Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0012833 (dizziness)
 9,689 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this large, randomized, double-blind, parallel-group study in hypertensive women was to compare the antihypertensive efficacy and effects on subjective symptoms and quality of life of the new angiotensin II type 1 (AT1) receptor blocker candesartan cilexetil, the angiotensin-converting enzyme inhibitor enalapril, and the diuretic hydrochlorothiazide (HCTZ). Women, aged 40 to 69 years, with a seated diastolic blood pressure (DBP) of 95 to 115 mm Hg, were randomized to candesartan cilexetil, 8 to 16 mg (n = 140), enalapril, 10 to 20 mg (n = 146), or HCTZ, 12.5 to 25 mg (n = 143), for 12 weeks; the higher doses were used if DBP was greater than 90 mm Hg after 6 weeks. Candesartan cilexetil lowered seated blood pressure by 17/11 and 19/11 mm Hg after 6 and 12 weeks of treatment, respectively. This reduction was greater (P < .01) than with enalapril (12/8 and 13/9 mm Hg) or HCTZ (12/7 and 13/8 mm Hg). The proportions of patients with controlled DBP (< 90 mm Hg) after 12 weeks of treatment with candesartan cilexetil, enalapril, or HCTZ were 60%, 51%, and 43%, respectively. Patients experienced less dry cough (P < 0.001) with candesartan cilexetil or HCTZ than with enalapril. No treatment differences were found in the incidence of dizziness and quality of life was well maintained in all groups. Compared with candesartan cilexetil and enalapril, HCTZ increased uric acid and decreased serum potassium (P < .001). In conclusion, candesartan cilexetil reduced blood pressure more effectively and was better tolerated than enalapril or HCTZ in women with mild to moderate hypertension.
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PMID:Angiotensin II type 1 (AT1) receptor blockade in hypertensive women: benefits of candesartan cilexetil versus enalapril or hydrochlorothiazide. 1082 1

The study was designed to assess the antihypertensive effect of combined angiotensin-converting enzyme (ACE) inhibition and angiotensin II type 1 receptor (AT1) antagonism in patients with essential hypertension. Twenty patients with uncontrolled ambulatory diastolic blood pressure (BP) after 6 weeks of ACE inhibitor monotherapy (benazepril, 20 mg, o.d.) were randomized to receive double-blind valsartan, 80 mg, o.d. (AT1 antagonist) or matching placebo for 5 weeks while continuing to receive background benazepril. Then patients crossed over to the alternative regimen for a second 5-week period. The 24-h ambulatory BP was monitored on the final day of the benazepril monotherapy period and on the final day of each double-blind treatment period. Valsartan added to benazepril produced a significant antihypertensive effect with a benefit over placebo of 6.5 +/- 12.6/4.5 +/- 8.0 mm Hg (systolic/diastolic) for average awake ambulatory BP (p < 0.05), 7.1 +/- 9.4/5.6 +/- 6.5 mm Hg for asleep BP (p < 0.01), and 6.8 +/- 9.7/4.9 +/- 6.8 mm Hg for average 24-h ambulatory BP (p < 0.01). Pulse rate was unaffected. Plasma active renin was higher on the benazepril-valsartan combination compared with benazepril-placebo (p < 0.05). There was no change in routine biochemical variables when valsartan was added to benazepril. Six patients reported mild dizziness or fatigue (three also with placebo). These data suggest that in hypertensive patients uncontrolled with an ACE inhibitor, the addition of an AT1 antagonist provides a powerful and safe antihypertensive drug combination.
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PMID:Additive hypotensive effect of angiotensin-converting enzyme inhibition and angiotensin-receptor antagonism in essential hypertension. 1083 30

Angiotensin II receptor blockers (ARBs) represent a new class of effective and well tolerated orally active antihypertensive agents. Recent clinical trials have shown the added benefits of ARBs in hypertensive patients (reduction in left ventricular hypertrophy, improvement in diastolic function, decrease in ventricular arrhythmias, reduction in microalbuminuria, and improvement in renal function), and cardioprotective effect in patients with heart failure. Several large long-term studies are in progress to assess the beneficial effects of ARBs on cardiac hypertrophy, renal function, and cardiovascular and cerebrovascular morbidity and mortality in hypertensive patients with or without diabetes mellitus, and the value of these drugs in patients with heart disease and diabetic nephropathy. The ARBs specifically block the interaction of angiotensin II at the AT1 receptor, thereby relaxing smooth muscle, increasing salt and water excretion, reducing plasma volume, and decreasing cellular hypertrophy. These agents exert their blood pressure-lowering effect mainly by reducing peripheral vascular resistance usually without a rise in heart rate. Most of the commercially available ARBs control blood pressure for 24 h after once daily dosing. Sustained efficacy of blood pressure control, without any evidence of tachyphylaxis, has been demonstrated after long-term administration (3 years) of some of the ARBs. The efficacy of ARBs is similar to that of thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors or calcium channel blockers in patients with similar degree of hypertension. Higher daily doses, dietary salt restriction, and concomitant diuretic or ACE inhibitor administration amplify the antihypertensive effect of ARBs. The ARBs have a low incidence of adverse effects (headache, upper respiratory infection, back pain, muscle cramps, fatigue and dizziness), even in the elderly patients. After the approval of losartan, five other ARBs (candesartan cilexetil, eprosartan, irbesartan, telmisartan, and valsartan) and three combinations with hydrochlorothiazide (irbesartan, losartan and valsartan) have been approved as antihypertensive agents, and some 28 compounds are in various stages of development. The ARBs are non-peptide compounds with varied structures; some (candesartan, losartan, irbesartan, and valsartan) have a common tetrazolo-biphenyl structure. Except for irbesartan, all active ARBs have a carboxylic acid group. Candesartan cilexetil is a prodrug, while losartan has a metabolite (EXP3174) which is more active than the parent drug. No other metabolites of ARBs contribute significantly to the antihypertensive effect. The variation in the molecular structure of the ARBs results in differences in the binding affinity to the receptor and pharmacokinetic profiles. The differences observed in lipid solubility, absorption/distribution, plasma protein binding, bioavailability, biotransformation, plasma half-life, and systemic elimination influence the time of onset, duration of action, and efficacy of the ARBs. On the basis of the daily mg dose, the antihypertensive potency of the ARBs follows the sequence: candesartan cilexetil > telmisartan approximately = losartan > irbesartan approximately = valsartan > eprosartan. After oral administration, the ARBs are rapidly absorbed (time for peak plasma levels = 0.5-4 h) but they have a wide range of bioavailability (from a low of 13% for eprosartan to a high of 60-80% for irbesartan); food does not influence the bioavailability, except for valsartan (a reduction of 40-50%) and eprosartan (increase). A limited dose-peak plasma levels/areas under the plasma level-time curve proportionality is observed for some of the ARBs. Most of these drugs have high plasma protein binding (95-100%); irbesartan has the lowest binding among the group (90%). The steady-state volumes of distribution vary from a low of 9 L (candesartan) to a high of 500 L (telmisartan). (ABSTRACT TRUNCATE
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PMID:Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension. 1085 85

Angiotensin II receptor blockers have shown widespread efficacy as antihypertensive medications. These agents bind selectively to angiotensin II type 1 (AT(1)) receptors, specifically blocking the renin-angiotensin system at the last step in its cascade. CS-866 is the most recently introduced drug in this class. This article presents integrated safety and efficacy data from 7 randomized, double-blind, placebo-controlled, parallel group studies in which once-daily CS-866 monotherapy was used in the treatment of patients with essential hypertension (sitting diastolic blood pressure > or =100 mm Hg and < or =115 mm Hg). Data from a total of 2,145 CS-866-treated patients were included in the efficacy analysis. Safety data were available from 2,540 CS-866-treated patients, with a cumulative exposure of 5,888 patient-months. The antihypertensive efficacy of the drug was assessed using both cuff blood pressure measurements and 24-hour ambulatory blood pressure monitoring. The data show that CS-866 is effective and safe for the treatment of hypertension. Dose-dependent reductions in both diastolic and systolic blood pressures occurred within 1 week of initiating treatment, and the response was almost maximal within 2 weeks. There was no difference in efficacy between younger (<65 years) and older (> or =65 years) groups of patients. Trough-to-peak ratios showed that CS-866 retains the majority of its peak effect 24 hours after treatment, and is therefore suitable for once-daily dosing. Dizziness was the only treatment-emergent adverse event with which CS-866 was associated.
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PMID:Clinical studies of CS-866, the newest angiotensin II receptor antagonist. 1133 67

Posttransplant erythrocytosis (PTE) is defined as a persistently elevated hematocrit to a level greater than 51% after renal transplantation. It occurs in 10% to 15% of graft recipients and usually develops 8 to 24 months after engraftment. Spontaneous remission of established PTE is observed in one fourth of the patients within 2 years from onset, whereas in the remaining three fourths it persists for several years, only to remit after loss of renal function from rejection. Predisposing factors include male gender, retention of native kidneys, smoking, transplant renal artery stenosis, adequate erythropoiesis prior to transplantation, and rejection-free course with well-functioning renal graft. Just as in other forms of erythrocytosis, a substantial number (approximately 60%) of patients with PTE experience malaise, headache, plethora, lethargy, and dizziness. Thromboembolic events occur in 10% to 30% of the cases; 1% to 2% eventually die of associated complications. Posttransplant erythrocytosis results from the combined trophic effect of multiple and interrelated erythropoietic factors. Among them, endogenous erythropoietin appears to play the central role. Persistent erythropoietin secretion from the diseased and chronically ischemic native kidneys does not conform to the normal feedback regulation, thereby establishing a form of "tertiary hypererythropoietinemia." However, erythropoietin levels in most PTE patients still remain within the "normal range," indicating that erythrocytosis finally ensues by the contributory action of additional growth factors on erythroid progenitors, such as angiotensin II, androgens, and insulin-like growth factor 1 (IGF-1). Inactivation of the renin-angiotensin system (RAS) by an angiotensin-converting enzyme (ACE) inhibitor, or an angiotensin II type 1 AT1 receptor blocker represents the most effective, safe, and well-tolerated therapeutic modality.
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PMID:Posttransplant erythrocytosis. 1263 34

Elevated blood pressure is a risk factor for a variety of cardiovascular disorders, including coronary heart disease, peripheral vascular disease, cardiac failure and cerebrovascular disease. The prevailing view is that an elevated systolic rather than diastolic blood pressure is the major contributor in mortality and morbidity attributed to cardiovascular disorders. Isolated high systolic blood pressure, especially in the elderly, is a major risk factor and should undoubtedly be a target for drug treatment. In the general population, systolic and diastolic blood pressure are highly correlated, and thus it is difficult to dissociate the effects of these two components of the blood pressure and specifically ascribe cardiovascular risk factors to just elevated systolic blood pressure. Therefore, the goal in therapy of an individual with hypertension must be to reduce elevated systolic and diastolic blood pressure in order to reduce mortality and morbidity. ACE and neutral peptidase inhibitors are a new class of drugs that may be beneficial in the treatment of patients with hypertension and heart failure. They may also be useful in the treatment of diabetic patients with hypertension and/or heart failure. Drugs of this class are dual inhibitors of ACE and neutral endopeptidase, and are capable of affecting vascular tone and fluid balance. They are capable of producing vasodilatation by virtue of inhibiting the production of angiotensin II, degradation of natriuretic peptides and bradykinin. They also appear to promote natriuresis and diuresis by amplifying the actions of natriuretic peptidase and reducing aldosterone effects. In addition, they should also attenuate trophogenic actions of the renin angiotensin system and the sympathetic nervous system. Omapatrilat is one drug that appears to be at the advanced stages of clinical development. This drug has been shown to be quite effective in the treatment of hypertension. Evidence also seems to indicate that treatment with omapatrilat results in a higher tendency towards preventing death and worsening heart failure when compared with treatment with a pure ACE inhibitor in patients with advanced heart failure. Overall safety with omapatrilat appears to be good, but like other ACE inhibitors the incidence of cough is higher when compared with placebo. Other common adverse effects noted are headaches, facial flushing/warm sensation, dizziness, nausea and dyspnoea. Of greater concern is the occurrence of angio-oedema, the true incidence of which remains to be fully established as part of the published medical literature.
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PMID:Dual ACE and neutral endopeptidase inhibitors: novel therapy for patients with cardiovascular disorders. 1501 94

An 89-year-old man with severe hypertension (190/82 mm Hg) and chronic heart failure (New York Heart Association class II) despite treatment with benidipine, doxazosin mesylate (INN, doxazosin), and furosemide was given oral candesartan cilexetil (4 mg/d), an angiotensin II type 1 receptor blocker metabolized via cytochrome p450 (CYP) 2C9. Two days later, he started to have severe dizziness and returned to the hospital on the fourth day without taking any of his medications. The blood pressure 30 hours after the last dose of candesartan was 126/64 mm Hg. Polymorphism analysis revealed the heterozygous poor metabolizer genotype CYP2C9*1/*3. The area under the concentration-time curve and the mean residence time of candesartan were both increased 2.5-fold, and the oral clearance of candesartan was 48% lower than that of the average elderly Japanese patient with hypertension. These results suggest that the CYP2C9*1/*3 genotype could be associated with decreased clearance and increased plasma concentration of candesartan, potentially enhancing its hypotensive effect.
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PMID:Altered pharmacokinetics and excessive hypotensive effect of candesartan in a patient with the CYP2C91/3 genotype. 1458 91

Valsartan, an orally active nonpeptide angiotensin II (AII) receptor antagonist with selectivity for the AII type I (AT(1)) receptor subtype, has recently been approved by the US Food and Drug Administration for the treatment of patients with heart failure (New York Health Association class II-IV) who are intolerant of ACE-inhibitor therapy. Results from the Valsartan Heart Failure Trial (Val-HeFT) showed that in patients with chronic heart failure (CHF) [n = 5010], valsartan 160 mg twice daily, when used in combination with conventional therapy for heart failure, reduced the risk of the combined endpoint of mortality and morbidity by 13.2% compared with placebo. However, there was no significant difference in overall mortality between the valsartan and placebo groups. Morbidity was defined as cardiac arrest with resuscitation, hospitalization for heart failure, or administration of intravenous inotropic or vasodilator drugs for > or =4 hours without hospitalization. Among patients not receiving an ACE inhibitor, irrespective of concomitant beta-blocker use, valsartan reduced the risk of mortality and the combined endpoint by 33.1% and 44% compared with placebo; total hospitalizations for heart failure were also significantly lower in the valsartan group (27.6 vs 64.6%). In the subgroup of patients who were taking an ACE inhibitor and a beta-blocker at baseline (n = 1610), mortality was significantly higher in the valsartan group than in the placebo group. The most common adverse events in the valsartan and placebo groups which led to discontinuation of treatment were dizziness, renal impairment (both of which occurred in significantly more valsartan recipients) and hypotension.
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PMID:Valsartan: in chronic heart failure. 1472 72

Candesartan cilexetil is the prodrug of candesartan, an angiotensin II receptor antagonist. Candesartan binds selectively and non-competitively to the angiotensin II receptor type 1, thus preventing the actions of angiotensin II. Clinical trials have demonstrated its efficacy at a dose range of 2 to 32 mg once daily in hypertension of all grades, heart failure, in reducing urinary albumin excretion in diabetes mellitus and in coexisting hypertension and renal failure. Pharmacokinetic properties of candesartan cilexetil in elderly patients are not significantly different from those in younger individuals. Hepatic impairment does not change pharmacokinetics of candesartan cilexetil at doses up to 12 mg/day. No dose adjustment is necessary in patients with mild or moderate renal impairment. Tolerability of candesartan cilexetil is not much different from that of placebo. All adverse events are usually of mild to moderate severity and not dose-related. The most common adverse events were headache, upper respiratory tract infection, back pain, and dizziness. The incidence of these adverse effects, as well as of cough, was similar in patients treated with candesartan cilexetil or placebo. The incidence of adverse events in long-term trials was not different from that in short-term trials. Tolerability of candesartan cilexetil does not differ with either age or gender.
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PMID:Candesartan. 1559 74

Agents that interfere with the renin-angiotensin system (RAS) reduce proteinuria and afford renal protection. The combination of different measures that serve maximization of RAS blockade is thought to improve the antiproteinuric efficacy. The feasibility and the efficacy of such a combination strategy were studied in nondiabetic patients with residual proteinuria during previous RAS blockade by individual antiproteinuric titration. Previous medication was replaced by irbesartan 300 mg combined with a diuretic. Lisinopril was added in increasing doses until a maximal dose of 40 mg/d. Titration stopped when target proteinuria (< 1 g/d) was reached or further dose titration was not tolerated because of side effects. Residual proteinuria (median, 3.2 g/d; 95% confidence interval, 1.8 to 5.2 g/d) was significantly reduced with 55.6% (95% confidence interval, 16.0 to 73.2%; P < 0.02) on the maximal additional tolerated dose of lisinopril. The maximal dose of lisinopril was 10 mg in two of eight, 20 mg in two of eight, 30 mg in one of eight, and 40 mg in three of eight patients. At this dose, target proteinuria of < 1 g/d was reached in two of eight patients. The number of patients with adverse events during dose titration was five of eight patients: two had cough; two had hyperkalemia (> 5.5 mmol/L), one of whom had > 50% increase of serum creatinine; and one had dizziness. In conclusion, individual titration for maximal RAS blockade, entailing dose titration of angiotensin-converting enzyme inhibitors on top of high-dose angiotensin II antagonists with diuretic, induces further reduction of residual proteinuria. However, this occurs at the expense of adverse events. To further improve renoprotective treatment strategies, it is important to explore other modes of antiproteinuric intervention in patients with residual proteinuria during RAS blockade.
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PMID:Individual titration for maximal blockade of the renin-angiotensin system in proteinuric patients: a feasible strategy? 1593 35


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