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Objective: This study aims to establish the benefits of lowering cholesterol in diabetic patients with well-controlled hypertension and average/below-average cholesterol concentrations, but without established coronary disease.Research Design and Methods: In the lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA), 10,305 hypertensive patients with no history of coronary heart disease (CHD) but at least three cardiovascular risk factors were randomly assigned to receive 10 mg atorvastatin or placebo. Effects on total cardiovascular outcomes in 2,532 patients who had type 2 diabetes at randomization were compared.Results: During a median follow-up of 3.3 years, concentrations of total and LDL cholesterol among diabetic participants included in ASCOT-LLA were approximately 1 mmol/l lower in those allocated atorvastatin compared with placebo. There were 116 (9.2%) major cardiovascular events or procedures in the atorvastatin group and 151 (11.9%) events in the placebo group (hazard ratio 0.77, 95% CI 0.61-0.98; P = 0.036). For the individual components of this composite end point, the number of events occurring in the diabetes subgroup was small. Therefore, although fewer coronary events (0.84, 0.55-1.29; P = 0.14) and strokes (0.67, 0.41-1.09; P = 0.66) were observed among the patients allocated atorvastatin, these reductions were not statistically significant.Conclusions: Atorvastatin significantly reduced the risk of major cardiovascular events and procedures among diabetic patients with well-controlled hypertension and without a history of CHD or markedly elevated cholesterol concentrations. The proportional reduction in risk was similar to that among participants who did not have diagnosed diabetes. Allocation to atorvastatin prevented approximately 9 diabetic participants from suffering a first major cardiovascular event or procedure for every 1,000 treated for 1 year. [ABSTRACT FROM AUTHOR]

Effective treatment of hypertension is essential to reduce the risk of renal and cardiovascular (CV) morbidity. The risks associated with hypertension are modulated by the presence of other factors. This has prompted the quest for agents that have benefits beyond blood pressure (BP) lowering. The angiotensin II receptor blocker (ARB) class of antihypertensive agents represents an important addition to the therapeutic options for elevated BP. Their ability to control BP is equivalent to existing therapies and there is a considerable and mounting evidence-base for their ability to reduce hypertension-associated target organ damage and comorbidities. Studies show that ARBs have clinical benefits across the spectrum of disease severity. In particular, recent large studies have demonstrated that these benefits extend to patients with conditions predisposing to CV events, such as diabetes, left ventricular hypertrophy and microalbuminuria, and where risk factors coexist. Data from these studies suggest that the CV protective effects of ARBs are at least, in part, independent from the BP lowering action. In addition, ARBs are extremely well tolerated, and strong evidence suggests that compliance with therapy-a key factor in achieving adequate BP control-with ARBs is higher than with other antihypertensive agents. Furthermore, flexible dosing and good tolerability profile mean that, where necessary, ARBs can be combined with other classes of antihypertensive agents to achieve adequate BP control and reduce the risk of hypertension-associated morbidity.Journal of Human Hypertension (2005) 19, 331-339. doi:10.1038/sj.jhh.1001831 Published online 3 March 2005 [ABSTRACT FROM AUTHOR]

ALLHAT, the largest ever antihypertensive trial, compared cardiac outcomes in 42,418 high-risk individuals with mild-to-moderate hypertension, including 36% with diabetes, randomised to: 1) the thiazide-type diuretic, chlorthalidone; or 2) the ACE inhibitor, lisinopril; or 3) the calcium channel blocker, amlodipine. No differences between the groups were observed for the primary outcome coronary heart disease (CHD) but chlorthalidone was superior in preventing some cardiovascular disease events. Since diuretics are less expensive, it might be inferred that these drugs should be the preferred first-line anti hypertensive therapy. However, the design and conduct of ALLHAT make interpretation of the results difficult. Despite its size, ALLHAT has few practical implications for management of hypertension. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of oral loprazolam and pharmacodynamic responses on the morning following nightly drug administration were examined after single and after seven consecutive 1 mg doses in six non-fasting healthy subjects. The serum concentration-time profiles for unchanged loprazolam measured by a specific high pressure liquid chromatography/gas chromatography (h.p.l.c./g.c.) method and for benzodiazepine material measured by radioimmunoassay (RIA) were qualitatively similar although RIA levels were consistently higher. Approximate elimination half-life of unchanged loprazolam after single doses was 8.0 h. For RIA measured material, approximate half-life was 11.7 h following acute administration and 12.8 h after seven consecutive doses. Compared to results after single doses, maximum serum concentration and AUC were greater following 1 week's treatment. Using RIA results, the increases were 27.2% (95% CL 6.9 to 47.4%) and 35.1% (95% CL 15.8 to 54.3%) respectively and using h.p.l.c./g.c. data, 11% (95% CL − 22.6% to 44.5%) and 41% (95% CL − 50.9 to 133.0%). After repeated doses of loprazolam, there were no significant changes with respect to results after single doses in psychomotor function assessed objectively by critical flicker fusion threshold or choice reaction time, or in sleep quality or behaviour on awakening assessed subjectively by 10 cm analogue scales. Mean time to maximum serum concentration was 4.95 h with considerable inter-individual variability (range 1-12 h) and there was a lag time of 1-1.5 h before drug was detectable in blood.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

The plasma potassium responses to the aldosterone antagonists prorenoate K (10 mg/day and 40 mg/day) and spironolactone (25 mg/day and 100 mg/day) were compared following treatment for 11 days in combination with the diuretic metolazone (2.5 mg/day) in a double-blind crossover study in twelve healthy men. The best estimate of the potency of prorenoate K relative to spironolactone in attenuating metolazone induced hypokalaemia was 5.6 with 95% confidence limits 2.4-35.2. The method employed allowed a statistically valid quantitative comparison of the potassium sparing properties of the mineralocorticoid antagonists after repeated doses and may be useful in the preclinical evaluation of these drugs. [ABSTRACT FROM AUTHOR]

Antipyrine metabolism, daily urinary 6-beta-hydroxycortisol excretion, carbamazepine (CBZ) half-lives and leucocyte delta-aminolaevulinic acid synthase (ALA.S) activities were measured following 2 weeks' treatment with CBZ 400 mg and 600 mg once daily in eight healthy male volunteers. Dose-dependent induction of antipyrine metabolism was demonstrated but cortisol hydroxylation appeared maximally induced by the 400 mg dose. CBZ half-lives fell significantly in both studies (P less than 0.01 in each case) but a greater fall was seen with the higher dose (P less than 0.01). Plasma CBZ concentrations were higher following the eighth doses (P less than 0.01) in both studies. Leucocyte ALA.S activity increased by a mean of 657% following 1 week's treatment with 400 mg CBZ and 1145% on the 600 mg dose. In both studies ALA.S activities fell towards baseline during the second week of treatment. CBZ possesses potent dose-dependent hetero- and auto-inducing properties. Leucocyte ALA.S activity may represent a novel in vivo index of extrahepatic enzyme induction in man. [ABSTRACT FROM AUTHOR]

Plasma potassium and aldosterone responses to 9 days treatment with hydrochlorothiazide (100 mg/day) alone or in combination with spironolactone (100 mg/day), prescribed once daily or in doses 12 h apart, were examined in a double-blind, crossover study in twelve healthy subjects. Plasma potassium concentrations were lower when the drugs were administered 12 h apart (P less than 0.01). Spironolactone attenuated significantly hydrochlorothiazide induced hypokalaemia-mean rise in plasma potassium, 0.36 mmol/l (P less than 0.001). The increase in plasma aldosterone was greater following combination therapies (P less than 0.001), but there were no significant differences between once daily and twice daily regimens. We conclude that plasma potassium concentration is better maintained when diuretics are given once daily and that this is not related closely to differences in plasma aldosterone responses. [ABSTRACT FROM AUTHOR]

1 The effect of single oral doses of spironolactone 25 mg, 50 mg, 100 mg, 200 mg, 400 mg, and placebo in reversing the urinary electrolyte changes induced by fludrocortisone between 2-10 h and 12-16 h after treatment was examined in healthy subjects. 2 In the two collection periods, there were statistically significant log linear dose-response relationships for sodium excretion (P less than 0.001), potassium excretion (P less than 0.001 and P less than 0.025 respectively) and log10 10 Na/K (P less than 0.001). 3 However, there was evidence that the log spironolactone dose-urinary sodium responses did not increase monotonically, while the relationship for urinary potassium appeared to enter the lower 'plateau' at doses between 100 mg and 200 mg, and when compared to placebo values, potassium excretion was not significantly depressed 12-16 h after treatment (P greater than 0.1). Thus, sodium and potassium responses were dissociated in dose producing maximal effect and in duration of activity, reinforcing the view that functions or the urinary sodium/potassium ratio alone cannot be considered an adequate description of renal antimineralocorticoid activity. 4 Dose- response relationships for all urinary electrolyte variables seem consistently steep and linear between 25 mg and 100 mg of spironolactone, suggesting that, in studies employing this model, the doses of spironolactone should be restricted to this range. [ABSTRACT FROM AUTHOR]

1 The renal antimineralocorticoid potency of single doses of thirteen compounds with properties in animals compatible with competitive aldosterone antagonism was compared to that of spironolactone in healthy men. 2 Twelve compounds showed significant activity when compared to placebo but only one, prorenoate potassium, was significantly more potent than spironolactone on a weight basis. 3 The results allowed ranking of the compounds in order of potency relative to spironolactone and general observations on structure activity relationships in man. 4 Animal bioassays and in vitro aldosterone binding studies are unreliable predictors of the human activity of competitive mineralocorticoid antagonists. [ABSTRACT FROM AUTHOR]

1 After repeated single daily doses, the aldosterone antagonists prorenoate potassium and spironolactone were compared with regard to renal antimineralocorticoid activity, plasma potassium concentration and steady state plasma levels of their active metabolites, prorenone and canrenone respectively, in a balanced crossover study of twelve healthy subjects. 2 Following challenge with the mineralocorticoid, fludrocortisone, best estimates of the potency of prorenoate potassium relative to spironolactone were 3.6 (95% confidence limits 1.6-10.4) for urinary sodium excretion and 3.4 (95% confidence limits 2.0-6.5) for urinary log10 10Na/K. Estimates with respect to urinary potassium excretion and plasma potassium concentration were imprecise, confirming the limitations of the fludrocortisone model in the evaluation of aldosterone antagonists at steady state. 3 Both compounds exhibited directly proportional relationships between daily dose and steady state plasma levels of active metabolites. The approximate mean terminal elimination half-life of prorenone at steady state was 32.6 h (range 18- 80 h). [ABSTRACT FROM AUTHOR]

1 The potency of single doses of the aldosterone antagonist SC8109 relative to spironolactone in reversing the urinary electrolyte effects of fludrocortisone was examined in a double-blind, balanced, crossover study in six healthy volunteers. 2 For the urinary ratio log10 10Na/K, the relative potency of SC8109; spironolactone on a weight basis was 0.08:1 (95% confidence limits 0.04-0.13:1). 3 The potency of SC8109 relative to spironolactone for natriuresis and antikaliuresis was 0.10:1 and 0.05:1, respectively. 4 The results show excellent agreement with clinical experience where SC8109 was considered to have one tenth the potency of spironolactone. We suggest that the human bioassay employed in this study provides quantitative information which should be predictive of the therapeutic potency of aldosterone antagonists. [ABSTRACT FROM AUTHOR]

1. Plasma drug concentrations, and heart rate and blood pressure responses to exercise at a predetermined load were examined in twelve hypertensive patients following single and repeated doses of oxprenolol administered once daily as oral osmotic drug delivery systems (10/170 and 16/260 oxprenolol OROS). 2. Plasma oxprenolol concentration profiles after each preparation were consistent with the criteria for sustained drug release. Levels immediately after exercise were significantly higher than those prior to exercise (P less than 0.001), but differences were slight. 3. Both OROS drug forms reduced exercise heart rate for 24 h after single and repeated doses; effects were greater for 16/260 OROS than for 10/170 OROS. Significant reductions in post-exercise systolic BP were observed 24 h after drug administration and after repeated doses there was little difference between the preparations. Effects on diastolic BP after exercise were slight. 4. The relationship between plasma oxprenolol concentrations and exercise heart rates fitted an exponential mathematical model which makes allowance for inter-individual variability. No such kinetic-dynamic relationship could be defined for post-exercise systolic or diastolic BP. [ABSTRACT FROM AUTHOR]

1 The effect of sodium valproate (VPA; 500 mg thrice daily for 7 days) and matched placebo on the disposition and psychomotor profile of a single dose of carbamazepine (CBZ; 10 mg kg-1) was studied in eight healthy male subjects using a randomised balanced crossover design. 2 VPA alone had no effect on antipyrine clearance, urinary 6 beta- hydroxycortisol excretion and a battery of psychomotor function tests after 3 days' treatment despite achieving a mean steady-state concentration (90 +/− 6 mg 1(-1)) well within the target range (50-100 mg 1(-1)) for the drug. 3 VPA pre-treatment did not alter total CBZ area under the concentration-time curve (AUC 0-59 h) but did prolong CBZ elimination half life by 12% (P less than 0.01). AUC 0-59 h for free plasma CBZ was 13% higher (P less than 0.02) and half-life of unbound CBZ 16% longer (P less than 0.02) during VPA treatment. CBZ- 10,11 epoxide (CBZ-E) levels (52%) and CBZ-E/CBZ ratios (45%) were both elevated by concurrent VPA (P less than 0.05) and free CBZ fraction was increased by 7% (P less than 0.02). 4 The sole effect of VPA on the psychomotor profile of CBZ was prolongation of card sorting time (P less than 0.05), although CBZ-related side effects were reported as more severe when VPA was also taken (P less than 0.01). 5 These data suggest that VPA displaces CBZ from plasma protein binding sites and inhibits the metabolism of both the parent drug and its epoxide.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

KEY POINTS AND PRACTICAL RECOMMENDATIONS: •  Hydralazine and minoxidil act by dilating resistance arterioles, thus reducing peripheral resistance, with no dilating effect on the venous side of the circulation. •  There is a baroreflex-mediated venoconstriction, resulting in an increase in venous return to the heart, along with a direct catecholamine-mediated positive inotropic and chronotropic stimulation of the heart. •  Hydralazine therapy is usually combined with a sympathetic inhibitor to prevent expression of this reflex, as well as with a diuretic agent to prevent sodium retention caused by reduction in renal perfusion pressure. •  Hydralazine is indicated in the long-term therapy of essential hypertension, in the short-term therapy of pregnancy-induced hypertension and eclampsia, and in the therapy of hypertensive crisis. •  Adverse effects include the anticipated tachycardia, fluid retention, and headache, caused by the vasodilation, especially in the early days of therapy, but may frequently be prevented by the concomitant use of a β-blocker. •  As with other drugs that are N-acetylated, there is a low risk of lupus-like syndrome with high doses and long-term use. •  Because of the severity of adverse effects with minoxidil, its usage is limited to persons with severe hypertension unresponsive to other treatments. •  Hirsutism, a common side effect of minoxidil, is particularly bothersome in women and reverses in a few months after discontinuation. •  Sodium nitroprusside is used in the intensive care setting to lower pressure in hypertensive crisis or to treat severe left ventricular failure, particularly valuable when elevated pressure or severe left ventricular failure threatens the patient's survival. •  Although nitrates have not achieved widespread use as antihypertensive agents, they are effective in producing sustained blood pressure (BP) reductions when added to other antihypertensive regimens. [ABSTRACT FROM AUTHOR]