Lack of effect of a single oral dose of cyclosporine on systemic blood pressure and on forearm blood flow and vascular resistance in humans. Cyclosporine-induced hypertension and decline in renal function in healthy volunteers. Sequential effects of cyclosporine therapy on blood pressure, renal function and neurohormones. The impact of lactotripeptides on blood pressure response in stage 1 and stage 2 hypertensives. Amlodipine reduces cyclosporin-induced hyperuricaemia in hypertensive renal transplant recipients. Serial changes in blood pressure, renal function, endothelin and lipoprotein (a) during the first 9 days of cyclosporin therapy in males. Blood pressure response to oral calcium in persons with mild to moderate hypertension. A randomized, double-blind, placebo-controlled, crossover trial. Calcium channel blockade and preservation of renal graft function in cyclosporine-treated recipients: a prospective randomized placebo-controlled 2-year study. Bendrofluazide fails to reduce elevated blood pressure levels in the immediate post-stroke period. Effect of nitrendipine on renal function in renal-transplant patients treated with cyclosporin: a randomised trial. A controlled, double-blind, randomized trial of verapamil and cyclosporine in cadaver renal transplant patients. Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: a randomized, double-blinded, placebo-controlled clinical trial. The Multiple Sclerosis Study Group. Double-blind, placebo-controlled trial of potassium chloride in the treatment of mild hypertension. A multifactorial trial design to assess combination therapy in hypertension. Treatment with bisoprolol and hydrochlorothiazide. Enalapril/amlodipine combination in cyclosporine-treated renal transplant recipients: a prospective randomized trial. Controlling hypertension and hypotension immediately post-stroke (CHHIPS): a randomised, placebo-controlled, double-blind pilot trial.
The acute hemodynamic effect of cyclosporine in man is controversial. A randomized, double blind, placebo-controlled, cross-over study was undertaken to evaluate the effect of a single oral dose of cyclosporine (20 mg/kg body weight) on mean blood pressure (MBP), heart rate (HR), forearm blood flow (FBF), and vascular resistance (FVR) in 16 healthy adult subjects. Subjects were studied twice, with an intervening period of 2 weeks, before and after the administration of either cyclosporine or the vehicle olive oil. Blood pressure was measured on brachial and digital arteries. After 30 min of rest, basal measurements were obtained and individuals were randomly assigned to receive either cyclosporine or the vehicle, and the same measurements were repeated 2 h later. Mean whole blood levels of cyclosporine were 1542+/-387 ng/mL (range 1000 to 2550) 2 h after the administration of a single oral dose of cyclosporine. Cyclosporine did not cause any significant change in the hemodynamic parameters when compared with vehicle. Pre- and post-cyclosporine data were as follows (means +/-/SD): MBP (determined by Finapres on the digital artery), 92+/-10 v 95+/-11 mm Hg; HR, 66+/-10 v 68+/-11 beats/min; FBF, 3.90+/-1.3 v 3.8+/-1.8 mL/ 100 mL/min; and FVR, 28+/-9 v 33 +/-18 units, respectively. For the vehicle the results were: MBP, 94+/-9 v 94+/-9; HR, 67+/-9v 67 /-11; FBF, 3.3+/-1.6 v 3.2+/-2.0; FVR, 35+/-14 v 37+/-15, respectively. These figures did not differ from those obtained with the auscultatory method applied to the brachial artery among 10 selected subjects studied with Finapres. In conclusion, we found no evidence that at supratherapeutic doses cyclosporine causes acute increase in blood pressure or peripheral vasoconstriction in humans. To investigate the effect of cyclosporine A (CsA; Sandimmun Neoral) on systemic and renal hemodynamics, tubular function, and sodium excretion in healthy volunteers. Furthermore, we studied whether CsA enhances the systemic and renal hemodynamic sensitivity to norepinephrine.
                Eighteen healthy volunteers were administered 10 mg/kg CsA or placebo capsules in a double-blind fashion. The mean arterial blood pressure (MAP), renal vascular resistance (RVR), glomerular filtration rate (GFR), and renal clearances of lithium (CLi) and sodium (CNa) were measured for 8 h after ingestion of the capsules. Norepinephrine (2 microg/kg per h) was infused intravenously for 1.5 h into nine subjects.
                CsA increased the MAP by 17+/-2 mmHg. The GFR decreased by 18+/-2% (P < 0.001) and the RVR increased by 37+/-4% (P< 0.001) after ingestion of CsA. The CsA-induced increase in MAP preceded the CsA-induced fall in GFR. The rise in MAP was followed by an early 35+/-8/0 increase in CNa (P < 0.001). At the end of the 8 h study period, CNa decreased by 25+/-7% (P < 0.001). Using CLi, it was found that the initial natriuresis had been caused by a relative decrease both in proximal and in distal tubular reabsorption of sodium, whereas the late sodium retention was secondary to the CsA-induced fall in GFR. Infusion of norepinephrine increased the MAP, RVR, and filtration fraction, and decreased the renal plasma flow, without CsA having any additional effect.
                It was demonstrated that a single oral dose of CsA caused a rise in blood pressure and transient natriuresis, followed by a fall in GFR and antinatriuresis. Thus, the present study confirms and extends earlier observations that renal dysfunction and sodium retention are not the initiating events in CsA-induced hypertension. The study also affords evidence suggesting that such rises in blood pressure are not mediated by an increased sensitivity to norepinephrine. We have studied the sequential effects of cyclosporine during the first four days after its initiation in an effort to elucidate the primary and secondary events in the pathogenesis of cyclosporine induced nephrotoxicity and hypertension. Knowledge about the earliest effects of cyclosporine provides a more logical approach for devising therapeutic strategies to counteract nephrotoxicity and hypertension. On day 1, cyclosporine acutely increased systemic BP and decreased urine volume. Plasma renin activity was suppressed by day 2 and remained so thereafter. Renal sodium excretion was not affected until day 4 at which point a natriuresis occurred. Cyclosporine exerted a more marked antidiuretic effect on day 4 compared to day 1, which was augmented by a physiological infusion of vasopressin. Over the first four days of therapy, glomerular filtration rate and effective renal plasma flow were unchanged. Our data show that cyclosporine induced hypertension in the initial stages is not sodium dependent, and that changes in renal water handling were not dependent on alterations in the glomerular filtration rate or effective renal plasma flow. In fact, a natriuresis occurred which was most likely due to a combination of pressure natriuresis and angiotensin II suppression. The cyclosporine induced antidiuresis may indicate a distal nephron effect since cyclosporine augmented the antidiuretic effect of vasopressin, although vasopressin levels per se were not increased by cyclosporine alone. Nearly 70 million Americans have hypertension, and approximately an equal number have prehypertension. The prevalence of both disorders increases with advancing age and obesity. Many at-risk individuals do not have controlled blood pressure (BP). Lifestyle modification for most persons is the first step in a plan to control these conditions. Non-drug treatments offer an appeal to many patients with modest BP elevation. The authors recently evaluated BP response using 24-hour ambulatory BP monitoring and office BP monitoring of lactotripeptides dosed twice daily in 91 previously treated and treatment-naive patients with stage 1 and stage 2 hypertension. In this population, daytime systolic BP, the primary efficacy end point, significantly decreased (-3.6 mm Hg; P=.013), while placebo did not affect systolic BP (0 mm Hg; P=not significant). Treatment-naive patients exhibited a more robust drop in their daytime systolic BP (-7.6 mm Hg; P=.005) compared with placebo (-3.6 mm Hg; P=not significant). Lactotripeptides may be an effective agent in the management of low-risk and low-grade hypertension and prehypertension. Hypertension and hyperuricaemia are common side-effects of cyclosporin A (CsA) treatment in renal transplant recipients. While it is well established that the calcium channel blocker amlodipine can control CsA-induced hypertension effectively in this patient population, recent evidence suggests amlodipine might also reduce hyperuricaemia. The present study was designed to compare the effects of the calcium channel blocker amlodipine (5-10 mg/day) and the beta-adrenoceptor antagonist tertatolol (5-10 mg/day) on CsA-induced hyperuricaemia in post-renal transplant recipients with hypertension.
                Forty-eight hypertensive renal transplant recipients on a stable dose of CsA were randomized in a double-blind, parallel-group manner to receive either amlodipine (n = 24) or tertatolol (n = 24) for 60 days. The primary outcome measure was the change from baseline in serum uric acid concentration. Secondary analyses of efficacy were based on changes in renal function and blood pressure.
                Amlodipine significantly decreased serum uric acid levels from 483 +/- 99 to 431 +/- 110 microM/l (P < 0.001), while tertatolol significantly increased uric acid from 450 +/- 98 to 476 +/-84 microM/l (P = 0.006). Amlodipine also significantly increased glomerular filtration rate (P = 0.0048) and the clearance rate of uric acid (P = 0.023) and it reduced the fractional proximal tubular reabsorption of sodium (P < 0.001), compared with tertatolol. Renal plasma flow and filtered fraction were unaffected by both treatments, as was trough CsA blood concentration. Amlodipine lowered systolic blood pressure to a significantly greater extent than did tertatolol (P = 0.007). The time-dependent profile of diastolic blood pressure did not differ significantly between treatment groups. Both drugs were well tolerated.
                Amlodipine could be more appropriate than tertatolol for CsA-induced hypertension and hyperuricaemia in renal transplant recipients. To elucidate the sequential mechanisms underlying cyclosporin-induced hypertension and nephrotoxicity.
                A study of healthy males over the first 9 days of drug ingestion to permit the detection of serial changes in renal function and blood pressure in a situation free from the confounding variables of concomitant disease or drugs.
                Double-blind, placebo-controlled, randomized crossover study with cyclosporin (5 mg/kg twice a day) or placebo. Blood pressure and urinary sodium excretion were measured each day, and glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured on days 1, 4, 7 and 9. Cholesterol, lipoprotein (a) and endothelin were measured on days 1 and 9.
                GFR decreased by 9% with cyclosporin and was significantly lower than with placebo on day 4 of therapy. ERPF fell by 24%. The fall in GFR correlated significantly with suppressed plasma renin activity (P < 0.0001). Cyclosporin-induced hypertension occurred in the absence of any change in urinary sodium output or in plasma endothelin. Cyclosporin did not affect lipoprotein (a) levels during 9 days of cyclosporin therapy.
                Cyclosporin-induced hypertension and renal vasoconstriction are well established after 9 days of cyclosporin 5 mg/kg twice a day. We found no evidence to implicate either circulating endothelin or renal sodium retention in the onset of cyclosporin-induced hypertension. Cyclosporin-induced renal vasoconstriction appeared to occur when the protective mechanism of plasma renin activity suppression became exhausted. The blood pressure response of 48 hypertensive persons and 32 normotensive persons to elemental calcium (as the carbonate or citrate salt), 1000 mg/d for 8 weeks, was assessed in a randomized, double-blind, placebo-controlled, crossover trial. Compared with placebo, Ca2+ significantly lowered supine systolic blood pressure by 3.8 mm Hg, standing systolic blood pressure by 5.6 mm Hg (p less than 0.02), and supine diastolic blood pressure by 2.3 mm Hg (p less than 0.05) in hypertensive persons. The response in normotensive persons differed significantly from that in hypertensives (p less than 0.03) as their blood pressure was unchanged. Twenty-one (44%) hypertensive and 6 (19%) normotensive persons achieved a reduction in standing systolic arterial pressure of 10 mm Hg or greater. Reported adverse effects were similar between calcium and placebo phases and did not necessitate withdrawal of any patient from the trial. Treatment with 1000 mg/d of oral Ca2+ for 8 weeks represents a safe, well-tolerated, nonpharmacologic intervention that lowers blood pressure in selected patients with mild to moderate hypertension. Studies have provided conflicting results as to the protective role of calcium channel blockers (CCB) in cyclosporine-treated patients with regard to blood pressure control and preservation of renal graft function. Lacidipine is a dihydropyridine CCB that possesses antioxidative, anti-atherosclerotic, and anti-adhesion properties and was shown to prevent cyclosporine-induced nephrotoxicity in a rat model.
                We conducted a multicenter prospective, randomized, placebo-controlled study in 131 de novo recipients of a cadaveric renal allograft on cyclosporine therapy. The aim of this 2-year study was to assess the effects of lacidipine on graft function (plasma iohexol clearance), renal plasma flow, anastomotic arterial blood flow, deterioration of renal function, blood pressure, acute rejection, and hospitalization rate.
                A total of 118 recipients were available for intention-to-treat analysis on efficacy (lacidipine: n=59; placebo: n=59). Graft function assessed by serum creatinine concentration and glomerular filtration rate measured as plasma iohexol clearance, was persistently better in lacidipine-treated patients from 1 year onwards (respectively, P<0.01 and P<0.05). Renal plasma flow and anastomotic blood flow were not significantly higher in lacidipine-treated patients. Three patients on lacidipine therapy and four on placebo experienced treatment failure defined as an increase in serum creatinine from baseline of more than 60% (log-rank test: P=0.57). Study groups did not differ in acute rejection rate, trough blood cyclosporine concentrations, blood pressure, number of antihypertensive drugs, hospitalization rate, and adverse event rate.
                The use of calcium channel blockers in cyclosporine-treated renal recipients results in a significantly better allograft function at 2 years and this effect is independent of blood pressure lowering. Blood pressure (BP) levels, beat-to-beat blood pressure variability, dynamic cerebral autoregulation and cardiac baroreceptor sensitivity are frequently abnormal following acute stroke and are associated with an adverse short- and long-term prognosis. Thiazide diuretics are effective antihypertensive agents in preventing primary and secondary stroke, but their hypotensive and cerebral autoregulatory effects in the immediate post-stroke period have not been studied.
                Thirty-seven hypertensive neuroradiologically proven ischaemic stroke patients were randomized in a double-blind, placebo controlled, parallel group study to bendrofluazide 2.5 mg daily or matching placebo, within 96 h of stroke onset, for a 7-day period. Casual and non-invasive beat-to-beat arterial BP levels, cerebral blood flow velocity, ECG and transcutaneous carbon dioxide levels were measured within 70 +/- 20 h of cerebral infarction and again 7 days later. Dynamic cerebral autoregulatory indices, pulse interval, BP variability and cardiac baroreceptor sensitivity were also calculated.
                Small, non-significant falls were seen in casual and beat-to-beat BP levels over the 7-day period in both active and placebo-treated patients with no differences between treatments. No significant changes were seen in dynamic cerebral autoregulation or in cardiac baroreceptor sensitivity during the follow-up in either group.
                Following acute ischaemic stroke, the standard dose of bendrofluazide at 2.5 mg daily in this study sample did not lower systemic BP levels over the subsequent 7-day period. There was no evidence that bendrofluazide significantly altered cerebral autoregulation or improved cardiac baroreceptor sensitivity post-ictus. Bendrofluazide appears to be an ineffective hypotensive agent at the standard dosage in the initial post-stroke period.
                Copyright 2005 S. Karger AG, Basel. Calcium antagonists such as nitrendipine reduce the effects of cyclosporin on renal haemodynamics, however, their long-term efficacy has not been established. We did a randomised trial to investigate the effects of nitrendipine on renal function in renal-transplant patients treated with cyclosporin.
                253 renal-transplant patients were recruited: 52 normotensive patients (diastolic blood pressure <90 mm Hg) were assigned placebo and 57 nitrendipine 5 mg twice daily; 71 hypertensive patients (diastolic blood pressure >90 to <115 mm Hg) were assigned placebo and 73 nitrendipine 10 mg twice daily. Nitrendipine was increased to 20 mg twice daily if the target diastolic blood pressure (<90 mm Hg) was not achieved. The patients were seen once a month for 24 months; blood pressure and serum creatinine concentration were recorded at each visit. Analysis was by intention to treat.
                63 patients were withdrawn (35 nitrendipine, 28 placebo). The mean serum creatinine concentration at baseline was slightly higher in the nitrendipine group (146.7 micromol/L [SE 4.42]) than in the placebo group (137.0 micromol/L [3.54]. At the 24-month endpoint or at dropout, serum creatinine concentration was significantly higher in the 123 patients in the placebo group than the 130 patients in the nitrendipine group (160.8 [7.1] vs 148.5 [5.3], p for effect of treatment=0.025, analysis of covariance in a two-way classification; 95% CI for difference -1.77 to -22.98). At study entry, the blood pressures of the placebo and the nitrendipine groups were almost identical. At 24 months, blood pressure was higher in the normotensive patients given a placebo than in those patients given nitrendipine. By contrast, blood-pressure values were similar in those hypertensive patients given a placebo and those given nitrendipine at the end of treatment.
                The calcium antagonist nitrendipine has no adverse effects on kidney function in renal-transplant patients with cyclosporin. The drug has a small but significant nephroprotective effect, that is independent of the drug's antihypertensive action. Calcium channel blockers have immunomodulating effects in vitro and may be effective in preventing cyclosporine nephrotoxicity. We studied the effect of verapamil following renal transplantation on the incidence of rejection and cyclosporine nephrotoxicity in a double-blind, placebo-controlled trial. Patients were randomly assigned to placebo (n = 28) or verapamil (n = 32) at doses of 80 mg twice a day. There was no difference in the incidence of rejection or cyclosporine toxicity in the two study arms. Recipients randomized to verapamil had lower mean cyclosporine doses at all intervals during a 1-year follow-up. Although cyclosporine doses were lower in the placebo group, the mean cyclosporine levels were equivalent in the two groups. Recipients in the verapamil-treated group had a higher mean serum creatinine at the end of the study--1.7 mg/dL versus 1.4 mg/dL in the placebo group. Actual 1-year graft survival was 89% for the placebo recipients versus 91% in the verapamil-treatment group. When compared with placebo, the concomitant use of low-dose verapamil results in lower cyclosporine doses but equivalent cyclosporine blood levels. Reduction in the incidence of rejection or cyclosporine nephrotoxicity were not observed. Patients with clinically definite multiple sclerosis, mild to moderately severe neurological disability (entry score on the Expanded Disability Status Scale (EDSS) between 3.0 and 7.0), and a progressive course defined by an increase in the EDSS of between 1 and 3 grades in the year prior to entry were randomized to receive either cyclosporine (n = 273) or placebo (n = 274) in a 2-year, double-blinded, multicenter trial. Treatment groups at entry proved balanced for age, gender, duration of illness, and neurological disability. Cyclosporine dosage was adjusted for toxicity and a median trough whole-blood level was maintained between 310 and 430 ng/ml. The mean increase in EDSS score was 0.39 +/- 1.07 grades for cyclosporine-treated patients and 0.65 +/- 1.08 grades for placebo-treated patients from entry until the time of early withdrawal or completion of the study (p = 0.002). Of three primary efficacy criteria, cyclosporine delayed the time to becoming wheelchair bound (p = 0.038; relative risk, 0.765), but statistically significant effects were not observed for "time to sustained progression" or on a composite score of "activities of daily living." Active treatment did have a favorable effect on several secondary measures of disease outcome. A large and differential withdrawal rate (44% for cyclosporine-treated patients, 32% for placebo-treated patients) complicated the analysis but did not appear to explain the observed effect of cyclosporine in delaying disease progression. Multivariate analysis did not show institutional effects but did demonstrate substantial effects of baseline neurological disability on outcome. Nephrotoxicity and hypertension were common troublesome toxicities and accounted for most of the excess loss of patients in the cyclosporine arm of the study. Thus, chronic cyclosporine therapy was associated with a statistically significant but clinically modest delay of progression of disability in a group of patients with multiple sclerosis selected for moderately severe and progressive disease. Close supervision by physicians familiar with cyclosporine is mandatory to minimize known adverse effects, particularly nephrotoxicity, when considering the use of this immunosuppressant. Epidemiological and experimental data suggest blood pressure-lowering effects of dietary potassium. A randomized, double-blind clinical trial was used to assess blood pressure response to orally administered potassium, 120 mEq/day, and to placebo in 101 adults with mild hypertension. Blood pressure was measured with a random-zero sphygmomanometer every 2 weeks of this 8-week trial. Systolic blood pressure in the potassium-treated group decreased by 6.4 +/- 13.7 (SD) mm Hg (p less than or equal to 0.025) compared with 0.11 +/- 13.0 mm Hg in the placebo-treated group (p = 0.96). Diastolic blood pressure in the potassium-treated group decreased by 4.1 +/- 8.3 mm Hg (p less than or equal to 0.05) compared with a 1.6 +/- 6.5 mm Hg decrease in placebo-treated subjects (p = 0.09). Baseline blood pressure of potassium-treated subjects was unexpectedly higher than that of controls. After correcting for baseline variation, blood pressure still decreased 3.4/1.8 mm Hg more in potassium recipients than in placebo recipients (p = 0.14 and 0.24, respectively). Blood pressure decreased by 19/13 mm Hg in five blacks taking potassium versus a 1/0 mm Hg increase in seven blacks taking placebo. Compliance with the potassium regimen was 91.5% by pill count; only one subject discontinued treatment because of side effects. In conclusion, 120 mEq/day of microencapsulated potassium chloride was well tolerated in adults with mild hypertension. An antihypertensive effect of potassium cannot be ruled out despite the fact that there was no statistically significant difference between potassium-treated and placebo-treated subjects after adjustment for differences in baseline blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS) The safety and effectiveness of different dosages and combinations of antihypertensive agents can be efficiently studied using a multifactorial trial design. In consultation with the Cardio-Renal Division of the Food and Drug Administration, we conducted a randomized, double-blind, placebo-controlled, 3 x 4 factorial trial of bisoprolol, a beta 1-selective adrenergic blocking agent, and hydrochlorothiazide.
                A total of 512 patients with mild to moderate essential hypertension were randomized to once-daily treatment with bisoprolol (0, 2.5, 10, or 40 mg), hydrochlorothiazide (0, 6.25, or 25 mg), and all possible combinations. Diastolic and systolic blood pressures were monitored during this 12-week trial.
                The effects of bisoprolol and hydrochlorothiazide were additive with respect to reductions in diastolic and systolic blood pressures over the dosage ranges studied. The addition of hydrochlorothiazide (or bisoprolol) to therapy with bisoprolol (or hydrochlorothiazide) produced an incremental reduction in blood pressure. Dosages of hydrochlorothiazide as low as 6.25 mg/d contributed a significant antihypertensive effect. A hydrochlorothiazide dosage of 6.25 mg/d produced significantly less hypokalemia and less of an increase in uric acid levels than a dosage of 25 mg/d. The low-dose combination of bisoprolol, 2.5 mg/d, and hydrochlorothiazide, 6.25 mg/d, reduced diastolic blood pressure to lower than 90 mm Hg in 61% of patients and demonstrated a safety profile that compared favorably with that of placebo.
                The utility of factorial design trials to characterize dose-response relationships and to test the potential interactions between various antihypertensive agents has been demonstrated. The combination of low dosages of bisoprolol and hydrochlorothiazide may be a rational alternative to conventional stepped-care therapy for the initial treatment of patients with mild to moderate hypertension. Most hypertensive renal transplant recipients require two or more antihypertensive medications to achieve blood pressure control. However, which medications must be combined is still a matter of debate.
                A prospective randomized open-label blinded evaluation trial comparing the six-month effects of the amlodipine-enalapril combination (n = 32) vs. enalapril alone (n = 33) and vs. amlodipine alone (n = 34) on arterial pressure, renal function, albuminuria and tolerability.
                At six months, diastolic arterial pressure was more adequately controlled (i.e., <90 mmHg) in the combination group than in the amlodipine and enalapril groups (100% vs. 82.4% and 84.8%, respectively, p = 0.038). The same trend was observed for systolic arterial pressure (65.6% vs. 58.8% and 51.5%, NS). The six-month change in albuminuria was similar in the combination group and in the enalapril group (-64.7% vs. -59.5%); however, patients in the combination group exhibited a greater reduction in albuminuria than in the amlodipine group (-64.7% vs. -29.0%, p = 0.002). As compared with baseline values, serum creatinine and potassium remained unchanged in the combination group, whereas they increased by 9 +/- 12 micromol/L (p = 0.01) and by 0.2 +/- 0.4 mmol/L (p < 0.01), respectively, in the enalapril group. The cyclosporine trough levels remained unchanged in the combination group, but increased in the amlodipine group.
                Angiotensin-converting enzyme inhibitor (ACEI)-calcium-channel blocker (CCB) combination controls arterial pressure more adequately than ACEI alone or CCB alone, reduces albuminuria and may prevent the ACEI-induced initial rise in serum creatinine. Raised blood pressure is common after acute stroke and is associated with an adverse prognosis. We sought to assess the feasibility, safety, and effects of two regimens for lowering blood pressure in patients who have had a stroke.
                Patients who had cerebral infarction or cerebral haemorrhage and were hypertensive (systolic blood pressure [SBP] >160 mm Hg) were randomly assigned by secure internet central randomisation to receive oral labetalol, lisinopril, or placebo if they were non-dysphagic, or intravenous labetalol, sublingual lisinopril, or placebo if they had dysphagia, within 36 h of symptom onset in this double-blind pilot trial. The doses were titrated up if target blood pressure was not reached. Analysis was by intention to treat. This trial is registered with the National Research Register, number N0484128008.
                179 patients (mean age 74 [SD 11] years; SBP 181 [SD 16] mm Hg; diastolic blood pressure [DBP] 95 [SD 13] mm Hg; median National Institutes of Health stroke scale [NIHSS] score 9 [IQR 5-16] points) were randomly assigned to receive labetolol (n=58), lisinopril (n=58), or placebo (n=63) between January, 2005, and December, 2007. The primary outcome--death or dependency at 2 weeks--occurred in 61% (69) of the active and 59% (35) of the placebo group (relative risk [RR] 1.03, 95% CI 0.80-1.33; p=0.82). There was no evidence of early neurological deterioration with active treatment (RR 1.22, 0.33-4.54; p=0.76) despite the significantly greater fall in SBP within the first 24 h in this group compared with placebo (21 [17-25] mm Hg vs 11 [5-17] mm Hg; p=0.004). No increase in serious adverse events was reported with active treatment (RR 0.91, 0.69-1.12; p=0.50) but 3-month mortality was halved (9.7%vs 20.3%, hazard ratio [HR] 0.40, 95% CI 0.2-1.0; p=0.05).
                Labetalol and lisinopril are effective antihypertensive drugs in acute stroke that do not increase serious adverse events. Early lowering of blood pressure with lisinopril and labetalol after acute stroke seems to be a promising approach to reduce mortality and potential disability. However, in view of the small sample size, care must be taken when these results are interpreted and further evaluation in larger trials is needed.
Cyclosporine statistically significantly increases blood pressure compared to placebo in a dose-related fashion. The magnitude of increase in blood pressure is clinically significant and increases the risk of stroke, myocardial infarction, heart failure and other adverse cardiovascular events associated with elevated BP. Consequently prescribers should try to find the lowest effective dose in all patients receiving cyclosporine chronically.