Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sulphonylureas and the biguanides are widely used as adjuncts to dietary measures in the treatment of non-insulin-dependent (type 2) diabetes mellitus (NIDDM). Adverse effect profiles differ markedly between the sulphonylureas and biguanides, reflecting differences in chemical structure and mode of action. Sulphonylureas are generally well tolerated, although pharmacokinetic differences between these agents have important clinical implications. The main adverse effect associated with sulphonylureas is hypoglycaemia. This effect is a predictable consequence of the principal pharmacological effect of these drugs, i.e. sensitisation of the islet beta-cell to glucose, resulting in enhanced endogenous insulin secretion. Sulphonylurea-induced suppression of hepatic glucose production may cause profound and protracted hypoglycaemia, especially in elderly patients, in individuals with intercurrent illnesses and reduced caloric intake, or when taken in combination with other compounds with hypoglycaemic potential, e.g. alcohol (ethanol). Sulphonylureas with a longer duration of action, notably chlorpropamide and glibenclamide (glyburide), are more liable to induce serious hypoglycaemia, particularly when drug elimination is reduced by renal impairment. Other drugs such as salicylates may potentiate the actions of sulphonylureas, thereby increasing the risk of hypoglycaemia. Biguanide therapy is associated with alterations in lactate homeostasis which under certain clinical circumstances may result in fatal lactic acidosis. Phenformin is associated with a markedly greater risk of lactic acidosis than metformin. Phenformin has been withdrawn in many countries for this reason. All biguanides must be avoided in patients with renal impairment, hepatic dysfunction and cardiac failure--conditions where drug accumulation or disordered lactate metabolism may predispose to lactic acidosis. Phenformin should not be given to individuals who exhibit a severe, genetically conferred hepatic defect of hydroxylation which impedes metabolism of this drug. Less seriously, the biguanides are associated with a relatively high incidence of gastrointestinal adverse effects which limit compliance. Acarbose, a competitive inhibitor of intestinal alpha-glucosidases, has recently been introduced. In contrast to the sulphonylureas and biguanides, acarbose has not been associated with life-threatening adverse effects. This reflects the low systemic absorption of the drug and, predictably, its principal unwanted effects are gastrointestinal disturbances resulting from iatrogenic carbohydrate malabsorption.
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PMID:Comparative tolerability profiles of oral antidiabetic agents. 784 43

First, we had the discussion 'Are all ACE inhibitors equal?', and the debate was really in relation to heart failure. I came away with the impression that although there might be variations with renal function, hypotension and so on, most of you felt that it was ACE inhibition that was of primary importance, and that it was therefore permissible to extrapolate from one study to another. The recently published AIRE study of post-infarct patients used ramipril, with a change in mortality that gives credence to the idea that it's not just captopril, not just enalapril, but is likely to be a class effect of ACE inhibitors. I think that's the feeling I got from you. Do ACE inhibitors prolong life? I think Professor Weich made a very simple and a very good point, because it allowed us a general extrapolation. The simple point is: the sicker the patient, certainly with heart failure, the more the benefit of the ACE inhibitor. It's like the idea that in elderly hypertensives, or the diabetic hypertensive, the greater the risk factor the greater the benefit. The more we want to treat prophylactically, whether it's micro-albuminuria, or transient hypertension, or minimal left ventricular dysfunction, the longer we will have to treat, and the more patients we will have to treat to get objective evidence of any differences. Professor Oosthuizen suggested that we should also be thinking of renal impairment, potential renal impairment with cardiovascular disease in diabetes as another valid end-point.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The Grande Roche ACE debate. 804 78

The conventional pharmacokinetic profile of the angiotensin converting enzyme (ACE) inhibitor, enalapril, is a lipid-soluble and relatively inactive prodrug with good oral absorption (60 to 70%), a rapid peak plasma concentration (1 hour) and rapid clearance (undetectable by 4 hours) by de-esterification in the liver to a primary active diacid metabolite, enalaprilat. Peak plasma enalaprilat concentrations occur 2 to 4 hours after oral enalapril administration. Elimination thereafter is biphasic, with an initial phase which reflects renal filtration (elimination half-life 2 to 6 hours) and a subsequent prolonged phase (elimination half-life 36 hours), the latter representing equilibration of drug from tissue distribution sites. The prolonged phase does not contribute to drug accumulation on repeated administration but is thought to be of pharmacological significance in mediating drug effects. Renal impairment [particularly creatinine clearance < 20 ml/min (< 1.2 L/h)] results in significant accumulation of enalaprilat and necessitates dosage reduction. Accumulation is probably the cause of reduced elimination in healthy elderly individuals and in patients with concomitant diabetes, hypertension and heart failure. Conventional pharmacokinetic approaches have recently been extended by more detailed descriptions of the nonlinear binding of enalaprilat to ACE in plasma and tissue sites. As a result of these new approaches, there have been significant improvements in the characterisation of concentration-time profiles for single-dose administration and the translation to steady-state. Such improvements have further importance for the accurate integration of the pharmacokinetic and pharmacodynamic responses to enalapril(at) in a concentration-effect model.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enalapril clinical pharmacokinetics and pharmacokinetic-pharmacodynamic relationships. An overview. 826 12

We measured concentrations of guanosine 3',5'-monophosphate (cGMP) in plasma and urine of healthy subjects and patients with congestive heart failure, renal impairment, neoplastic disease, and hepatic cirrhosis. There was no correlation between cGMP concentrations in urine and in plasma. In all patients except those with renal impairment, urinary cGMP concentrations were significantly higher than in healthy persons. Only patients with heart failure or renal impairment showed significantly increased plasma cGMP concentrations. In contrast, cGMP in urine does not relate to the clinically assessed severity of heart failure (New York Heart Association functional classes). Determination of cGMP in plasma results in higher sensitivity and specificity for diagnosing heart failure than measurement of cGMP in urine.
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PMID:Clinical significance of urinary cyclic guanosine monophosphate in diagnosis of heart failure. 828 51

The initial phase of heart failure is characterized by peripheral mechanisms such as sympathetic stimulation and neuroendocrine activation, which attempt to compensate for the decline in cardiac pump function and tissue underperfusion. However, the resulting vasoconstriction and sodium and water retention lead to a vicious circle wherein the subsequent increase in afterload and in circulating volume eventually leads to a further decline in cardiac output, blood pressure and tissue perfusion on the one hand, and to systemic and pulmonary congestion on the other. Intrinsic cardiac alterations during progressive failure preclude efficient cardiac compensation. These alterations include downregulation of the beta-receptor, upregulation of its inhibitor subunit (Gi), changes in adenylate cyclase and phosphodiesterase activity, depletion of catecholamine stores, overexpression of abnormal contractile proteins and inherent changes in ATP-ase activity, a derangement of calcium cycling by the sarcoplasmic reticulum, and abnormalities in myocardial energy production and transfer. These multiple changes underline the importance of the heart per se in heart failure. However, it should be realized that the heart failure syndrome depends to a large extent on various intrinsic alterations in peripheral tissue function. Renal impairment, baroreceptor dysfunction, neuroendocrine activation, abnormalities in skeletal muscle metabolism and in vascular control, and electrolyte disturbances all add to the overall clinical picture. Both cardiac and peripheral alterations in heart failure will markedly affect future diagnostic and therapeutic approaches to this syndrome.
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PMID:Pathophysiology and therapy of heart failure, new insights and developments. Part II. Cardiac and peripheral alterations during progressive heart failure. 830 92

NSAIDs pose little threat of renal insult in normal, healthy persons at therapeutic dosages. However, NSAID administration to susceptible persons may cause decrements in renal plasma flow and glomerular filtration rate within hours. Such acute noxious renal effects are mediated by products of arachidonic acid metabolism. Precipitous decrements in glomerular filtration and renal ischemia, manifested by increased serum creatinine and urea nitrogen, are possible. However, these effects are usually fully reversible with prompt discontinuation of the offending NSAID. Risk factors for the development of these acute renal effects are known. Acute interstitial nephritis with or without nephrotic syndrome is a rare form of renal toxicity that typically occurs between 2-18 months of use. Renal impairment may be so severe as to require temporary hemodialysis; however, renal function usually returns to normal upon discontinuation of the NSAID. The mechanism of acute interstitial nephritis is presumed to be of allergic origin but could also be caused by a reactive metabolite. Fenoprofen use appears to be associated with a much higher risk for its development. In contrast to the acute effects of NSAIDs, irreversible, analgesic-associated nephropathy manifested by papillary necrosis and chronic interstitial nephritis may occur following months to years of high doses of analgesic mixtures. The mechanism by which combination analgesics produce this form of renal injury is unknown and could be either a result of medullary ischemia or a direct effect of a reactive metabolite. An important issue to be resolved is the relationship between the acute, reversible, prostaglandin-mediated renal effects of the NSAIDs and chronic, irreversible destruction, if such a relationship exists. Theoretically, continual or repeated decrements in renal function in patients with predisposing risk factors could cause or contribute to progressive deterioration in renal function. Elevations in blood pressure or interference with the effects of antihypertensive medications could theoretically also contribute to long-term renal deterioration. In addition to renal syndromes caused by NSAIDs that result in renal impairment, other transient effects on electrolyte and water metabolism may also occur. Reduced secretion of sodium may result in formation of edema, exacerbation of heart failure, or increased blood pressure. Hyporeninemic-hypoaldosteronism may produce hyperkalemia. Finally, reduced excretion of water has rarely caused hyponatremia. It has been suggested that NSAIDs may be renoprotective in patients with nephrotic syndrome. Others have suggested that sulindac is "renal-sparing" because of a unique metabolic pathway that supposedly limits the exposure of the kidney to the active sulfide metabolite.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Renal toxicity of the nonsteroidal anti-inflammatory drugs. 849 47

Slow Continuous ultrafiltration (SCUF) was first used in 1980 as an alternative mode of fluid removal for patients with oliguric acute renal dysfunction from whatever causes. The advantage of this treatment is that haemodynamic parameters remain stable in the presence of significant removal of fluid. We are describing our experience in 7 patients [age: 57 +/- 9 years; 4 male, 3 female] with cardiac failure and fluid overload who had undergone 8 sessions of SCUF. All of them had renal impairment and were resistant to diuretics. Blood lines were attached to a Kawasumi Renak-E dialyser (Cuprophane membrane) in series using Gambro AK10 dialysis blood pump. The following parameters were monitored: Blood pump (Qb): 175 +/- 26 ml/min, time (T): 393 +/- minutes. Venous pressure averaged a55 +/- 24 mmHg. We achieved ultrafiltration of 2,189 +/- 699 ml/session or 5.5 +/- 1.7 ml/hr. There was no significant change in blood pressure [systolic pre: 143 +/- 14, post: 136 +/- 13 mmHg, not significant; diastolic pre: 87 +/- 10, post: 83 + 10 mmHg, not significant and pulse rate [pre: 87 +/- 9 vs post: 84 +/- 2 per minute, not significant. Heparin dosage averaged 274 +/- 26 IU/hr during the SCUF. We conclude that SCUF is beneficial to diuretic resistant patients with cardiac failure and fluid overload in whom dialysis treatment is not required.
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PMID:Slow continuous ultrafiltration (SCUF)--the safe and efficient treatment for patients with cardiac failure and fluid overload. 855 91

Severe sustained hypertension occurs in only 0.1% of the paediatric population and only about 2% of these patients will have an underlying endocrine cause. Phaeochromocytoma as a catecholamine-secreting tumour causing severe hypertension is exceedingly rare in children. A high index of suspicion and an awareness of the clinical spectrum are therefore necessary to make the diagnosis. Phaeochromocytomas can have protean manifestations which may be mistaken for a variety of clinical conditions. We highlight the problems encountered in making the diagnosis in an 11-year-old Chinese girl who presented with sustained hypertension, heart failure and transient renal impairment with two normal 24-hour urinary vanillyl mandelic acid (VMA) results before a third produced the diagnosis. We emphasize that total reliance on a single biochemical urinary screening is not acceptable. The measurement of urinary catecholamines or their metabolites increases the sensitivity of diagnosis. We recommend that in situations where biochemical screening is doubtful, appropriate imaging should be undertaken to exclude the diagnosis.
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PMID:Phaeochromocytoma--a rare cause of hypertension in an 11-year-old girl. 889 35

Despite having lower levels of plasma renin activity than younger individuals, elderly patients with hypertension respond well to ACE inhibitors and the drugs have few adverse effects. Plasma concentrations of the active ACE inhibitor are generally higher in the elderly because of decreased renal clearance. These altered pharmacokinetics, combined with impairment of cardiovascular reflexes and the increasing prevalence of heart failure and renal impairment with age, render elderly patients more susceptible to first-dose hypotension. Although many studies have shown that standard dosages are well tolerated it is safer to use lower initial dosages of ACE inhibitors in elderly hypertensive patients because hypotensive reactions are not always predictable. The maintenance dosage may be determined more by the presence of renal disease or heart failure than by age per se. In elderly patients with heart failure, ACE inhibitors should be introduced even more cautiously, using low dosages and preferably under supervision. It may also be necessary to interrupt diuretic treatment for a few days to prevent severe hypotension. The ACE inhibitor dosage should then be titrated up to the maximum that is well tolerated, as this appears to offer the greatest benefit.
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PMID:Optimal dosage of ACE inhibitors in older patients. 889 24

Treatment with angiotensin converting enzyme inhibitors confers significant morbidity and mortality benefits in patients with heart failure, yet previous studies have repeatedly shown that these drugs are underutilised in general practice. To investigate why this is the case, we conducted an anonymous questionnaire survey of 515 general practitioners in the Nottingham Health District. The response rate was 60.2%. We found that although 39.3% of respondents underestimated the poor prognosis associated with heart failure, 98% were aware of the prognostic benefits conferred by angiotensin converting enzyme inhibitors. However, 46.3% of respondents expressed concern about the potential adverse effects associated with angiotensin converting enzyme inhibitors, the main fears being hypotension and renal impairment. General practitioners who were concerned about adverse effects were significantly less likely to have initiated an angiotensin converting enzyme inhibitor for heart failure than those who were not (P<0.01). Further research is needed to identify which patients can safely be commenced on angiotensin converting enzyme inhibitors in general practice. In the meantime, general practitioners should be encouraged to refer patients whenever they are concerned about initiating angiotensin converting enzyme inhibitors in the community.
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PMID:Why are angiotensin converting enzyme inhibitors underutilised in the treatment of heart failure by general practitioners? 908 20


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