladder V(40) dose percentage decreased (55.5±13.0) % vs (84.4±13.0) %. Bone marrow V(20) lower: (67.9±5.4) % vs (79.5±6.6) %, V(1)0 lower: (82.1±6.0) % vs (86.3±6.6) %; there were significant differences (all P<0.05). There was no significant difference between the dose of V(45) in the intestinal pouch and bladder (P>0.05). (3) Acute radiation injury classification for IMRT vs 3D-CRT: big or small intestine: Ⅱ-Ⅲ reaction [13% (11/85) vs 24% (24/98); χ(2)=3.925, P=0.048], there was significant difference. Bladder: Ⅲ reaction [19% (16/85) vs 26% (25/98); χ(2)=1.171, P=0.279], there was no significant difference. Radiochemotherapy of bone marrow suppression: Ⅲ-Ⅳ reaction (14/20), the incidence rate [26% (14/54) vs 31% (20/65); χ(2)=0.339, P=0.562], the difference was not statistically significant. (4) Quality of life scale by FACT-Cx scale in IMRT vs 3D-CRT: there were no significant difference before radiotherapy (82±16 vs 85±16; t=1.279, P=0.203), while there was significant difference after radiotherapy (76±14 vs 71±18; t=-2.160, P=0.032). EPIC-CP scale score: before radiotherapy they were (16±7 vs 15±6; t=-0.174, P=0.862),but after radiotherapy (18±7 vs 22±7; t=3.158, P=0.002), there was significant difference between them. Before and after radiotherapy, the increased EPIC-CP scale of the IMRT group vs 3D-CRT group were 3±4 and 6±4, the 3D-CRT group was significantly higher, the difference was statistically significant (t=5.500, P=0.000). Conclusion: IMRT has shown that there are a significant benefit for the post-operative patients with cervical cancer and endometrial cancer compared to 3D-CRT.

A LYVE-1/CRSBP-1 Mutation in Inherited Primary Lymphedema.

Primary lymphedema is clinically and genetically heterogeneous with germline mutations identified in approximately 20 primary lymphedema genes. The lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) gene, also known as cell-surface retention sequence binding protein-1 (CRSBP-1), encodes the major hyaluronan receptor in lymphatic endothelia and is one of the most specific lymphatic vessel markers. However, the role of this lymphatic endothelial specific protein in the development of the lymphatic system and lymphatic diseases remains unclear. Here, we report a missense mutation c.18C>G (p.S6R) in exon 1 within the N-terminal extension domain (outside the hyaluronan binding region) of LYVE-1 in three generations of an inherited lymphedema family with or without clinical symptoms. Lymphatic imaging revealed a partial, weak and delayed enhancement of tortuous lymph collectors in the distal part of the lymphedematous lower limb. Our findings revealed that LYVE-1/CRSBP-1 mutation in primary lymphedema cases is connected with both structural and functional lymphatic defects.

Role and timing of second-line therapies for patients with recurrent platinum-resistant ovarian epithelial cancer.

OBJECTIVE: To explore the regimens and prognoses of second-line therapies for recurrent platinum-resistant ovarian epithelial cancer (OEC). MATERIALS AND METHODS: The clinical profiles and second-line regimens were retrospectively analyzed for 65 recurrent platinum-resistant OEC patients treated at Zhejiang Provincial Tumor Hospital during January 2003 to January 2013. In conjunction with literature reviews, the second-line therapies for platinum-resistant recurrent OEC were discussed. RESULTS: Their average age was 55.2 years. The stages were I (n=4), II (n=3), III (n=45), and IV (n=13). The predominant type was serous adenocarcinoma (n=47, 72.3%). Chemotherapy was refused (n=14) and resistant (n=5 1). One case was lost to follow-up and another three withdrew early. An average of four chemotherapeutic courses were offered in 61 cases. Among them, five cases selected chemotherapy after a second operation. The average therapy-free interval (TFI) was 3.5 months. The efficacies were evaluated for 61 cases. CR (n=5) and partial remission (PR, n=22). The overall survival (OS) rate was 43.6% and average progression-free survival (PFS) was 15.44 months. CONCLUSION: The efficacy of second-line therapy for recurrent platinum-resistant OEC is rather poor and the feasibility and efficacy of second operation are to be further explored.

Rare Variants in LAMA5 Gene associated with FLT4 and FOXC2 Mutations in Primary Lymphedema May Contribute to Severity.

Mutations in the Fms-related tyrosine kinase 4 (FLT4) and forkhead box protein C2 (FOXC2) genes cause Milroy disease (MD) and lymphedema-distichiasis syndrome (LDS), respectively, but the mechanism underlying disease pathology remains unclear. Applying whole-exome sequencing to two families with MD, one LDS family, and one sporadic LDS case, we identified four rare variants in the laminin subunit alpha-5 gene (LAMA5) in subjects carrying novel and known missense FLT4 mutations and a 7-bp duplication and 1-bp insertion in FOXC2. Phenotyping was expanded in some individuals using magnetic resonance lymphangiography, indiocyanine green fluorescence lymphography, and immunofluorescent lymphatic staining of skin tissue. Skin lymphatic staining showed the existence of dermal lymphatic vasculature in the MD case. Significant lymphatic dysfunction was observed in both MD and LDS patients. In the MD patient, tortuous lymphatics in the dorsum of the foot were slowly enhanced on indocyanine green fluorescent lymphography (ICG) imaging. Dilated lymph collectors with disruption and lymph leakage were observed in the familial LDS case on magnetic resonance lymphangiography (MRL). Numerous tortuous lymph collectors were visualized along the entire length of affected lower limbs on MRL imaging, and retrograde lymph flow was observed in the lymph collectors during ICG lymphography in the isolated LDS case. The finding of rare LAMA5 variants together with FLT4 and FOXC2 mutations suggests that these mutations may be co-responsible for these disorders and most likely interfere with the function of lymphatics. Further, larger studies are needed to confirm these results.

A NOVEL FLT4 GENE MUTATION AND MR LYMPHANGIOGRAPHY IN A CHINESE FAMILY WITH MILROY DISEASE.

Milroy disease is a congenital onset lymphedema linked to FLT4 gene mutations in the tyrosine kinase domain. So far, a total of 59 different FLT4 variants have been identified. Here, we report a novel FLT4 gene mutation in a Chinese family with Milroy disease and present their clinical symptoms and MR lymphangiographic findings.

Which is the appropriate surgical procedure for Stage I endometrial carcinoma?

OBJECTIVE: To study the appropriate surgical procedure for Stage I endometrial carcinoma (EC), the clinical and pathological features and prognosis factors, as well as types were analyzed retrospectively. MATERIALS AND METHODS: This is a retrospective study of 277 patients with early-stage EC in clinical Stages I that received surgery between January 2000 and March 2008. The appropriate surgical procedures were divided into three types (procedure I-III: hysterectomy with or without ovary preservation, subradical hysterectomy plus pelvic lymph node biopsy, and radical hysterectomy pelvic plus lymphadenectomy) according to the clinical stage. RESULTS: Tumor invasion of the cervix and deep muscularis as well as the parametrium, EC Stage Ib, grade 3 and ascites had carcinoma cells, were high-risk factors of EC metastasis to the retroperitoneum (p < 0.05). The ovarian preservation of EC Stage Ia had no effect on overall survival. The three types of procedure for the EC Stage Ia were not correlated significantly to the three-year and five-year survival rates. The three-year and five-year survival rates of three surgical procedures for the EC Stage Ib were significantly correlated. The survival rates of surgical procedures II and III were significantly higher than that of procedure I (P < 0.05). CONCLUSION: Subradical hysterectomy plus pelvic lymph node biopsy was recommended for EC Stage 1b with high-risk factors. There was no evidence of benefit in terms of overall or recurrence-free survival for radical hysterectomy plus pelvic lymphadenectomy in women with Stage I EC.

Magnetic resonance lymphography demonstrates spontaneous lymphatic disruption and regeneration in obstructive lymphedema.

The present study was aimed at observing both the damage and change process undergone in lymphatic collectors in obstructive extremity lymphedema. Forty-five patients with obstructive extremity lymphedema who had been examined with magnetic resonance lymphangiography (MRL) were enrolled in the study. Among this group, 36 were diagnosed with secondary lymphedema of the lower extremity and 9 exhibited upper extremity lymphedema after mastectomy. Morphological damage as a result of obstruction of collecting lymph vessels was recorded and analyzed. Obvious damage to the lymph vessels was found in all of the 36 lower extremity lymphedema cases with different lengths of history, including vessel disruption in 21 and lymphatic regeneration in 15. Lymphatic damage occurred in the anterior tibial area of the lower leg in almost every case. In 9 cases with upper extremity lymphedema, collecting lymphatic disruption and lymph tracer leakage was seen in multiple patterns. Imaging displayed that ruptured lymph collectors healed spontaneously or regenerated into a segment of the lymphatic network. The present study provided real-time images of collecting lymphatic vessels in obstructive lymphedema. These were seen to have undergone disruption, displayed lymphorrhoea, and/or lymphatic regeneration. In addition, the images suggest that the anterior tibial lymphatic is the weak point of the lymphatic pathway in the lower limb.

Magnetic resonance lymphography (MRL): point and counter-point.

Two preeminent lymphologists debate the findings, implications, interpretations, and value of magnetic resonance lymphography (MRL) in the evaluation of peripheral lymphedema. Their contrasting views are discussed in the context of different lymphatic imaging modalities including MRL, lymphoscintigraphy, and microscopic anatomy.

Classification of lymphatic-system malformations in primary lymphoedema based on MR lymphangiography.

OBJECTIVES: The study aims to investigate lymphatic-system malformations and proposes a classification of primary lymphoedema based on comprehensive imaging data of both lymph vessel- and lymph-node abnormalities. MATERIALS AND METHODS: A total of 378 patients with primary lymphoedema of the lower extremity were examined with magnetic resonance lymphangiography (MRL) using gadobenate dimeglumine as contrast agent. Lymph vessels and drainage lymph nodes were evaluated, leading to the proposal of the classification of primary lymphoedema and the relative proportions. RESULTS: A total of 63 (17%) patients exhibited defects of the inguinal lymph nodes with mild or moderate dilatation of afferent lymph vessels. A total of 123 (32%) patients exhibited lymphatic anomalies as lymphatic aplasia, hypoplasia or hyperplasia with no obvious defect of the drainage lymph nodes. The involvement of both lymph vessel- and lymph-node abnormalities in the affected limb was found in 192 (51%) patients. The primary lymphoedema was classified as three major types as: (1) lymph nodes affected only; (2) lymph vessel affected only with three subtypes and (3) both lymph vessel and lymph node affected with subgroups. CONCLUSIONS: A comprehensive classification of lymphatic-system malformation in primary lymphoedema is proposed, which clearly defines the location and pathologic characteristics of both lymphatics and lymph node and may lead to further study of the aetiology as well as rational treatment of the disease.

Magnetic resonance lymphography at 3T: a promising noninvasive approach to characterise inguinal lymphatic vessel leakage.

PURPOSE: To explore the feasibility of using 3T high-resolution MR lymphangiography to characterize inguinal lymphatic vessel leakage (LVL). MATERIALS AND METHODS: Sixteen patients with known inguinal LVL underwent 3T MR lymphangiography and T(2)-weighted imaging. The presence or absence of inguinal LVL and the responsible lymphatic vessels were determined using the above imaging modalities and confirmed by surgical procedure. Afterwards, fifteen patients with recurring LVL following conservative treatment were referred to surgical intervention. RESULTS: Specific inguinal LVL enhancement patterns and leaking lymphatic vessels were detected in 15 of 16 patients. Compared to the SNR of enhanced lymph nodes, that of the enhanced LVL was significantly greater (t = 7.149, p < 0.01), thereby making it possible to differentiate between LVL sites and enhancing inguinal lymph nodes. Furthermore, the steepest contrast enhancement curve slope of enhanced LVL was lower than that of enhanced lymph nodes (t = -2.860, p = 0.02). After MR diagnosis, 15 patients successfully underwent open exploration and ligation of the leaking lymphatic vessel. Clinical follow-up did not demonstrate recurrence of lymphatic fluid in the groin. CONCLUSIONS: High-resolution MR lymphangiography combined with T(2)-weighted imaging is a promising approach to identifying specific features of lymphatic vessel leakage in the groin.

FOXC2 transcription factor: a novel regulator of lymphangiogenesis.

Lymphangiogenesis is the critical process of forming new lymphatic vessels under physiological and pathological conditions and involves both molecular and morphological changes. Despite evidence that lymphangiogenic factors, including vascular endothelial growth factors (VEGFs) and Prox1, regulate lymphangiogenesis, the molecular mechanisms underlying gene regulation in lymphatic vessel remodeling and maturation are not fully understood. Importantly, recent studies demonstrate that Forkhead transcription factor FOXC2 controls later steps of lymphatic vascular development and is responsible for establishing a collecting lymphatic vessel identity by regulating expression of downstream genes involved in lymphangiogenesis, including PDGF-beta, Delta-like 4 (Dll4) and angiopoietin (Ang)-2. Thus, FOXC2 is now recognized as a novel regulator of lymphatic vascular formation and remodeling. This review summarizes current knowledge about the function of FOXC2 in lymphangiogenesis and discusses prospects for future research in FOXC2-mediated pathological lymphangiogenesis in lymphatic-related disease.

Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers.

BACKGROUND AND OBJECTIVE: CYP2C9 is the major contributor to gliclazide metabolic clearance in vitro, while the pharmacokinetics of gliclazide modified release are affected mainly by CYP2C19 genetic polymorphisms in vivo. This study aims to investigate the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers. METHODS: Eighteen healthy Han subjects with various combinations of CYP2C9 and CYP2C19 genotypes received 80 mg gliclazide. Plasma gliclazide concentrations were measured by a liquid chromatography-tandem mass spectrometry method for 84 h and plasma glucose and insulin levels were measured up to 15 h post-dose. RESULTS AND DISCUSSION: There was no difference in either pharmacokinetic and or pharmacodynamic parameters of gliclazide when group A (CYP2C9*1/*1, CYP2C19 extensive metabolizers) was compared with group B (CYP2C9*1/*3, CYP2C19 *1/*1). When group C (CYP2C9*1/*1 and CYP2C19 poor metabolizers) was compared with group A, the AUC(0-∞) and C(max) in group C were significantly higher [83.94 ± 40.41 vs. 16.39 ± 5.10 µg·h/mL (P = 0.000) and 1.50 ± 0.85 vs. 0.45 ± 0.18 µg/mL (P = 0.000)], and the oral clearance was significantly lower [1.17 ± 0.63 vs. 5.38 ± 1.86 L/h (P = 0.000)]. The half-life of gliclazide was also significantly prolonged in group C subjects when compared with that of group A (33.47 ± 12.39 vs. 19.34 ± 10.45 h), but the difference was not significant (P = 0.052). The increase in serum glucose level at 11 h after dosing (ΔC(glu11)) in group C was significantly higher than that of group A (-1.08 ± 0.42 vs. 0.22 ± 1.01 mmol/L, P = 0.022). The corresponding insulin levels showed no difference between the two groups. CONCLUSION: CYP2C9*3 was not associated with any change in the disposition of gliclazide. CYP2C19 polymorphisms appear to exert the dominant influence on the pharmacokinetics of gliclazide in healthy Chinese Han subjects, and may also affect the observed pharmacodynamics of the drug as a result.