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A large-scale, 8-week, open-label, clinical experience trial evaluated the efficacy of the angiotensin II receptor (AT1 subtype) blocker candesartan cilexetil (16 to 32 mg once daily) either alone or as add-on therapy in 6465 hypertensive patients. The study population was 52% female and 16% African American with a mean age of 58 years. It included 5,446 patients who had essential hypertension (HBP) and 1,014 patients who had isolated systolic hypertension (ISH). These patients had either untreated or uncontrolled hypertension (systolic blood pressure [SBP] 140 to 179 mm Hg or diastolic blood pressure [DBP] 90 to 109 mm Hg inclusive at baseline) despite a variety of antihypertensive medications including diuretics, calcium antagonists, angiotensin converting enzyme (ACE) inhibitors, and alpha- or beta-blockers, either singly or in combination. The mean baseline blood pressure for the HBP group was 156/97 mm Hg. Candesartan cilexetil as monotherapy (in 51% of HBP patients) reduced mean SBP/DBP by 18.7/ 13.1 mm Hg. As add-on therapy (in 49% of HBP patients) to various background therapies, candesartan cilexetil consistently reduced mean SBP/DBP further, irrespective of the background therapy: diuretics (17.8/11.3 mm Hg), calcium antagonists (16.6/11.2 mm Hg), beta-blockers (16.5/ 10.4 mm Hg), ACE inhibitors (15.3/10.0 mm Hg), alpha-blockers (16.4/10.4 mm Hg). The mean baseline blood pressure for the ISH group was 158/81 mm Hg. Candesartan cilexetil, as monotherapy (in 34% of ISH patients), reduced SBP/DBP by 17.0/4.4 mm Hg. As add-on therapy (in 66% of ISH patients) to various background therapies, candesartan cilexetil consistently reduced mean SBP/DBP further, irrespective of the background therapy: diuretics (17.4/5.1 mm Hg), calcium antagonists (15.6/3.6 mm Hg), beta-blockers (14.0/4.8 mm Hg), ACE inhibitors (13.4/4.3 mm Hg), and alpha-blockers (11.6/4.5 mm Hg). The further blood pressure lowering effects of candesartan cilexetil as add-on therapy were seen regardless of age, sex, and race. Overall, 6.8% of the 6465 patients withdrew because of adverse events, most commonly headache (6.3%) and dizziness (5.0%). Orthostatic hypotension was infrequent; 0.2% with candesartan cilexetil alone, and 0.8% with candesartan cilexetil as add-on therapy. Thus, candesartan cilexetil either alone or as add-on therapy was highly effective for the control of systolic or diastolic hypertension regardless of demographic background when used in typical clinical practice settings.
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PMID:Efficacy of candesartan cilexetil as add-on therapy in hypertensive patients uncontrolled on background therapy: a clinical experience trial. ACTION Study Investigators. 1141 37

Ambulatory blood-pressure monitoring (ABPM) is accepted in the evaluation and management of hypertension. The use of ABPM in heart failure has received considerably less attention. Many patients with advanced heart failure experience disabling fatigue, orthostatic dizziness and symptoms of coronary and cerebrovascular insufficiency that may relate to periods of hypotension. These may be exacerbated by vasodilator drug therapy and may be difficult to evaluate by casual clinic recordings. ABPM in heart failure may help in the following: (i) evaluating time-dependent pharmacodynamic drug effects, such as peak and end-of-dose phenomena, tolerance and rebound; (ii) titrating ACE inhibitors and other drugs to highest-tolerated doses; and (iii) correlating circadian blood-pressure profiles with symptoms, quality of life, severity of heart failure, progression of ventricular and renal dysfunction, risks of stroke and myocardial infarction, and life expectancy. Devices for ABPM have been beset by problems of inaccuracy and unreliability. Standards for their manufacture and sale (including bench tests of accuracy against sphygmomanometry and intra-arterial recordings, and field tests of reliability) have been devised independently by several agencies, including the British Hypertension Society (BHS) and US Association for the Advancement of Medical Instrumentation (AAMI). A joint BHS/AAMI set of guidelines is in preparation. These guidelines emphasize the suitability of ABPM devices for hypertensive patients and those under general anesthesia, and may not be applicable to ambulant individuals with heart failure and blood pressures at or below the lower end of the evaluated ranges. Prospective studies of the accuracy and reliability of ABPM devices, their clinical utility and research potential should be undertaken in patients with heart failure before their informal and uncontrolled use in this population becomes widespread.
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PMID:Ambulatory blood pressure in heart failure. 1152 34

Intracranial aneurysms (ICA) are a well-known feature of autosomal dominant polycystic kidney disease. There is only one report about ICA in an adult patient with autosomal recessive polycystic kidney disease (ARPKD). We observed a 2-year, 6-month old girl with ARPKD and multiple ICA. The family history is negative for kidney disease. The diagnosis of ARPKD was based on the typical findings in ultrasonography and computed tomography. Cystic ectasia of biliary ducts 6.3/4.8 cm in diameter was found in the liver. Arterial hypertension in a range of 140/100-170/120 mm Hg was registered. The child has polyuria, polydipsia and enuresis. Blood urea was 15 mmol/l, creatinine in a range of 120 to 75 micromol/l. One episode of vomiting, dizziness and lethargy was the reason for a brain magnetic resonance imaging. Multiple fusiform and saccular aneurysms in the branches of middle and posterior cerebral arteries were seen bilaterally. The girl is growing well without neurological symptoms during an observation period of 1.5 years. Blood pressure is well controlled with an ACE inhibitor (Enalapril 2.5 mg daily). It was concluded that ICA can be found in patients with ARPKD. Blood pressure control is essential to reduce the risk of intracranial hemorrhage.
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PMID:Intracranial aneurysms in a child with autosomal recessive polycystic kidney disease. 1179 94

The ideal antihypertensive drug should be effective in reducing blood pressure, but have a low incidence of adverse effects. Angiotensin II receptor blockers, such as eprosartan, are as effective as ACE inhibitors in reducing blood pressure, but lack the main adverse effect of ACE inhibitors, namely cough. Eprosartan has been shown to be well tolerated with a placebo-like adverse-effect profile. When given as monotherapy it is effective in reducing blood pressure; however, some patients require additional blood pressure control, which may be provided by combination therapy. Indeed, the combination of eprosartan and the thiazide diuretic hydrochlorothiazide has been shown to be effective in further reducing blood pressure in patients not optimally responding to eprosartan monotherapy. This article reviews the safety and tolerability of eprosartan in combination with hydrochlorothiazide from 17 studies of 1899 patients with hypertension and normotensive volunteers. Of these studies, four were controlled with patients receiving a fixed-dose combination, six were long-term, open-label, and another four were controlled studies with hydrochlorothiazide being given to eprosartan non-responders. The other three studies included healthy subjects receiving the combination of eprosartan and hydrochlorothiazide. There was a high completion rate in all studies evaluated. Most of the patients receiving eprosartan 600mg in combination with hydrochlorothiazide 12.5mg daily completed the studies, which supports acceptance of this combination therapy by patients. The most frequently reported adverse events in these combination studies were headache, dizziness, myalgia, and upper respiratory tract infection in patients with hypertension. The majority of adverse events were mild to moderate in intensity, and were not considered to be related to study treatment. The adverse event that was more common in patients receiving combination therapy compared with those receiving monotherapy was dizziness. This adverse event may be due to hydrochlorothiazide as it has previously been observed in patients taking thiazide diuretics. In healthy volunteers, the most frequently reported adverse events were headache, dizziness, and upper respiratory tract infection. However, none of these adverse events were considered related to study medication. In summary, the combination of eprosartan/hydrochlorothiazide is well tolerated, both as short- and long-term therapy, with most adverse events occurring early. The most frequent adverse events were headache, dizziness, and upper respiratory infection, which would be expected based on the safety profile of each of the components. Therefore, the combination of eprosartan with hydrochlorothiazide can be effectively and safely used in patients not adequately responding to eprosartan monotherapy.
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PMID:Safety and tolerability of eprosartan in combination with hydrochlorothiazide. 1211 44

In well designed studies in patients with mild to moderate hypertension, combinations of the sustained-release (SR) formulation of the nondihydropyridine calcium channel antagonist verapamil 120 to 240 mg/day and the ACE inhibitor trandolapril 0.5 to 8 mg/day were significantly more effective in reducing sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline than placebo. In most randomised studies, combinations of verapamil SR 120 to 240 mg/day and trandolapril 0.5 to 8 mg/day were significantly more effective in lowering sitting DBP and SBP than the corresponding monotherapies administered at the same dosage. Trandolapril/verapamil SR 2/180 mg/day provided significantly more effective 24-hour ambulatory blood pressure (BP) control than of the corresponding monotherapies. Moreover, trandolapril/verapamil SR reduced BP in patients inadequately controlled with either of the corresponding monotherapies. The antihypertensive efficacy of trandolapril/verapamil SR 2/180 mg/day was generally similar to that of other combinations of antihypertensive agents (metoprolol/hydrochlorothiazide, atenolol/chlorthalidone, lisinopril/hydrochlorothiazide, enalapril/hydrochlorothiazide) in patients with hypertension, including those with type 2 diabetes mellitus. Trandolapril/verapamil SR reduced BP in patients with hypertension and type 2 diabetes or primary renal disease, Black patients and elderly patients. Trandolapril/verapamil SR was more effective than the individual components administered as monotherapy in reducing proteinuria in patients with type 2 diabetes or primary renal disease. Trandolapril/verapamil SR had a neutral or beneficial effect on metabolic parameters (glucose, insulin, lipids) in patients with hypertension, including those with type 2 diabetes. Trandolapril/verapamil SR preserved left ventricular function in patients with heart failure. Fewer cardiac events occurred after therapy with trandolapril/verapamil SR than after trandolapril alone in post-myocardial infarction patients with congestive heart failure. The incidence of adverse events in recipients of trandolapril/verapamil SR was similar to that of the individual components, and that of other combination therapies. In placebo-controlled trials conducted in the US, headache, upper respiratory tract infections, cough, constipation, atrioventricular block (first degree) and dizziness were the most commonly reported adverse events in recipients of combinations of verapamil SR (120 to 240 mg/day) and trandolapril (0.5 to 8 mg/day). In conclusion, the fixed-dose combination of trandolapril/verapamil SR is an effective treatment for patients with hypertension, including those with type 2 diabetes. Trandolapril/verapamil SR tended to be more effective than monotherapy with either verapamil SR or trandolapril, and generally showed antihypertensive efficacy similar to that of other combination antihypertensive therapies. Current data support the use of trandolapril/verapamil SR as an alternative treatment when monotherapy with either agent is not effective. Data from large clinical trials currently being conducted will assist in fully defining the role of trandolapril/verapamil SR as a cardio- and renoprotective agent.
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PMID:Fixed combination trandolapril/verapamil sustained-release: a review of its use in essential hypertension. 1242 Nov 12

Bisoprolol is a highly selective beta(1)-adrenoceptor antagonist. Administration of bisoprolol to patients with chronic heart failure is associated with increases in left ventricular function and reductions in heart rate; increases in heart rate variability are also seen. Two major randomised, double-blind, placebo-controlled, multicentre trials have examined the clinical efficacy of bisoprolol in combination with ACE inhibitors and diuretics in patients with stable chronic heart failure (New York Heart Association class III or IV): the Cardiac Insufficiency Bisoprolol Study (CIBIS; n = 641) and CIBIS II (n = 2 647). All-cause mortality (primary endpoint) was significantly lower in bisoprolol than in placebo recipients in CIBIS II (11.8 vs 17.3%) and was reduced by bisoprolol regardless of dosage. All-cause mortality was also lower in CIBIS (16.6 vs 20.9%) although the difference did not achieve statistical significance. In a meta-analysis of CIBIS and CIBIS II (n = 3 288), a relative reduction of 29% in the incidence of all-cause mortality was seen in bisoprolol versus placebo recipients; this analysis also demonstrated that bisoprolol reduces mortality in patients with chronic heart failure regardless of aetiology or severity. In CIBIS II, there were significantly fewer cardiovascular deaths, admissions to hospital for any reason, or cardiovascular deaths or cardiovascular hospitalisations (combined endpoint) in bisoprolol, compared with placebo, recipients (secondary endpoints). Compared with standard treatment alone, the addition of bisoprolol was a cost-effective option in chronic heart failure in UK, French, German and Swedish pharmacoeconomic studies. Bisoprolol is generally well tolerated in patients with chronic heart failure. In CIBIS II, adverse events occurring more commonly in bisoprolol than placebo recipients, regardless of causal relationship with the study medication, included dizziness, bradycardia, hypotension and fatigue. Bisoprolol recipients were less likely than placebo recipients to experience worsening of heart failure, dyspnoea or tachycardia. In both CIBIS and CIBIS II there was no significant difference between bisoprolol and placebo recipients in the incidence of permanent treatment withdrawal. In conclusion, adding the highly selective beta(1)-blocker bisoprolol to a treatment regimen comprising an ACE inhibitor and a diuretic significantly improves survival in patients with stable chronic heart failure and reduces the need for hospitalisation. The use of bisoprolol in this disorder is generally well tolerated and is cost effective. Thus, bisoprolol should be considered a standard treatment option when selecting a beta-blocker for use in combination with ACE inhibitors and diuretics in patients with stable, moderate to severe chronic heart failure.
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PMID:Bisoprolol: a review of its use in chronic heart failure. 1246 13

The current prescription patterns for essential hypertension and the efficacy, safety, tolerability and cost-effectiveness of the newer antihypertensive drugs were evaluated in Nigerian patients. The findings were compared with that of a previous study conducted in the same tertiary hospital 10 years earlier. A cross-sectional evaluation of blood pressure (BP) control in a hypertension clinic was undertaken among 150 Nigerian patients aged 61 +/- 12 years (55% females), with a duration of treatment on a particular drug class or combination of 9 +/- 3 months. The initial blood pressure was 176 +/- 20/108 +/- 11 mmHg and 22% of the patient had concurrent diabetes mellitus. Thiazide diuretics (D) alone or in combination remained the most commonly prescribed drugs in 56% of all patients. There were significant increases in the prescriptions of calcium channel blockers (CCBs) (51%), P < 0.0001, and ACE-inhibitors (ACEIs) (24%), P < 0.0001, but a slight reduction in the use of methyldopa, and fixed drug combinations (P < 0.01) compared to the previous study. The fall in systolic blood pressure on D (r = 0.65, P < 0.001) or CCB (r = 0.48, P < 0.02) was significantly correlated with the initial systolic blood pressure, but not age. More patients achieved normotension BP < 140/90 mmHg on CCB monotherapy (71%), than D monotherapy (56%). Combination therapy with ACEIs + D or methyldopa+thiazides normalized BP in 63 and 68%, respectively. Pulse pressure, a surrogate marker for cardiovascular complications and mortality in essential hypertension, was significantly reduced (P < 0.01) equally by all treatments, with 95% confidence intervals ranging from -28 to -1 mmHg. However, hypertensive-diabetic (HT-DM) patients (n = 33) exhibited no significant change in pulse pressure in response to treatment. Adverse drug reactions that occurred in 11% were impotence or postural dizziness with D, headache and pitting oedema with CCB, and dry cough with ACEI. Pharmaco-economic comparison of the drug classes revealed that for every US dollar (dollar) spent per month, the percentage of treated patients attaining normotension was 18.6 for D, 4.73 for CCB, 3.5 for ACEI + D and 13.6 for methyldopa + thiazides. A combination of ACEI + CCB or D was the preferred treatment for hypertensive-diabetic Nigerians, but only 24% attained a BP < 130/85 mmHg. These results demonstrate a shift in trend to a more rational and efficacious treatment of hypertension over a 10 year period. This may be associated, at least in part, with the intensive and continuous education of the prescribers in rational drug use and the introduction of a hospital formulary. Methyldopa is still a highly efficacious and cost-effective drug in this population. Black HT-DM Africans still constitute a subgroup who not only require more and costlier antihypertensive drugs, but whose BP control is suboptimal, and exhibit a poor therapeutic response to other risk factors (pulse pressure) that constitute a continuing risk for cardiovascular mortality.
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PMID:Shifting trends in the pharmacologic treatment of hypertension in a Nigerian tertiary hospital: a real-world evaluation of the efficacy, safety, rationality and pharmaco-economics of old and newer antihypertensive drugs. 1271 73

Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes. Despite its relationship to an increased risk of cardiovascular mortality and its association with multiple symptoms and impairments, the significance of DAN has not been fully appreciated. The reported prevalence of DAN varies widely depending on the cohort studied and the methods of assessment. In randomly selected cohorts of asymptomatic individuals with diabetes, approximately 20% had abnormal cardiovascular autonomic function. DAN frequently coexists with other peripheral neuropathies and other diabetic complications, but DAN may be isolated, frequently preceding the detection of other complications. Major clinical manifestations of DAN include resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastroparesis, erectile dysfunction, sudomotor dysfunction, impaired neurovascular function, "brittle diabetes," and hypoglycemic autonomic failure. DAN may affect many organ systems throughout the body (e.g., gastrointestinal [GI], genitourinary, and cardiovascular). GI disturbances (e.g., esophageal enteropathy, gastroparesis, constipation, diarrhea, and fecal incontinence) are common, and any section of the GI tract may be affected. Gastroparesis should be suspected in individuals with erratic glucose control. Upper-GI symptoms should lead to consideration of all possible causes, including autonomic dysfunction. Whereas a radiographic gastric emptying study can definitively establish the diagnosis of gastroparesis, a reasonable approach is to exclude autonomic dysfunction and other known causes of these upper-GI symptoms. Constipation is the most common lower-GI symptom but can alternate with episodes of diarrhea. Diagnostic approaches should rule out autonomic dysfunction and the well-known causes such as neoplasia. Occasionally, anorectal manometry and other specialized tests typically performed by the gastroenterologist may be helpful. DAN is also associated with genitourinary tract disturbances including bladder and/or sexual dysfunction. Evaluation of bladder dysfunction should be performed for individuals with diabetes who have recurrent urinary tract infections, pyelonephritis, incontinence, or a palpable bladder. Specialized assessment of bladder dysfunction will typically be performed by a urologist. In men, DAN may cause loss of penile erection and/or retrograde ejaculation. A complete workup for erectile dysfunction in men should include history (medical and sexual); psychological evaluation; hormone levels; measurement of nocturnal penile tumescence; tests to assess penile, pelvic, and spinal nerve function; cardiovascular autonomic function tests; and measurement of penile and brachial blood pressure. Neurovascular dysfunction resulting from DAN contributes to a wide spectrum of clinical disorders including erectile dysfunction, loss of skin integrity, and abnormal vascular reflexes. Disruption of microvascular skin blood flow and sudomotor function may be among the earliest manifestations of DAN and lead to dry skin, loss of sweating, and the development of fissures and cracks that allow microorganisms to enter. These changes ultimately contribute to the development of ulcers, gangrene, and limb loss. Various aspects of neurovascular function can be evaluated with specialized tests, but generally these have not been well standardized and have limited clinical utility. Cardiovascular autonomic neuropathy (CAN) is the most studied and clinically important form of DAN. Meta-analyses of published data demonstrate that reduced cardiovascular autonomic function as measured by heart rate variability (HRV) is strongly (i.e., relative risk is doubled) associated with an increased risk of silent myocardial ischemia and mortality. The determination of the presence of CAN is usually based on a battery of autonomic function tests rather than just on one test. Proceedings from a consensus conference in 1992 recommended that three tests (R-R variation, Valsalva maneuver, and postural blood pressure testing)or longitudinal testing of the cardiovascular autonomic system. Other forms of autonomic neuropathy can be evaluated with specialized tests, but these are less standardized and less available than commonly used tests of cardiovascular autonomic function, which quantify loss of HRV. Interpretability of serial HRV testing requires accurate, precise, and reproducible procedures that use established physiological maneuvers. The battery of three recommended tests for assessing CAN is readily performed in the average clinic, hospital, or diagnostic center with the use of available technology. Measurement of HRV at the time of diagnosis of type 2 diabetes and within 5 years after diagnosis of type 1 diabetes (unless an individual has symptoms suggestive of autonomic dysfunction earlier) serves to establish a baseline, with which 1-year interval tests can be compared. Regular HRV testing provides early detection and thereby promotes timely diagnostic and therapeutic interventions. HRV testing may also facilitate differential diagnosis and the attribution of symptoms (e.g., erectile dysfunction, dyspepsia, and dizziness) to autonomic dysfunction. Finally, knowledge of early autonomic dysfunction can encourage patient and physician to improve metabolic control and to use therapies such as ACE inhibitors and beta-blockers, proven to be effective for patients with CAN.
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PMID:Diabetic autonomic neuropathy. 1271 21

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

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


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