Effect of polymerized-type I collagen in knee osteoarthritis. II. In vivo study

Background Polymerized‐Type I Collagen (Polymerized‐Collagen) is an anti‐inflammatory and a tissue regenerator biodrug. The aim of the study was to evaluate the efficacy and safety of intra‐articular injections of Polymerized‐Collagen in patients with knee osteoarthritis (OA). Methods and design Patients (n = 53) were treated with 12 intra‐articular injections of 2 mL of Polymerized‐Collagen (n = 27) or 2 mL of placebo (n = 26) during 6 months. Follow up period was 6 months. The primary endpoints included Western Ontario and McMaster University Osteoarthritis Index, Lequesne index, and pain intensity on a visual analogue scale (VAS). Secondary outcomes were patient global score, investigator global score and drug evaluation. Clinical improvement was determined if the decrease in pain exceeds 20 mm on a VAS and patients achieved at least 20% of improvement from baseline. Urinary levels of C‐terminal crosslinking telopeptide of collagen type II (CTXII) and serum high‐sensitivity C‐reactive protein (hsCRP) were determined by enzyme immunoassays. Statistical analysis was performed by intention to treat. Results Polymerized‐Collagen was safe and well tolerated. Patients had a statistically significant improvement (P < 0·05) from baseline vs. Polymerized‐Collagen and vs. placebo at 6 months in: Lequesne Index (13·1 ± 0·5 vs. 7·1 ± 0·7 vs. 9·6 ± 0·8; P = 0·027), WOMAC (9·0 ± 0·5 vs. 4·0 ± 0·6 vs. 5·80 ± 0·8; P = 0·032), patient VAS (60·0 ± 2·6 vs. 20·6 ± 2·4 vs. 36·1 ± 4·5; P = 0·003), physician VAS (49·8 ± 1·9 vs. 16·8 ± 2·9 vs. 29·8 ± 2·9; P = 0·002), patient global score (1·08 ± 0·1 vs. 2·7 ± 0·1 vs. 1·9 ± 0·2; P = 0·028) and analgesic usage (30·1 ± 9·4 vs. 11·0 ± 3·4 vs. 17·9 ± 4·9; P = 0·001). This improvement was persistent during the follow up. A threefold increase in CTXII was determined in placebo group. No differences were found on hs CRP and incidence of adverse events between groups. Conclusion Polymerized‐Collagen is safe and effective in the treatment of knee OA.     

Nateglinide and glibenclamide metabolic effects in naïve type 2 diabetic patients treated with metformin

Background and objective: Most antidiabetic agents target only one of several underlying causes of diabetes. The complementary actions of the glinides and the biguanides may give optimal glycemic control in patients with type 2 diabetes mellitus. The aim of the present study was to compare the effects of nateglinide plus metformin with glibenclamide plus metformin on glucose and lipid metabolism, and haemodynamic parameters in patients with type 2 diabetes mellitus. Methods: We enrolled 248 type 2 diabetic patients. Patients were randomly assigned to receive nateglinide (n = 124) or glibenclamide (n = 124), after 6 months of run‐in, in which we titrated nateglinide (starting dose 180 mg/day), glibenclamide (starting dose 7·5 mg/day), and metformin (starting dose 1500 mg/day). The final doses were (mean ± standard deviation), 300 ± 60, 12·5 ± 2·5, and 2500 ± 500 mg/day, respectively. We followed these patients for 1 year after titration. We assessed body mass index (BMI), fasting (FPG) and post‐prandial (PPG) plasma glucose, glycosylated haemoglobin (HbA_1c), fasting (FPI) and post‐prandial (PPI) plasma insulin, homeostasis model assessment (HOMA) index, and lipid profile [total cholesterol (TC), low density lipoprotein‐cholesterol (LDL‐C), high density lipoprotein‐cholesterol (HDL‐C), triglycerides (Tg), apolipoprotein A‐I (Apo A‐I), and apolipoprotein B (Apo B)], systolic blood pressure (SBP), and diastolic blood pressure (DBP). All variables were evaluated at baseline and after 3 and 6 months in the run‐in period, and at baseline, and after 3, 6, 9 and 12 months for both treatment groups. Results and discussion: Body mass index did not show any significant change during the study. We observed a significant improvement from baseline to 1 year on HbA_1c (P < 0·01 vs. baseline and vs. glibenclamide group, respectively), FPG (P < 0·01 vs. baseline), PPG (P < 0·01 vs. baseline), and on HOMA index (P < 0·05 vs. baseline) in the nateglinide group. In the glibenclamide group, we found significant changes in HbA_1c (P < 0·05 vs. baseline), FPG (P < 0·01 vs. baseline), PPG (P < 0·05 vs. baseline), and HOMA index (P < 0·05 vs. baseline). No significant change was observed in TC, LDL‐C, HDL‐C, Tg, Apo A‐I, Apo B, SBP, DBP and HR in either group after 3, 6, 9 and 12 months. These effects of nateglinide and glibenclamide on insulin‐resistance parameters are in agreement with previous reports. Contrarily to previous reports, we did not observe any significant BP change in patients treated with glibenclamide. Although both nateglinide and glibenclamide attenuated PPG and HOMA index, they did not have significant effects on lipid metabolism, as already shown in subjects with type 2 diabetes and good glycemic control. Conclusion: Nateglinide improved glycemic control better than glibenclamide in combination with metformin.     

Withdrawal of inhaled steroids in children with non‐cystic fibrosis bronchiectasis

Background: To study the effects of inhaled steroid withdrawal on bronchial hyperreactivity, sputum inflammatory markers and neutrophilic apoptosis in children with non‐cystic fibrosis (non‐CF) bronchiectasis. Objectives: To evaluate the role of inhaled steroids in the treatment of children with non‐CF bronchiectasis with specific emphasis on the bronchial hyperreactivity and neutrophilic apoptosis. Methods: Twenty‐seven children with steady‐state non‐CF bronchiectasis were evaluated primarily with metacholine challenge tests and apoptotic neutrophil ratios in induced sputum and secondarily with symptom scores, pulmonary function tests and tumour necrosis factor‐alpha (TNF‐α), interleukin‐8 (IL‐8) levels and neutrophil ratios in induced sputum before and after 12‐week withdrawal of inhaled steroids. Results: There were 16 girls and 11 boys. Median (interquartile range) age was 11·4 (9·5–13·6) years, follow‐up duration was 3·5 (2–6·5) years. Symptom scores (4 vs. 3; P = 0·27), oxygen saturation (95% vs. 97%; P = 0·06), pulmonary function tests (FEV1: 82% predicted vs. 83% predicted; P = 0·73), sputum neutrophil ratios (29·9% vs. 46·8%; P = 0·20), TNF‐α (58 pg/mL vs. 44·5 pg/mL; P = 0·55) and IL‐8 (2·7 ng/mL vs. 2·4 ng/mL; P = 0·82) levels in induced sputum were similar before and after 12‐week withdrawal of inhaled steroids. However, the number of patients with bronchial hyperreactivity increased (37% vs. 63% of patients; P = 0·016) and neutrophilic apoptosis in induced sputum decreased (42·8% vs. 20·2%; P = 0·03) after withdrawal. Conclusion: In this study, 12 week‐withdrawal of inhaled steroid treatment resulted in a significant increase in bronchial hyperreactivity and decrease in neutrophil apoptosis, but no change in sputum inflammatory markers in children with non‐CF bronchiectasis was observed.     

Hyperproinsulinaemia in normoglycaemic lipodystrophic HIV-infected patients

Background We aimed to investigate whether the insulin precursors, intact (IP) and 32–33 split proinsulin (SP), which are elevated in states of insulin resistance and predict type 2 diabetes, would be elevated in human immunodeficiency virus (HIV)‐infected patients with lipodystrophy (LIPO). Materials and methods Forty‐three normoglycaemic HIV‐infected patients [18 LIPO and 18 without lipodystrophy (NONLIPO) receiving antiretroviral drugs, and seven patients naïve to antiretroviral drugs (NAÏVE)] were examined. Insulin precursors were measured during fasting, during an intravenous glucose tolerance test and during a hyperinsulinaemic–euglycaemic clamp, respectively. Insulin secretion rates (ISR) were determined by deconvolution of C‐peptide concentrations. Disposition index (DI) was calculated as insulin sensitivity (Si_RD) multiplied by the first‐phase insulin response to intravenous glucose. Results LIPO exhibited increased fasting IP and SP (P < 0·05), a higher proportion of elevated fasting IP (3·1 pmol L^?1, 66% vs. 33% and 28%, P < 0·05) and SP (7·2 pmol L^?1, 50%, 11% and 0%, P < 0·01), reduced Si_RD (> 50%, P < 0·001) and increased ISR (P < 0·001) compared with NONLIPO and NAÏVE. Fasting SP and IP correlated positively with ISR (P < 0·001) and inversely and hyperbolically with Si_RD (P < 0·001). Fasting SP/insulin ratio correlated inversely with Si_RD (P < 0·05). Incremental IP + SP/insulin ratio after an intravenous glucose bolus correlated inversely with DI (P < 0·01), but did not differ between study groups. Conclusions Proinsulin appeared to be increased in HIV‐lipodystrophy, but no more than caused by the increased ISR. Nevertheless, the inverse correlations between SP/insulin ratio versus Si_RD and incremental total proinsulin/insulin ratio versus DI may argue for a subtle β‐cell dysfunction in those patients with insulin resistance and low DI.     

Persistence of counter-regulatory abnormalities in insulin-dependent diabetes mellitus after pancreas transplantation

Abstract Conventional insulin therapy does not correct the counter-regulatory abnormalities of insulin-dependent diabetes mellitus. Pancreas transplantation is an alternative therapy that restores the endogenous insulin secretion in diabetes. In this study, the effects of segmental pancreas transplantation on counter-regulation to mild hypoglycaemia were evaluated. Glucose kinetics and the counter-regulatory hormonal responses were assessed in eight insulin-dependent diabetics with end-stage renal failure who had received pancreas and kidney transplantation 1 year previously, seven diabetic uraemic subjects (candidates for combined transplantation), five patients with chronic uveitis on immunosuppressive therapy comparable to pancreas recipients and 10 normal subjects. Insulin (0·3 mU kg^-1 min^-1) was infused for 2h to induce mild hypoglycaemia (plasma glucose 3·2–3·5-mmol l^-1) and exogenous glucose was infused as required to prevent any glucose decrease below 3·1 mmol l^-1. After transplantation, two of eight recipients had hypoglycaemic episodes reported in their medical records. During the study, hepatic glucose production was rapidly suppressed in the controls and in the patients on immunsuppression (–80 ± 7 and –54 ± 7%, P < 0·001 vs. basal), and rebounded to the baseline values within 1 h (–3 ± 1 and –6 ± 2%, P= NS vs. basal). The transplant recipients had similar suppression in the first hour (–88 ± 8%, P < 0·001 vs. basal), but the suppression persisted in the second hour (–69 ± 11%, P < 0·001 vs. basal) indicating a lack of glucose counter-regulatory response. The uraemic-diabetics had reduced suppression of hepatic glucose production (–45 ± 14%, P < 0·001 vs. basal) with respect to the recipients (P < 0·001), but had the same lack of response in the second hour (suppression: –39 ± 12%, P < 0·001 vs. basal). In addition, the response of glucagon to hypoglycaemia was blunted in both the recipients and in the diabetic subjects. In conclusion, the alterations in glucose counter-regulation of insulin-dependent diabetes persists after segmental pancreas transplantation. Specifically, the increased sensitivity of hepatic glucose production to the action of insulin renders this defect more evident after transplantation.     

In cirrhotic patients reduced muscle strength is unrelated to muscle capacity for ATP turnover suggesting a central limitation

Background and aims: We investigated whether in patients with liver cirrhosis reduced muscle strength is related to dysfunction of muscle mitochondria. Methods: The mitochondrial respiratory capacity of the tibial anterior muscle was evaluated in seven patients and eight healthy control subjects by ³¹P nuclear magnetic resonance spectroscopy (³¹PMRS) to express ATP turnover in vivo and by respirometry of permeabilized fibres from the same muscle to express the in vitro capacity for oxygen consumption. Results: Maximal voluntary contraction force for plantar extension was low in the patients (46% of the control value; P<0·05), but neither the capacity for mitochondrial ATP synthesis, V_max‐ATP (0·38 ± 0·26 vs. 0·50 ± 0·07 mM s^?1; P = 0·13) nor the in vitro VO_2max (0·52 ± 0·21 vs. 0·48 ± 0·21 μmol O₂ (min g wet wt.)^?1P = 0·25) were lowered correspondingly. Also, the activity of citrate synthesis and the respiratory chain complexes II and IV were similar in patients and controls. However during the contractions, the contribution to initial anaerobic ATP production from glycolysis relative to that from PCr was reduced in the patients (0·73 ± 0·22 vs. 0·99 ± 0·09; P<0·01). Conclusions: These results demonstrate that the markedly lower capacity for force generation in patients with liver cirrhosis is unrelated to their capacity for muscle ATP turnover, but the attenuated initial acceleration of anaerobic glycolysis suggests that these patients could be affected by a central limitation to force generation.     

Hypertension control, predictors for medication adherence and gender differences in older Chinese immigrants

Title. Hypertension control, predictors for medication adherence and gender differences in older Chinese immigrants Aim. This paper is a report of a study to explore the relationship between demographic and cultural factors and antihypertensive medication adherence in older Chinese immigrants. Background. Hypertension is a well‐known controllable risk factor for cardiovascular diseases worldwide, but only 20–80% of patients who take antihypertensive medications adhere adequately to their treatment regimen. Methods. A cross‐sectional study was conducted between 2002 and 2003, with a convenience sample of 75 older men and 69 older women (n = 144, response rate 80%). Medication adherence was defined as ≥80% of the total score on the Morisky scale. Findings. Age (75·2 ± 5·7 vs. 75·9 ± 7·0 years, P = 0·51) and length of stay in the United States of America (12·7 ± 6·4 vs. 12·7 ± 6·6 years, P = 0·97) were similar for men and women. More men were married (85% vs. 46%, P < 0·01). A smaller proportion of men were poor (39% vs. 65%, P < 0·01), believed in religion (49% vs. 70%, P = 0·01), and could speak no English (32% vs. 57%, P < 0·01). Fewer men used Chinese herbs to treat hypertension (4% vs.13%). Hypertension control was low for men and women (53% and 48%, P = 0·51). Adherence in men and women was 69% and 75% (P = 0·42) respectively. For men, shorter length of stay in the United States of America was negatively associated with non‐adherence (OR = 0·16; 95% CI: 0·05, 0·57). No association between length of stay and non‐adherence was found for women. Conclusion. More research, including gender‐specific studies, is needed to understand better how to develop an effective and culturally sensitive strategy to help older Chinese immigrants manage their hypertension.     

Serum sialic acid changes in type 2 diabetic patients on metformin or rosiglitazone treatment

What is known and objective: Serum sialic acid is a recently investigated potential risk‐marker for cardiovascular complications. There is a known association between sialic acid and cardiovascular complications in diabetes mellitus. We aimed to investigate the effect of antidiabetic drugs on the serum concentration of sialic acid. Methods: We investigated the effect of metformin and rosiglitazone on the concentration of sialic acid in 120 type 2 diabetic patients, divided into a group (n = 60) receiving metformin and a group (n = 60) receiving rosiglitazone treatment. Results: Serum sialic acid was significantly higher in patients on rosiglitazone (66·90 ±8·80 mg/dL vs. 57·6 ± 8·46 mg/dL, P <0·01) and metformin (61·95 ± 10·49 mg/dL vs. 57·6 ±8·46mg/dL, P < 0·04) when compared with control subjects. In addition, rosiglitazone‐treated patients showed a significant increase in cardiovascular risk factors, notably total cholesterol (246·45 ± 20·2 mg/dL vs. 170·6 ± 15·1 mg/dL, P =0·01), triglyceride (178 ± 9·20 mg/dL vs. 149·35 ±6·31 mg/dL, P < 0·04) and glycohemoglobin (HbA1‐c) concentration (8·17 ± 1·43% vs. 4·38 ±0·96%, P < 0·02) compared with normal control subjects. The patients on metformin also showed significantly higher levels of serum glucose (133·7 ± 9·63 mg/dL vs. 88·35 ± 6·31 mg/dL, P <0·04) and glycohemoglobin (HbA1‐c) (8·23 ±1·75% vs. 4·38 ± 0·96%, P < 0·02) when compared with control subjects. Comparison of the two groups of patients revealed a significantly higher serum sialic acid (66·90 ± 8·80 mg/dL vs. 61·95 ±10·49 mg/dL, P < 0·05), total cholesterol (246·45 ±20·2 mg/dL vs. 192 ± 14·23 mg/dL, P <0·02) and triglyceride (178 ± 9·20 mg/dL vs. 158 ± 14·51mg/dL, P < 0·05) concentrations in the rosiglitazone‐treated patients. What is new and conclusions: This study suggests significantly higher levels of serum sialic acid and other cardiovascular risk factors in rosiglitazone‐treated patients than in metformin‐treated patients. The lower sialic acid concentration may explain a better metformin antidiabetic effect than with rosiglitazone.     

A comparison of HIV positive and negative pregnant women at a public sector hospital in South Africa

Aim. The aim of the study was to compare HIV positive and negative pregnant women with respect to maternal and neonatal outcome to inform the development of clinical practice guidelines. Background. HIV infection in pregnancy places an added burden on the physical ability of the woman's body to cope with pregnancy. As a result HIV causes an exaggeration of the problems related to pregnancy. Method. Data were collected by means of a retrospective record review conducted on 212 stratified randomly selected HIV positive and 101 matched HIV negative pregnant women. The two sample t‐test and Fisher exact test were used to compare the maternal and neonatal outcomes of HIV positive and negative pregnant women. Results. HIV positive pregnant women had a significantly lower haemoglobin (10·85 vs. 11·48 g/dl; P = 0·001), attended significantly fewer antenatal clinic appointments (4·03 vs. 4·63; P = 0·04), weighed significantly less (72·07 vs. 76·69 kg; P = 0·02) and were significantly more likely to present with an abnormal vaginal discharge (32·55 vs. 24·75%; P = 0·02) than HIV negative pregnant women. The difference in the prevalence in HIV positive pregnant women of pregnancy induced hypertension (16·98 vs. 9·90%; P = 0·06), syphilis infection (5·95 vs. 0·99%; P = 0·062) and urinary tract infection (15·53 vs. 7·92%; P = 0·06) approached significance when compared with HIV negative pregnant women. HIV positive pregnant women were significantly more likely to present with intrauterine growth retardation (4·72 vs. 0%; P = 0·03), significantly more likely to deliver earlier (37·92 vs. 38·51 weeks; P = 0·03) and significantly more likely to deliver neonates weighing less (2969·98 vs. 3138·43 g; P = 0·01) than HIV negative pregnant women. Conclusion. The Department of Health attributes the high rate of HIV and AIDS related maternal morbidity and mortality in South Africa to the absence of accepted and practical guidelines for midwives’ antenatal assessment and management of HIV positive pregnant women. Relevance to clinical practice. This study identifies maternal and neonatal outcomes related to HIV infection in pregnancy and provides evidence required to inform the development of clinical practice guidelines.     

Myocardial perfusion defects in Bartter and Gitelman syndromes

Background Normotensive hypokalaemic tubulopathies (Bartter and Gitelman syndromes (BS/GS)) are genetic diseases that are considered benign. However, QT prolongation, left ventricular dysfunction and reduction of cardiac index upon exercise leading to arrhythmias and sudden cardiac death have been reported in these patients. Hence, we aimed to verifying whether an isometric exercise could represent a useful tool for the identification of patients at risk for future cardiac events. Patients and methods Myocardial function (MF) and perfusion, evaluated as myocardial blood flow (MBF) of 10 BS/GS patients and 10 healthy controls, were investigated at rest and during isometric exercise. MF and MBF were evaluated using quantitative two‐dimensional and myocardial contrast echocardiography. Results BS/GS patients had normal baseline MF and MBF. During exercise in BS/GS patients, corrected QT (QTc) was prolonged to peak value of 494 ± 9·1 ms (P < 0·001). In controls, MF increased from resting to peak exercise (left ventricular ejection fraction: 65 ± 4% to 78 ± 5%, P < 0·003) while in seven BS/GS patients (Group 1) it declined (64 ± 5% to 43 ± 9%, P < 0·001). Myocardial perfusion increased upon exercise in controls as shown by changes of its markers: β (a measure of myocardial flow velocity; 0·89 ± 0·12 vs. 0·99 ± 0·12, P < 0·001) and myocardial blood volume (14·4 ± 2 vs. 20·2 ± 0·25, P < 0·001), while in Group 1 BS/GS it decreased (0·87 ± 0·15 vs. 0·67 ± 0·15, P < 0·001; and 14·5 ± 1·9 vs. 8·3 ± 0·22, P < 0·001, respectively). Conclusions Our results document for the first time that exercise induce coronary microvascular and myocardial defects in BS/GS patients. Therefore, this may challenge the idea that BS/GS are benign diseases. In addition, the diagnostic approach to these syndromes should include an in‐depth cardiac assessment in order to identify patients at higher risk.     

Biliary proteins and their redox status changes in gallstone patients

Background Proteins might act as pronucleating agents of cholesterol crystallization in bile. However, little is known about the redox status of biliary proteins in humans and their interaction with crystallization of biliary cholesterol. Materials and methods Gallbladder biles were obtained at cholecystectomy from 86 symptomatic patients with either cholesterol gallstones (32 multiple and 32 solitary stones) or pigment stones (n = 22), and studied for protein redox status [carbonyl and sulfhydryl (PSH) concentrations], total lipid and protein levels and cholesterol saturation index (CSI). First appearance of cholesterol crystals in ultrafiltered bile (crystal observation time, COT) was studied with polarizing light microscopy during 21 days. Results Patients with cholesterol stones had significantly shorter COT (3 days vs. >21 days, P < 0·05), higher CSI (149 ± 10% vs. 97 ± 7%, P < 0·05) and higher total biliary proteins (1·96 ± 0·1 mg mL^?1 vs. 0·55 ± 0·1 mg mL^?1, P < 0·05) than patients with pigment stones. Patients with cholesterol stones had significantly lower (P < 0·05) level of protein sulfhydryl concentrations (18 ± 4 nmol mg^?1 protein vs. 49 ± 16 nmol mg^?1 protein), while total lipid and carbonyl proteins concentrations were similar between cholesterol and pigment stone patients. Crystallization probability was influenced by the number/type of gallstones (multiple > solitary > pigment stones, P = 0·009) and total protein concentration (high > low levels, P = 0·004). COT was negatively correlated with total protein content (r = ?0·45, P = 0·03). Conclusions Biles with cholesterol stones show high CSI and total protein concentration, and rapid COT, which is even faster in patients with multiple stones and high protein concentration. Low PSH levels in cholesterol stone patients point to a biochemical shift, potentially able to affect cholesterol crystallization.     

Na+/H+ antiporter activity in peripheral blood lymphocytes of obese and type 2 diabetic patients is increased only in the presence of arterial hypertension

Abstract. The aim of this work is to evaluate whether type 2 diabetes mellitus, obesity and arterial hypertension, three conditions characterized by the presence of insulin resistance, share some common genetic markers. A potential candidate is the Na⁺/H⁺ anti-porter, the increased activity of which is considered a marker of essential hypertension. This ion exchanger seems to be related to the Na⁺/Li⁺ countertransport, that is considered a marker of insulin resistance in essential hypertension and in type 1 diabetes mellitus. In this study we wished to clarify whether the activity of the Na⁺/H⁺ antiporter is increased not only in hypertensive subjects, but also in obese and type 2 diabetic patients, both in the presence and in the absence of arterial hypertension. The activity of the ion exchanger was measured in peripheral blood lymphocytes (PBL) by clamping intracellular pH (pH_i) at 5·8–6·2 and then detecting the rate of the proton efflux after sodium addition. In the absence of arterial hypertension, no significant difference in this parameter was observed in obese and type 2 diabetic patients in comparison with normal subjects. In the presence of arterial hypertension, there was a significant increase in the Na⁺-induced H⁺ efflux at the internal pH (pHi) values of 5·8 and 6·2 both in hypertensive controls and in hypertensive obese and type 2 diabetic patients (P= 0·05–0·0001 vs. normotensive subjects and patients). In particular, H⁺ efflux at pH 5·8 (mmol l^-1 min^-1) was 35·36 ± 2·48 in normotensive and 42·77 ± 1·63 in hypertensive control subjects (P= 0·045), 33·06 ± 1·88 in normotensive and 50·40 ± 5·21 in hypertensive obese patients (P= 0·009), 31·16 ± 1·84 in normotensive and 55·54 ± 5·83 in hypertensive type 2 diabetic patients (P= 0·0001). H⁺ efflux showed a significant correlation with both systolic (at pHi 5·8, r = 0·473, P= 0·001; at pHi 6·2, r = 0·357, P= 0·016) and diastolic blood pressure (at pHi 5·8, r = 0·600, P= 0·0001; at pHi 6·2, r = 0·555, P= 0·0001). Therefore, our study demonstrates that the hyperactivity of the Na⁺/H⁺ exchanger in peripheral blood lymphocytes is also a marker of arterial hypertension in obesity and in type 2 diabetes mellitus, and that the exchanger activity is not increased in these two conditions in the absence of arterial hypertension.     

Exercise increases insulin clearance in healthy man and insulin-dependent diabetes mellitus patients

Exercise is known to decrease insulin secretion, but the effect on insulin clearance is unclear. We examined the effect of exercise on insulin clearance with euglycaemic insulin clamp in 28 healthy men either 12 h after a marathon run (n=14) or 44 h after a 2-h treadmill exercise (n=14), and in seven insulin-dependent diabetes mellitus (IDDM) patients 12 h after a marathon run, and after a resting, control day. During the post-exercise insulin infusion, steady-state plasma insulin concentration was reduced by 9% in healthy men after both types of exercise, and by 16% in the diabetic subjects compared with the control study (P<0·05 in all). In healthy men, C-peptide concentrations were more than one-third lower during insulin infusion, both after the marathon run (P<0·001) or treadmill exercise (P<0·02) compared with the control study. Insulin clearance was significantly increased by exercise both in healthy men (9%, P<0·05) and in IDDM subjects (15%, P<0·05). After exercise, endogenous insulin secretion in healthy men is reduced and insulin clearance is enhanced both in healthy men and in IDDM patients. Decreased insulin availability may allow enhanced muscle lipid utilization and spare glucose after long-term exercise.     

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.     

Capecitabine for the treatment for advanced gastric cancer: efficacy, safety and ethnicity

What is known and Objective: Capecitabine‐ and 5‐fluorouracil (5‐FU)‐based regimens are widely used for the treatment for advanced gastric cancer (AGC). We aimed to compare the efficacy of the two regimens for both Caucasian and Asian subjects, through a meta‐analysis of the available trial evidence. Methods: We searched PubMed, ASO, ECCO, ESMO, Wanfang database (Chinese), CNKI (Chinese), Weipu database (Chinese) and J‐STAGE (Japanese) using combinations of keywords, including ‘capecitabine’, ‘5‐fluorouracil’, ‘chemotherapy’, ‘stomach neoplasms’ and ‘gastric cancer’. We identified relevant trial evidence and pooled the results on both efficacy and adverse events. Results and Discussion: Capecitabine‐based chemotherapy for AGC prolonged the overall survival (OS; 10·7 months vs. 9·5 months, P = 0·03) and enhanced the response rate (RR; OR = 1·32; 95% CI, 1·11–1·57; P = 0·002) over 5‐FU‐based chemotherapy. Similar trends were observed in both Caucasian and Asian patients. Capecitabine‐based regimens were associated with reduced incidence rates of grade 3 or grade 4 leukopenia (OR = 0·42; P = 0·005), stomatitis (OR = 0·43; P = 0·004) and nausea and vomiting (OR = 0·60; P = 0·002) compared with 5‐FU‐based treatment. Incidence of haematological toxicity such as anaemia (OR = 0·88; P = 0·53), thrombocytopenia (OR = 0·58; P = 0·06), neutropenia (OR = 1·03; P = 0·78) and treatment‐related mortality was similar between capecitabine‐ and 5‐FU‐based treatments. Higher frequency of grade 3 or grade 4 hand‐foot syndrome (HFS; OR = 2·45; P = 0·0007) was observed in capecitabine‐based combination therapies. Asian patients with AGC receiving capecitabine‐based combination therapies showed less frequent occurrence of grade 3 or grade 4 gastrointestinal toxicity including nausea and vomiting (OR = 0·24; P = 0·0002) and stomatitis (OR = 0·33; P = 0·02) than those receiving 5‐FU‐based regimens. These differences in GI toxicity between treatment regimens were not significant in Caucasian subjects. No significant difference was found for the occurrence of anaemia (Caucasian subgroup: OR = 0·97, P = 0·88; Asian subgroup: OR = 0·63, P = 0·29), neutropenia (Caucasian subgroup: OR = 1·16, P = 0·27; Asian subgroup: OR = 0·75, P = 0·21) or thrombocytopenia (Caucasian subgroup: OR = 0·62, P = 0·18; Asian subgroup: OR = 0·51, P = 0·17) between the two ethnic subgroups. What is new and Conclusion: Capecitabine‐based chemotherapy strategies show prolonged OS and enhanced ORR compared with traditional 5‐FU‐based treatments and therefore should be considered as one of the first choices for treatment for AGC. Asian patients also showed less grade 3 or grade 4 gastrointestinal toxicity with the capecitabine‐based regimens.     

Control of modifiable risk factors in ischemic stroke outpatients by pharmacist intervention: an equal allocation stratified randomized study

Objective: To evaluate the adequacy of management of modifiable risk factors (MRF) in a group of ischemic stroke outpatients and the value of pharmacist intervention in a randomized controlled study in a tertiary referral hospital. Methods: 160 ischemic stroke outpatients from the same catchment area and with the same financial arrangements for healthcare, went through a 6‐month equal allocation stratified randomized study. Routine practice was not altered except for a monthly 1‐hour pharmacist‐intervention education programme. We evaluated the differences in blood pressure (BP), blood glucose and lipid profiles before and after study. The proportion of patients with adequate management of MRF was studied. Results: There were no differences in the demographic characteristics, MRF and medications prescribed throughout the study. Before the study, the proportions of adequate control of BP in the control and intervention groups were 43% vs. 40% (P = 0·64), lipid 27% vs. 13% (P = 0·09) and glucose 36% vs. 21% (P = 0·15) . At the end of the study, the corresponding proportions were for BP 43% vs. 83% (P = 0·00), lipid 27% vs. 40% (P = 0·16) and glucose 46% vs. 35% (P = 0·40). Conclusion: Pharmacist intervention was associated with improved BP control but not with the other MRF. Earlier initiation and longer duration of intervention may improve the outcome further, and whether targeting of high‐risk subjects may be particularly rewarding is worthy of investigation.     

Retinopathy in type 2 diabetes mellitus is associated with increased intima‐media thickness and endothelial dysfunction

Background Microangioathy and macroangiopathy in type 2 diabetes mellitus (T2DM) frequently coexist. Both types of vascular complications share traditional risk factors. It is not clear whether the presence of microangiopathy, such as diabetic retinopathy (DR), constitutes a predictor of atherosclerosis in T2DM. Here we described the search for the association between DR and intima‐media thickness (IMT) in T2DM. We also compared endothelial function in subjects with and without DR. Material and methods We examined 182 consecutive patients with T2DM for at least 5 years (mean age at examination 56·3 ± 6·52 years). We assessed (i) IMT of carotid artery by ultrasound and (ii) endothelial function by flow‐mediated dilatation (FMD) method as well as by measurement of concentrations of von Willebrand factor (vWF) and s‐ICAM‐1. All patients underwent ophthalmological examination. Statistical analysis included Student's, Mann–Whitney, chi‐square, Fisher tests and multiple regression. Results DR was found in 71 (39·0%) subjects. IMT was higher in patients with DR than those without DR (0·87 mm vs. 0·79 mm, respectively, P = 0·0001). FMD was lower in the complication group than in subjects without DR (8·38% vs. 10·45%, respectively, P = 0·0023). Concentrations of s‐ICAM‐1 and vWF were not different between the groups. In multiple regression analysis, DR was among the predictors of increased IMT (P = 0·016) and decreased FMD (P = 0·002). We did not find a significant association of DR with vWF and s‐ICAM‐1 (P = 0·09 and P = 0·11, respectively). Conclusions DR is associated with increased IMT and endothelial dysfunction in T2DM. Impaired endothelial function may be a common denominator of pathogenesis of microvascular complications and atherosclerosis in T2DM.     

Effects of physical exercise on insulin absorption in insulin-dependent diabetics. A comparison between human and porcine insulin

Summary. Nine insulin-dependent diabetics with undetectable plasma C-peptide (<0·05 nmol 1^-1) and without insulin antibodies (insulin binding to IgG<0·05 Ul^-1) received subcutaneous injections of 10 U ¹²⁵I-labelled soluble human or porcine insulin in the thigh on 2 consecutive days. Disappearance rates of ¹²⁵I were monitored continuously by external counting and plasma insulin levels were determined during rest for 30 min, bicycle exercise of moderate intensity for 40 min, and 60 min recovery. Subcutaneous blood flow was measured concomitantly in the contralateral thigh by the ¹³³Xenon clearance technique. During the initial period of rest human insulin was absorbed approximately 40% faster than its porcine analogue (first order rate constants 0·37±0·06 vs 0·27±0·06% min^-1, P<0·05) and the increment of the area under the plasma insulin curve was greater after hum-ii than after porcine insulin (184±46 vs 112±42 mUl^-1 min, P<0·05). Exercise enhanced the absorption rates for both ¹²⁵I-insulins to 0·50±0·06 and 0·48±0·10% min^-1 for human and porcine insulin, respectively (P<0·05). This increase was less pronounced for human compared to porcine insulin (49±19 vs 105±40%, P=0·06). During exercise plasma insulin rose to 37±5 mUl^-1 after human and 30±5 mUl^-1 after porcine insulin and the areas under the plasma insulin curves were similar. During the recovery phase the absorption rates decreased slightly compared to the exercise value for both insulins. The blood glucose lowering effect was similar for the two insulins. Subcutaneous blood flow was not significantly altered by exercise in either group. It is concluded that during rest human soluble insulin is more rapidly absorbed than porcine insulin. Physical exercise tends to increase porcine insulin absorption more and eliminates the basal difference in the absorption kinetics between human and porcine insulin. The increased insulin absorption during exercise is not coupled to corresponding changes in the subcutaneous blood flow.     

Improvement of glycaemic control by nateglinide decreases systolic blood pressure in drug-naive patients with type 2 diabetes

Background It has been speculated that oral hypoglycaemic agents that block K‐ATP channels could potentially increase blood pressure by blocking such channels in vascular myocytes. No information about this issue exists regarding nateglinide. Design A multicentre, double‐blind, placebo‐controlled, randomized trial was conducted in 109 drug‐naive 30‐ to 75‐year‐old patients with type 2 diabetes and < 5 years of diabetes diagnosis, who are not taking antihypertensive drugs. These patients were assigned to receive placebo or fixed doses of nateglinide (120 mg before each main meal: breakfast, lunch and dinner) and evaluated at weeks 0 and 12 for (i) body mass index and blood pressure; (ii) standard laboratory tests, including haemoglobin A1c (HbA1c) and fasting plasma glucose; and (iii) incremental area under the curve for glucose and C‐peptide after a standardized liquid breakfast challenge, homeostasis model assessment (HOMA)‐B% (as surrogate of β‐cell activity) and HOMA‐S% (as surrogate of insulin sensitivity). Results At the end of the follow‐up period, patients in the nateglinide group (n = 55), compared to patients in the placebo group (n = 54), showed lower values of HbA1c (6·7 ± 0·6 vs. 7·2 ± 0·7%, respectively; P < 0·001), fasting plasma glucose (7·9 ± 2·1 vs. 8·5 ± 2·0 mmol L^?1; P = 0·023) and systolic blood pressure (125·3 ± 15·4 vs. 129·3 ± 18·7 mmHg; P = 0·015), and higher values of HOMA‐B%[75·7 (51·8–99·4) vs. 57·7 (42·2–83·4); P = 0·033]. A positive correlation was found between changes in HbA1c and systolic blood pressure in the nateglinide group (r = 0·355, P = 0·011). Conclusions In drug‐naive patients with type 2 diabetes, the improvement in glycaemic control with nateglinide is associated with a decrease in systolic blood pressure.     

Acute dexfenfluramine administration normalizes glucose tolerance in rats with insulin-deficient diabetes

Abstract. Dexfenfluramine has been shown to lower blood glucose concentrations independently of its effects in reducing food intake and body weight, in human and animal syndromes of non-insulin dependent diabetes. This study aimed to determine whether dexfenfluramine could also reduce glycaemia in rats with severe insulin-deficient diabetes induced by the β-cell toxin, streptozotocin (55 mg kg^-1). Three weeks after diabetes induction, nine groups (each n= 10) of diabetic and non-diabetic rats underwent oral glucose tolerance tests (1 g kg^-1, by gavage). These tests were preceded by 12–18 h of fasting to remove the confounding effects of hyperphagia in diabetic rats, and to stabilize glycaemia. Dexfenfluramine (1·0 mg kg^-1), given 2 h before the glucose challenge, significantly reduced basal glycaemia and decreased the post-challenge glycaemic rise (P<0·01 vs. untreated diabetics). Dexfenfluramine dosages of 2·5 and 5·0 mg kg^-1 both further flattened the post-challenge glycaemic profiles (both P<0·01 vs. untreated diabetics) and achieved levels that did not differ significantly from those in non-diabetics (both P> 0·05). Subsequently, the studies using dexfenfluramine dosages of 2·5 and 5·0 mg kg^-1 were repeated to determine whether the drug affected plasma insulin levels 2 h after dosing. In diabetic rats, plasma insulin concentrations were reduced to 10–20% of non-diabetic values, and were not significantly altered by dexfenfluramine. Acute dexfenfluramine administration therefore improves and (at dosages of 2·5 and 5·0 mg kg^-1) essentially normalizes glucose tolerance in rats with severe insulin-deficient diabetes. As circulating insulin concentrations were not increased, dexfenfluramine probably acts by enhancing and/or mimicking insulin action. The magnitude of this effect suggests that dexfenfluramine could find application as adjunctive treatment in the management of human insulin-dependent diabetic patients with insulin insensitivity, such as that associated with obesity.