Effect of Bisoprolol and Atenolol on Left Ventricular Mass in Patients with Essential Hypertension

A new beta-blocker, bisoprolol, was compared to atenolol for antihypertensive efficacy and ability to cause regression of left ventricular mass. Twenty-eight patients were randomized into this 8-week, double-blind, dose-escalating trial. Echocardiography was performed in 18 of these patients at baseline and after 8 weeks of therapy to determine left ventricular (LV) mass indices. Both drugs caused a reduction in blood pressure, although bisoprolol caused a significantly greater reduction than did atenolol in diastolic pressure (p < 0.05) and a trend toward a greater reduction in systolic pressure (p < 0.096) as measured by cuff. Comparisons showed a significantly greater reduction in mean LV mass indices with bisoprolol than with atenolol (p < 0.05). A new beta-blocker, bisoprolol, was compared to atenolol for antihypertensive efficacy and ability to cause regression of left ventricular mass. Twenty-eight patients were randomized into this 8-week, double-blind, dose-escalating trial. Echocardiography was performed in 18 of these patients (bisoprolol treated = 8, atenolol treated = 10) at baseline and after 8 weeks of therapy to determine left ventricular (LV) mass indices. Both drugs caused a reduction in blood pressure, although bisoprolol caused a significantly greater reduction than did atenolol in diastolic pressure (p < 0.05) and a trend toward a greater reduction in systolic pressure (p < 0.096) as measured by cuff (bisoprolol means: 152.6 plus minus 9.7/102.8 plus minus 2.8 to 134.0 plus minus 10.0/84.4 plus minus 5.6 mm Hg; atenolol means: 158.4 plus minus 13.8/101.4 plus minus 3.5 to 148.0 plus minus 21.4/91.4 plus minus 5.9 mm Hg). Ambulatory blood pressure monitoring results suggested bisoprolol had longer effectiveness at lowering systolic pressure than did atenol. Comparisons showed a significantly greater reduction in mean LV mass indices with bisoprolol (from 110.0 plus minus 212.3 to 101.8 plus minus 22.0 g m(minus sign2)) than with atenolol (116.9 plus minus 25.5 to 121.7 plus minus 22.2 g m(minus sign2)) (p < 0.05). Bisoprolol was safe and efficacious in blood pressure control and significantly better than atenolol in reducing LV mass.     

The Determinants of Early Nephropathy in Insulin-dependent Diabetes Mellitus: A Prospective Study Based on the Urinary Excretion of Albumin

A four-year prospective study of the factors predicting albuminuriawas carried out in 172 normotensive, insulin-dependent diabeticpatients without overt nephropathy. Urinary albumin excretionwas estimated as the urinary albumin:creatinine ratio (U_A/U_C)in an early morning sample. Multivariate analysis showed thatU_A/U_C on the return visit was positively associated with theU_A/U_C (p<0.001) and glycosylated haemoglobin (HbA₁; p<0.001) at initial examination; weaker associations were foundwith a history of hospital admission (p<0.05) and smoking(p<0.05), and with treatment of blood pressure (p<0.05).Neither initial blood pressure, heart rate, nor creatinine clearancewere significant predictors of the U_A/U_C. Two patients diedfrom coronary heart disease, both of whom had raised albuminexcretion at initial examination. Eleven (6.8 per cent) of the160 patients who were studied repeatedly developed macroalbuminuria(U_A/U_C >45.5 mg/mmol): they had a significantly higher initialU_A/U_C (p<0.005), HbA₁ (p<0.05) and a greater frequencyof retinopathy (p<0.05) than patients matched for age, sexand duration of diabetes who did not develop macroalbuminuria.Simultaneous measurements of the U_A/U_C and HbA₁ should be usedwhen screening for microalbuminuria in diabetets mellitus: patientswith a high U_A/U_C(e.g. >3.5 mg/mmol) and HbA₁ (e.g. >13 per cent) should be closely monitored even when blood pressureis normal.     

A comparison of the beta1-selectivity of three beta1-selective beta-blockers

OBJECTIVE: To determine the relative beta1-selectivity of three beta-blockers (nebivolol, bisoprolol and atenolol), administered orally at normal therapeutic doses, by assessing their impact on the beta2-mediated, haemodynamic and biochemical responses to a terbutaline infusion, which decreases serum potassium and increases serum glucose and insulin. METHODS: Twenty-four healthy volunteers (14 men, 10 women), with no history of respiratory disease, attended on five separate occasions; beta-blockers (nebivolol 5 mg, bisoprolol 10 mg, atenolol 50 and 100 mg) or placebo were supplied in random order. Three baseline blood samples were collected at 65-85 min post-beta-blocker. A 60-min terbutaline infusion was started 90 min after taking the beta-blocker. Blood samples were taken and blood pressure and heart rate recorded at 15 min intervals up to 30-min post-infusion. Blood samples were analysed for serum potassium, glucose and insulin concentrations. RESULTS: Terbutaline increased heart rate. Pretreatment with nebivolol caused a modest and non-significant reduction in terbutaline-induced tachycardia whilst bisoprolol produced a more marked effect. Atenolol at both 50 and 100 mg doses caused a highly significant reduction in terbutaline-induced tachycardia. All active preparations had a comparable impact on the terbutaline-induced increase in systolic blood pressure, but the drugs had no impact on the changes produced in diastolic blood pressure. After pretreatment with placebo, the terbutaline infusion caused a significant decrease in serum potassium and increases in serum glucose and insulin. Pretreatment with nebivolol had no discernible effect on potassium compared with placebo. In contrast, when compared with either placebo or nebivolol, bisoprolol (P < 0.01) and both doses of atenolol (P < 0.001) significantly attenuated the hypokalaemic effect of terbutaline. Treatment with nebivolol and bisoprolol modestly but significantly reduced the terbutaline-induced increases in glucose (P < 0.05). The blocking effects of both doses of atenolol were highly significant (P < 0.001) when compared with placebo and also significant (P < 0.05 and P < 0.01, respectively) when compared with nebivolol and bisoprolol. A similar pattern of responses with the different beta-blocker treatments was observed for the effects on insulin concentrations during the terbutaline infusion. CONCLUSION: The beta1-selectivity of three different beta1-blockers has been demonstrated in healthy volunteers using the blocking of biochemical and haemodynamic responses to a beta2 stimulus. Terbutaline alone caused an increase in heart rate, a rise in systolic blood pressure, a fall in serum potassium and a rise in both serum glucose and insulin. In this study, for both haemodynamic and biochemical responses, atenolol 100 mg had the greatest beta2-blocking effect, nebivolol 5 mg the least. Bisoprolol 10 mg and atenolol 50 mg had intermediate effects; bisoprolol was the more beta1-selective of these two.     

拉西地平联合比索洛尔治疗老年高血压的疗效观察

目的观察拉西地平与比索洛尔联合治疗老年高血压的临床疗效。方法用药前停服其他任何降压药物1周,给予口服拉西地平4mg,1次/日,比索洛尔5mg,1次/日。两种药物根据血压情况可调整剂量至:拉西地平8毫克/日,比索洛尔10毫克/日,口服,直至血压降至正常。用药时间均连续4周。结果治疗后收缩压(140.1±12.6)mm Hg、舒张压(91.2±5.4)mm Hg、心率(63.2±5.7)次/分与治疗前(163.3±18.7)mm Hg、(108.2±7.6)mm Hg、(74.3±8.3)次/分比较差异有统计学意义(P<0.01);空腹血葡萄糖、胆固醇、三酰甘油、低密度脂蛋白胆固醇、丙氨酸氨基转移酶、血清肌酐治疗后与治疗前比较差异无统计学意义(P>0.05)。结论拉西地平与比索洛尔联合应用治疗老年高血压,在控制收缩压、舒张压、心率方面能发挥各自优势,起到协同作用。     

A STUDY TO INVESTIGATE THE COMPARATIVE EFFICACY AND TOLERABILITY OF NISOLDIPINE COAT-CORE AND ATENOLOL IN THE TREATMENT OF MILD TO MODERATE HYPERTENSION

SUMMARY The efficacy and tolerability of nisoldipine coat-core (nisoldipine CC 10, 20, 40 mg) and atenolol (50, 100 mg) were compared in 230 patients with mild to moderate essential hypertension. Treatment was titrated at two-weekly intervals as necessary to control blood pressure. After eight weeks of active therapy, the two treatments proved to be equally effective in reducing sitting diastolic blood pressure (13.7 ± 8.3 mmHg and 14.2 ± 9.1 mmHg for nisoldipine CC and atenolol, respectively), and provided equivalent reduction in systolic blood pressure and identical response rates (69%). Heart rate was reduced from baseline in the atenolol group but remained unchanged in the nisoldipine CC group (p < 0.001 difference between the two groups). Both nisoldipine CC and atenolol were well tolerated and had no detectable metabolic effects. Adverse events were minor and of the type commonly associated with drugs of these classes.     

Safety and efficacy of increasing wintertime vitamin D and calcium intake by milk fortification

We studied the safety and efficacy of milk fortified with vitaminD₃ and calcium. Over the winter, we conducted a double-blind,placebo-controlled trial of fortified milk (12µg vitaminD₃ and 1525 mg calcium per litre) compared to unfortified milk(0.3µg vitamin D₃ and 1270 mg calcium per litre) in 102adults (aged 17–54 years). Serum 25-hydroxyvitamin D [25(OH)D],ionized calcium, and creatinine were measured at baseline andafter intervention. Fortification reduced the seasonal declinein serum 25(OH)D concentrations by >50%. In the fortifiedgroup, serum 25(OH)D decreased by 15nmol/l from 77±35nmol/l to 62±26 nmol/l (p<0.001). In the control group,serum 25(OH)D fell by 31 nmol/l from 85±39 nmol/l to54±25 nmol/l (p<0.001). We suggest that milk enrichedwith vitamin D be provided in high-latitude European countriesto diminish the wintertime fall in serum 25(OH)D.     

Atenolol and amiodarone: a comparative study of their anti-ischaemic effect

A total of 10 patients with mixed angina were entered into a study to compare the anti-ischaemic efficacy of atenolol and amiodarone. The study was divided into three parts: (a) placebo for 2 weeks; (b) 100 mg atenolol given for 8 weeks; and (c) amiodarone given for 8 weeks, divided into week 1, 200 mg three times daily; week 2, 200 mg twice daily; weeks 3 and 4, 200 mg once daily; weeks 5-8, 200 mg once daily for 5 days a week. Clinical examination, basal and multi-stage effort electrocardiograms were performed at the end of each treatment. The number of anginal attacks and the amount of trinitrin taken by the patients were significantly reduced by both drugs with no significant difference between them. Compared with placebo, both drugs induced a significant increase in work capacity and in the time to decrease the ST-segment by 1 mm. At rest, atenolol reduced systolic blood pressure, heart rate and the systolic blood pressure--heart rate product compared with placebo. Systolic blood pressure was also reduced significantly compared with patients given amiodarone. Amiodarone did not influence these parameters. At maximum effort, amiodarone reduced heart rate and the systolic blood pressure--heart rate product compared with placebo. This reduction was greater for atenolol. The ST-segment depression was comparable between patients given either test drug. Amiodarone, therefore, exerts an anti-ischaemic effect similar to that shown by atenolol with different haemodynamics: atenolol reducing myocardial oxygen demand, amiodarone having an additive increase of coronary flow. Such an effect was obtained with a lower dose of amiodarone than is commonly used.     

Blood pressure control and weight loss in overweight or obese patients with previously treated or untreated mild to moderate hypertension given valsartan: An open-label study comparing pretreatment and posttreatment values

Background: Hypertension is associated with obesity. Recent studies have indicated that therapy with an angiotensin II antagonist, in addition to having an antihypertensive effect, may cause a reduction in body weight.Objective: The aim of this study was to assess the efficacy and tolerability of valsartan in the treatment of overweight or obese patients with mild to moderate essential hypertension.Methods: Overweight or obese outpatients aged 18 to <70 years with previously treated or untreated mild to moderate essential hypertension were eligible for this open-label study conducted at the Department of Internal Medicine and Aging, Clinica Medica II, Policlinico S. Orsola-Malpighi (Bologna, Italy). After a 1-week pharmacologic washout period, patients were treated with valsartan capsules at a fixed dosage of 80 mg once daily for 8 weeks. The dosage was increased to 160 mg once daily if, at 8 weeks, diastolic blood pressure (DBP) was not normalized; otherwise, the 80-mg/d dosage was maintained. Treatment was continued for an additional 16 weeks. Patients' heart rate, systolic blood pressure (SBP) and DBP, body mass index (BMI), and waist-hip ratio (WHR) were measured/calculated at baseline (week 0) and 8, 16, and 24 weeks. Patients were asked to maintain a 1600-kcal/d diet throughout the study.Results: Forty-eight patients (28 men, 20 women; mean [SD] age, 57 [9] years) were included in the study. In the 45 patients (93.8%) who completed the study, mean SBP, DBP, and BMI were significantly decreased compared with baseline (all P < 0.001), but WHR was significantly increased (P < 0.05). After 24 weeks of treatment, 71.1 % of patients had SBP/DBP ≤ 140/≤90 mm Hg. Three patients (6.3%) withdrew from the study due to treatment-related adverse events.Conclusion: In this population of overweight or obese patients with mild to moderate hypertension, valsartan was well tolerated, and could be effective in controlling blood pressure and achieving weight loss in such patients.     

Evaluation of the Efficacy and Tolerability of Fixed-Dose Combination Therapy of Azilsartan and Amlodipine Besylate in Japanese Patients With Grade I to II Essential Hypertension

Background

Guidelines for the management of hypertension recommend using drugs with different mechanisms of action in antihypertensive regimens that include simple single-pill fixed-dose combination (FDC) products.

Objective

The objective of this study was to compare the efficacy and tolerability of the FDC of azilsartan (AZI) and amlodipine besylate (AML) with those of AZI monotherapy and AML monotherapy in Japanese patients with grade 1 to 2 essential hypertension.

Methods

This was a multicenter, randomized, double-blind, parallel-group study. After receiving placebo during a 4-week run-in period in a single-blind manner, patients were randomized to receive 1 of the following 5 treatments for 8 weeks: FDC containing AZI 20 mg and AML 5 mg (AZI/AML 20/5 mg), FDC containing AZI 20 mg and AML 2.5 mg (AZI/AML 20/2.5 mg), AZI 20 mg, AML 5 mg, or AML 2.5 mg once daily in a fasting or fed state. The primary end point was the change from baseline (week 0) in the seated trough diastolic blood pressure at week 8 (last observation carried forward [LOCF]), and the secondary end point was the change from baseline in the seated trough systolic blood pressure at week 8 (LOCF). Tolerability was assessed based on adverse events, vital signs, and physical examination findings.

Results

Of the 800 patients who provided informed consent, 603 were randomized to receive AZI/AML 20/5 mg (150 patients), AZI/AML 20/2.5 mg (151 patients), AZI 20 mg (151 patients), AML 5 mg (75 patients), or AML 2.5 mg (76 patients). The mean baseline systolic/diastolic blood pressure was 160.7/100.3 mm Hg. The mean change from baseline in seated blood pressure at week 8 (LOCF) was −35.3/−22.3 mm Hg in the AZI/AML 20/5 mg group and −31.4/−19.2 mm Hg in the AZI/AML 20/2.5 mg group, indicating a reduction significantly greater than that in corresponding monotherapy groups (−21.5/−13.9 mm Hg in the AZI 20 mg group, −26.4/−15.5 mm Hg in the AML 5 mg group, and −19.3/−11.6 mm Hg in the AML 2.5 mg group; p < 0.0001 for all contrast tests). No remarkable difference was found in the incidences of adverse events, vital signs, and physical examination findings among the treatment groups.

Conclusion

This study found that the FDC of AZI/AML 20/5 mg and 20/2.5 mg exhibited greater antihypertensive effects compared with each monotherapy. The FDC of AZI/AML had a similar safety profile to that of each monotherapy and was tolerable to Japanese patients with grade 1 to 2 essential hypertension.

Japan Pharmaceutical Information Center registration

Japic CTI-111606.     

Effects of the fixed combination of manidipine plus delapril in the treatment of hypertension inadequately controlled by monotherapy with either component: a phase III, multicenter, open-label, clinical trial

Background: Failure to achieve good blood pressure (BP) control is probably the most important reason for high rates of morbidity and mortality in patients with hypertension. Combination therapy has been shown to increase the percentage of patients in whom BP control is achieved. One combination is a calcium channel blocker (CCB) and an angiotensin-converting enzyme inhibitor (ACE-I).Objective: The aim of this study was to assess the effects of the fixed combination of the CCB manidipine and the ACE-I delapril in the treatment of hypertensive patients already given monotherapy with either component but with poor results (ie, insufficient BP control or adverse events [AEs]).Methods: In this Phase III, multicenter, open-label, clinical trial, patients with mild to moderate hypertension were assigned to 1 of 2 groups. Group 1 comprised patients whose diastolic BP (DBP) was >90 mm Hg or who experienced AEs with manidipine 20 mg once daily. Group 2 comprised patients who had a DBP >90 mm Hg or who experienced AEs with delapril 30 mg BID. In both groups, patients aged <65 years were to be treated with a fixed combination of manidipine 10 mg plus delapril 30 mg once daily for 12 weeks, whereas patients aged ≥65 years were to be treated with manidipine 5 mg plus delapril 15 mg once daily for 2 weeks and then manidipine 10 mg plus delapril 30 mg once daily for 10 weeks. Patients were assessed at baseline and at 2, 4, 8, and 12 weeks of treatment. At each visit, systolic blood pressure (SBP), DBP, and heart rate were measured 24 hours after dosing, and AEs were recorded.Results: Group 1 included 154 patients (80 men, 74 women; mean [SD] age, 55 [6] years); group 2 included 158 patients (79 men, 79 women; mean [SD] age, 56 [5] years). Mean BP decreased significantly in both groups (P<0.01). Compared with baseline values, mean SBP/DBP decreased 16.2 (3.8)/10.1 (1.9) mm Hg in group 1 and 15.8 (3.1)/11.0 (1.5) mm Hg in group 2 at the last visit. The success rate—rate of normalized DBP (≤90 mm Hg) and responder rate (DBP reduction ≥10 mm Hg)—was 79% in group 1 and 82% in group 2. The rates of treatment-related AEs were 11% in group 1 and 8% in group 2. In group 1, heart rate significantly increased from baseline only at 2 weeks (P<0.05); in group 2, at each visit (P<0.05) except at week 12. However, none of these differences were clinically significant.Conclusion: In this study population of patients whose BP was not adequately controlled by monotherapy, the fixed combination of manidipine 10 mg plus delapril 30 mg, once daily, was effective and well tolerated.     

Low-dose Cyclopenthiazide in the Treatment of Hypertension: A One-year Community-based Study

After an 8-week placebo period, 73 patients whose diastolicblood pressures were between 90 and 110 mmHg were randomly assignedto receive 125 µg (low dose) or 500 µg of cyclopenthiazide(standard dose) for a period of one year. Blood pressure wasmeasured in the patient's home by the same observer at two-weeklyintervals during an 8-week placebo run-in period, every 4 weeksfor a further 12 weeks and at 24, 36 and 52 weeks thereafter.Serum potassium, urate, glucose, glycosylated haemoglobin, totaland HDL cholesterol, and apolipoproteins were measured at theend of the placebo period and at 4, 8, 24 and 52 weeks of activetreatment. Twelve of the 73 patients had an inadequate antihypertensiveresponse—five on the higher dose and seven on the lowerdose. One patient receiving 500 µg was withdrawn becauseof adverse effects. In the remaining 60 patients, systolic anddiastolic blood pressures were significantly reduced when comparedwith pretreatment values in both treatment groups throughoutthe one year period. The decreases in blood pressure were notsignificantly different from each other (p>0.65). Three patientson 500 µg required potassium supplements. Maximum decreasesin the serum potassium of 0.52 mmol/l(500 µg dose) and0.14 mmol/l(125 µg dose) were observed at 24 weeks oftreatment in the remaining 57 patients. The differences betweenthe two doses at this time were statistically significant (p< 0·05), as were the increases in serum urate observedat 4, 8 and 24 weeks (p<0.05). Five hundred micrograms ofcyclopenthiazide increased total serum cholesterol at eightand 24 weeks (0.35, 0.36 mmol/l respectively) when comparedwith pretreatment values (p<0.01) and almost achieved statisticalsignificance when compared with the corresponding low dose value(p = 0.066). This study confirms that 125 µg of cyclopenthiazideis a useful antihypertensive agent with a favourable metabolicprofile which is maintained in the long term.     

Low-dose combination treatment for hypertension versus single-drug treatment-bisoprolol/hydrochlorothiazide versus amlodipine, enalapril, and placebo: combined analysis of comparative studies

To assess the efficacy and safety of 2.5, 5, and 10 mg bisoprolol/6. 25 mg hydrochlorothiazide (HCTZ), 2.5, 5, and 10 mg amlodipine; and 5, 10, 20, and 40 mg enalapril in subjects (n = 541) with a sitting diastolic blood pressure of 95 to 114 mm Hg, data from two comparative studies were pooled. All drugs were titrated to a diastolic blood pressure 90 mm Hg or less. Both studies were double-blind, randomized, parallel dose escalation trials with similar designs and included three active treatments. The second study also had a placebo group. The mean change from baseline of systolic and diastolic blood pressure for placebo (n = 79) was -0. 1/-2.2 mm Hg; amlodipine (n = 154), -12.4/-10.3 mm Hg; enalapril (n = 155), -9.4/-8.2 mm Hg; and bisoprolol/HCTZ (n = 155), -14.0/-12.0. Overall efficacy analyses documented a statistically significant decrease in sitting diastolic blood pressure for bisoprolol/6.25 mg HCTZ compared with placebo, amlodipine, and enalapril. There was a significant reduction in sitting systolic blood pressure for bisoprolol/6.25 mg HCTZ compared with placebo and enalapril but not amlodipine. Also, there was a significant decrease in sitting heart rate for bisoprolol/6.25 mg HCTZ (-6.2 beats/min) compared with placebo (+0.1 beats/min), amlodipine (+1.2 beats/min), and enalapril (+0.5 beats/min). The control rate (diastolic blood pressure < or = 90 mm Hg) for bisoprolol/6.25 mg HCTZ (66.5%) was significantly better than for placebo (21.8%) and enalapril (47.1%) but not amlodipine (58.4%). Of those patients achieving and maintaining control, 49% of the bisoprolol/6.25 mg HCTZ subjects were on the lowest two doses compared with 30% of the amlodipine and 26% of the enalapril subjects. Percentages of patients reporting at least one drug-related adverse event through week 12 were 27%, 24%, 28%, and 25% for placebo, bisoprolol/6.25 mg HCTZ, amlodipine, and enalapril (not significant). Lower doses of two drugs in fixed combination can provide as good or better blood pressure control compared with higher doses of a single drug with similar tolerability and safety.     

Irbesartan monotherapy in systemic hypertension: An open-label, uncontrolled trial

Background: Irbesartan is an orally active, specific blocker of the AT₁ receptor of angiotensin II that produces insurmountable antagonism. Irbesartan's plasma half-life of 11 to 15 hours and higher affinity for the AT₁ receptor versus other angiotensin II receptor subtypes may make it a suitable choice for once-daily treatment of hypertension. Few studies have examined the efficacy of this agent in Asian patients.Objective: The purpose of this open-label, uncontrolled study was to assess the 24-hour efficacy of irbesartan once-daily monotherapy in Chinese outpatients with mild to moderate hypertension.Methods: Patients with stage I or stage II hypertension (as defined by the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) were treated with irbesartan once daily for 6 to 8 weeks. The dose of irbesartan was titrated from an initial dose of 150 mg to 275 mg or 300 mg if adequate blood pressure (BP) control was not achieved by week 3 or 4; doses were taken once daily between 8 am and 9 am. For each patient, 24-hour ambulatory BP monitoring was performed twice, once before and once after 6 to 8 weeks of treatment.Results: A total of 25 patients (mean age, 54 years) were enrolled; 24 completed the study. Mean 24-hour systolic/diastolic BP after irbesartan treatment was significantly decreased compared with baseline values (128 ± 14 mm Hg/82 ± 8 mm Hg vs 143 ± 12 mm Hg/91 ± 7 mm Hg, P < 0.05 for both). The mean final dose of irbesartan was 243.8 ± 63.5 mg daily after a 7-week titration period. Mean daytime (6 am to 6 pm) BP decreased from 146 ± 11 mm Hg/94 ± 7 mm Hg to 130 ± 14 mm Hg/84 ± 8 mm Hg (P < 0.05), and nighttime (6 pm to 6 am) BP decreased from 139 ± 14 mm Hg/88 ± 7 mm Hg to 127 ± 15 mm Hg/81 ± 9 mm Hg (P < 0.05). The BP decrease was more pronounced during the day. Before treatment, the circadian variation showed a peak BP at 11 am and a nadir at 4 am. After treatment, significant BP reductions versus baseline (P < 0.05 for both diastolic and systolic BP) were observed for 23 of the 24 hourly mean points. The circadian rhythm of BP cycles was preserved. Mean heart rate did not change after treatment. Two patients reported dizziness and 1 reported heartburn.Conclusions: Irbesartan administered as once-daily monotherapy provided effective BP control during 23 of the 24 hourly mean points while preserving the circadian rhythm of BP cycles, and was well tolerated.     

Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects

Blood was taken at the first antenatal clinic from 56049 pregnantwomen. Neural tube defect (NTD) pregnancies (81) were comparedto controls (247) for plasma vitamin B₁₂ (B₁₂) (ng/l), plasmafolate (µg/1), and red cell folate (RCF) (µg/l).Median values were significantly different and were, respectively,243 and 296 (p = 0.001); 3.47 and 4.59 (p = 0.002); and 269and 338 (p < 0.001). There was a significant correlationbetween plasma B₁₂ and RCF in cases (r = 0.31, p = 0.004) butnot in controls (r = 0.02, p = 0.725). In cases only, multipleregression showed that both plasma B₁₂ and plasma folate influencedthe maternal RCF (multiple r = 0.68, p < 0.001). Plasma folateand plasma B₁₂ were independent risk factors for NTDs, suggestingthat the enzyme methionine synthase is involved directly orindirectly in the aetiology. The levels of folate and B₁₂ whereincreased risk occurred were not those usually associated withdeficiency, calling for a re-evaluation of their recommendeddaily allowances. Whether the aetiology is purely nutritionalor a metabolic defect, this study suggests that considerationshould be given to including B₁₂ as well as folic acid in anyprogramme of supplementation or food fortification to preventNTDs.     

Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects

Blood was taken at the first antenatal clinic from 56049 pregnantwomen. Neural tube defect (NTD) pregnancies (81) were comparedto controls (247) for plasma vitamin B₁₂ (B₁₂) (ng/l), plasmafolate (µg/1), and red cell folate (RCF) (µg/l).Median values were significantly different and were, respectively,243 and 296 (p = 0.001); 3.47 and 4.59 (p = 0.002); and 269and 338 (p < 0.001). There was a significant correlationbetween plasma B₁₂ and RCF in cases (r = 0.31, p = 0.004) butnot in controls (r = 0.02, p = 0.725). In cases only, multipleregression showed that both plasma B₁₂ and plasma folate influencedthe maternal RCF (multiple r = 0.68, p < 0.001). Plasma folateand plasma B₁₂ were independent risk factors for NTDs, suggestingthat the enzyme methionine synthase is involved directly orindirectly in the aetiology. The levels of folate and B₁₂ whereincreased risk occurred were not those usually associated withdeficiency, calling for a re-evaluation of their recommendeddaily allowances. Whether the aetiology is purely nutritionalor a metabolic defect, this study suggests that considerationshould be given to including B₁₂ as well as folic acid in anyprogramme of supplementation or food fortification to preventNTDs.     

Efficacy and Tolerability of Amlodipine Camsylate/Losartan 5/100-mg Versus Losartan/Hydrochlorothiazide 100/12.5-mg Fixed-Dose Combination in Hypertensive Patients Nonresponsive to Losartan 100-mg Monotherapy

Purpose

The aim of this study was to determine whether the efficacy and tolerability of amlodipine camsylate/losartan 5/100 mg/d (AML/LOS) are noninferior to those of losartan/hydrochlorothiazide 100/12.5 mg/d (LOS/HCTZ) fixed-dose combination in hypertensive patients unresponsive to losartan 100-mg/d monotherapy.

Methods

Male and female patients aged ≥18 years with hypertension despite 4-week, stable treatment with losartan 100-mg/d monotherapy were eligible for inclusion in this multicenter, randomized, double-blind study. Patients were randomly assigned to receive AML/LOS or LOS/HCTZ once daily for 8 weeks. The primary end point was the change from baseline to week 8 in sitting diastolic blood pressure (ΔsiDBP), and the secondary end points were the changes from baseline to 4 weeks in siDBP and sitting systolic BP (ΔsiSBP) and changes from baseline to 4 and 8 weeks in BP response rate. Tolerability was evaluated by physical examination, including vital sign measurement; laboratory analysis; and ECG.

Findings

Of 275 patients screened at 9 cardiovascular centers, 199 were enrolled (AML/LOS, n = 101; LOS/HCTZ, n = 98), and 183 completed the study. The demographic characteristics were similar between the 2 groups (mean age, 51.56 [9.97] years; men, 70.53%). At 8 weeks, the mean ΔsiDBP values were –11.54 (7.89) and –9.05 (6.57) mm Hg in the AML/LOS and LOS/HCTZ groups, respectively (both, P < 0.0001 vs baseline). The mean difference between the 2 groups was –2.57 mm Hg, a nonsignificant difference, meaning that AML/LOS was noninferior to LOS/HCTZ with regard to the primary end point. At 8 weeks, the mean uric acid level was changed significantly from baseline in the LOS/HCTZ group (+0.41 [0.80] mg/dL; P < 0.0001) but not in the AML/LOS group (–0.12 [0.82] mg/dL), representing a significant intergroup difference (P < 0.0001). Nineteen patients each in the AML/LOS (18.81%) and LOS/HCTZ (20.00%) groups experienced ≥1 adverse event, with 4 (3.96%) and 3 (3.16%) patients, respectively, experiencing 1 or more events considered by the investigators to have been treatment related.

Implications

The efficacy and tolerability of AML/LOS 5/100 mg/d was found to have been noninferior to those of LOS/HCTZ 100/12.5 mg/d in these hypertensive patients nonresponsive to losartan 100-mg/d monotherapy.     

Hyperparathyroidism, glucose tolerance and platelet intracellular free calcium in chronic renal failure

Disturbance in the vitamin D/parathyroid hormone (PTH) axismay be important in the pathogenesis of glucose intoleranceand insulin resistance in uraemia. To investigate possible relationshipsbetween hyperparathyroidism, intracellular free calcium ([Ca²⁺]₁),and glucose tolerance in chronic renal failure, we measuredserum intact PTH (l-PTH) by two-site immunometric assay, platelet[Ca²⁺]₁ using the fluorescent indicator fura-2, and plasma glucoseand insulin after 14 h overnight fast and at 30, 60 and 120min following a 75 g oral glucose load, in 18 chronic haemodialysispatients with elevated serum l-PTH. Calcitriol (1 µg)was administered parenterally at the end of each dialysis sessionfor four weeks. This significantly decreased serum l-PTH (p<0.001)and platelet [Ca²⁺], (p<0.01). Uraemic patients initiallyshowed marked glucose intolerance, with increased area belowthe glucose curve compared to healthy controls, but after 4weeks of calcitriol treatment, this effect was significantlydecreased, and there was a significant rise in the area underthe insulin curve after glucose load. The insulinogenic indexalso increased significantly after calcitriol treatment. These data suggest that calcitriol treatment of haemodialysispatient with secondary hyperparathyroidism is associated withincreased insulin secretion in response to glucose challenge,and that this change is linked to the decrease in intracellularfree calcium.     

Patterns of Insulin Dependence in an African Diabetic Clinic

SUMMARY Analysis of the age of onset of diabetes amongst insulin-treatedpatients in a large African diabetic clinic revealed a bimodaltype of distribution, 23 per cent having an age of onset before30 years and 77 per cent with onset at 30 years of age. All66 of the young insulin-treated group (21.7±4.8 years(mean±1 SD)), and a random selection of 50 older insulin-treatedpatients (49.7±10 years), were studied. The older groupwere better controlled (HbA₁ 8.4±1.7 per cent vs. 10.8±2.6per cent, p<0.001), on lower doses of insulin (49±23vs. 71±23 u/day, p<0.001) and had higher body massindex (26.0±5.6 vs. 21.8±3.5, p<0.001). SerumC-peptide (0.24±0.15 vs. 0.07±0.10 nmol/l, p<0.0001),and C-peptide/glucose ratio (2.57±2.65 vs. 0.56+0.98nmol/mmolx 10², p<0.001) were very significantly higher inolder patients. Patients with later onset disease thus had betterpreservation of pancreatic function, higher body mass indexand better glycaemic control on lower doses of insulin. Thesefeatures suggest that older insulin-treated patients could infact be ‘Type 2’ or non-insulin dependent patients,and the condition may be controllable with diet and/or oralhypoglycaemic agents, at least in some.     

Percutaneous Transluminal Angioplasty for Atheromatous Renal Artery Stenosis - Blood Pressure Response and Discriminant Analysis of Outcome Predictors

Percutaneous transluminal angioplasty was performed in 39 consectivepatients with atheromatous renal artery stenosis associatedwith hypertension. The mean blood pressure before angioplastywas 191/107 mm Hg and this had dropped to a mean of 167/90 mmHG at the patient's most recent visit, representing a significantfall in both systolic (p<0.01) and diastolic pressures (p<0.001).The mean serum creatinine was 166.7 µmol/l before percutaneoustransluminal angioplasty and 155.3 µmol/1 at the mostrecent visit (not statistically significant. The mean numberof anti-hypertensive drugs fell from 2.4 to1.9 after percutaneoustransluminal angioplasty (p<0.05). Three patients (eightper cent) were ‘cured’ (diastolic blood pressure<90 mm Hg without medication), 25 (64 per cent) had ‘improved’(diastolic blood pressure <109 mmHg, with a fall of morethan 15 per cent) and 11 (28 per cent) had not improved. Logisticdiscriminant analysis showed that pre-percutaneous transluminalangioplasty diastolic blood pressure, age, serum creatinineand smoking habit together correctly predicted the outcome ofpercutaneous transluminal angioplasty in 90 per cent of patients,with four ‘false positives’ and no ‘falsenegatives’. Ten patients suffered, a total of 12 seriouscomplications related to the procedure: one death in acute renalfailure, one myocardial infarction, one severe hypotension,just after the procedure, one deep vein thrombosis, one episodeof transient ischaemia of the toes and seven groin haematomas.Thus percutaneous transluminal angioplasty for atheromatousrenal artery stenosis rarely ‘cures’ hypertension,but improved blood pressure control is often achieved, albeitat the expense of troublesome complications. A prospective,randomized trial is needed to establish whether or not the improvementis due directly to percutaneous transluminal angioplasty.     

Metabolic and antihypertensive effects of nebivolol and atenolol in normometabolic patients with mild-to-moderate hypertension.

This was a double-blind, randomized, two-center, active-controlled, prospective, parallel study designed to evaluate the effects of nebivolol at daily doses of 5 mg on lipid and carbohydrate metabolism and on blood pressure in comparison with atenolol at daily doses of 50 mg. Normometabolic subjects with mild-to-moderate essential hypertension were recruited for this study, which included a 4-week, single-blind placebo washout phase and a 12-week double-blind treatment phase. After 12 weeks of treatment, both drugs demonstrated a significant decrease from baseline in high-density lipoprotein (HDL) apolipoprotein A-I (HDL-apoA-I) (nebivolol, P <.02; atenolol, P <.05). A significant reduction in HDL cholesterol (HDL-C) from baseline was also observed with nebivolol (P <.05). There were no significant differences between the drugs for these parameters, and the ratio low-density lipoprotein cholesterol (LDL-C)-to-HDL-C did not change significantly after 12 weeks of active treatment with nebivolol or atenolol. There were no significant changes in total cholesterol, HDL (2) -C, HDL (3) -C, LDL-C, very-low-density lipoprotein cholesterol (VLDL-C), total triglycerides, HDL-triglycerides (TG), LDL-TG, VLDL-TG, total apoB, LDL-B, VLDL-B (including the ratio LDL-C-to-LDL-apoB), or Lp(a) during treatment with both drugs. No significant differences in plasma apoA-I and apoC-III as well as in apoA-I-, C-III-containing lipoprotein particles (including the apoC-III ratio) were observed between the drugs, neither before nor after each active treatment. There were no significant differences between the drugs or within each treatment group in plasma glucose, insulin, or C-peptide concentrations after a 2-hour oral glucose tolerance test. Mean clinic trough sitting systolic blood pressure (SBP)/diastolic blood pressure (DBP) significantly decreased from 150/98 mm Hg at baseline to 141/90 mm Hg at termination for nebivolol and from 160/99 mm Hg at baseline to 145/88 mm Hg at termination for atenolol. No significant between-treatment differences were observed for the mean clinic trough sitting SBP/DBP. Both drugs significantly increased the atrial natriuretic factor (ANF) N-terminal plasma levels, whereas no changes were observed in ANF C-terminal plasma concentrations. A significant decrease (P <. 05) in the plasma adrenocorticotropic hormone levels was observed after administration of both drugs. A significant decrease (P <.05) in plasma cortisol levels was observed only after atenolol treatment. The incidence of adverse events reported during nebivolol treatment was comparable to that observed during atenolol treatment. Heart rate was significantly reduced by both drugs. There were no significant changes in hematology, biochemistry, or urinalysis studies. Neither nebivolol nor atenolol adversely affected lipid or carbohydrate metabolism in normometabolic hypertensive patients. Both treatments demonstrated adequate and similar antihypertensive effects and were well tolerated.