Gene/Protein Disease Symptom Drug Enzyme Compound
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This article attempts to help in the understanding of the mechanisms responsible for a modified drug pharmacokinetic profile in disease states. The main factors influencing the fate of the drug as it moves from the site of administration to the sites of elimination are depicted. Changes in absorption kinetics can be due to altered gastrointestinal peristalsis and secretions as well as modifications of splanchnic blood flow. Pathological states may affect the binding of drugs to plasma proteins, mainly human serum albumin and alpha 1 acid glycoprotein. The resulting modifications in the free fraction of the drug can cause a change in the volume of distribution. The distribution can also be influenced by circulatory disorders modifying local blood flows and thus impeding drug entry into the tissues. Many diseases can alter hepatic and/or renal clearance. This is not surprising since the elimination mechanisms are dependent upon many factors such the enzymatic status of the liver, plasma protein binding, and blood flow to both the liver and the kidney. Some examples such as the modification of furosemide pharmacokinetics in acute renal failure, the impaired metabolism of opiate analgesics in hepatic insufficiency, the alterations of the usual disposition process in salicylic acid intoxication, and the influence of cardiac failure upon some drugs pharmacokinetics, have been chosen to illustrate some of the aspects discussed. Some simple rules for making a rational selection of drugs in pathological states are also outlined.
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PMID:Disease-induced modifications of drug pharmacokinetics. 638 35

Sixteen infants, 2 to 35 days of age, had acute renal failure, a diagnosis based on serum creatinine concentrations greater than 1.5 mg/dL for at least 24 hours. Eight infants were oliguric (urine flow less than 1.0 mL/kg/h) whereas the remainder were nonoliguric. To determine clinical parameters useful in prognosis, urine flow rate, duration of anuria, peak serum creatinine, urea (BUN) concentration, and nuclide uptake by scintigraphy were correlated with recovery. Nine infants had acute renal failure secondary to perinatal asphyxia, three had acute renal failure as a result of congenital cardiovascular disease, and four had major renal anomalies. Four oliguric patients died: three of renal failure and one of heart failure. All nonoliguric infants survived with mean follow-up serum creatinine concentration of 0.8 +/- 0.5 (SD) mg/dL whereas that of oliguric survivors was 0.6 +/- 0.3 mg/dL. Peak serum creatinine concentration did not differ between those patients who were dying and those recovering. All infants who were dying remained anuric at least four days and revealed no renal uptake of nuclide. Eleven survivors were anuric three days or less, and renal perfusion was detectable by scintigraphy in each case. However, the remaining survivor (with bilateral renal vein thrombosis) recovered after 15 days of anuria despite nonvisualization of kidneys by scintigraphy. In neonates with ischemic acute renal failure, lack of oliguria and the presence of identifiable renal uptake of nuclide suggest a favorable prognosis.
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PMID:Prognostic factors in neonatal acute renal failure. 646 25

Sixty-five patients who developed postoperative acute renal failure requiring hemodialysis were retrospectively analyzed to identify variables that could be used to predict outcome. Our aim was to identify patients who would have an unfavorable outcome despite hemodialysis and to identify those factors that might be altered to improve outcome. A linear discriminant function capable of segregating survivors from nonsurvivors in the retrospective analysis was subsequently validated in a prospective fashion using a second patient population. Variables used were age, sex, number of transfusions, interval from onset of acute renal failure to dialysis, type of surgery, preoperative hypotension, and the presence of cardiac failure. Scores were formulated for each patient and then segregated into three groups: patients with no precedence for survival, patients with an intermediate risk of dying, and patients with low risk of dying. Based on the univariant analysis, the interval from onset of acute renal failure to first dialysis and the maximum serum creatinine prior to first dialysis were the only factors that might be altered to change mortality. The prognostic index we have developed enables one to select patients without a chance of survival.
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PMID:Probability of surviving postoperative acute renal failure. Development of a prognostic index. 646 76

In most normal subjects, the fractional excretion of sodium is usually less than 1 percent but may be raised with an increase in salt intake. In acutely azotemic patients, a low fractional excretion of sodium usually indicates a prerenal process that is responsive to volume repletion. However, such a low fractional excretion of sodium also can be seen with azotemia due to hepatic or cardiac failure, as well as acute glomerulonephritis, pigment nephropathy, contrast nephrotoxicity, polyuric renal failure associated with burns, acute obstruction, renal transplant rejection, and occasionally non-oliguric acute renal failure, none of which is a volume-responsive process. A fractional excretion greater than 1 percent in acutely azotemic patients usually indicates intrinsic renal injury, but is consistent with volume depletion in patients receiving diuretics or in some patients with chronic renal insufficiency. Similarly, a low quotient in acute renal parenchymal injury is usually interpreted to indicate widespread tubular integrity, but is consistent with several different pathophysiologic processes. The fractional excretion of sodium must be interpreted in light of the specific clinical setting and other laboratory data to be useful in patient management.
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PMID:Interpreting the fractional excretion of sodium. 648 45

An isolated iliac aneurysm is an uncommon entity with a relative incidence to abdominal aortic aneurysm of 0.9 to 1.9 percent. Analysis of 16 cases with 20 isolated iliac aneurysms experienced at our vascular service makes the basis of this report. Seventeen aneurysms involved the common iliac artery, two the internal iliac artery and one the external iliac artery. As we experienced 341 abdominal aortic aneurysms during the same period, relative incidence of isolated iliac aneurysm to abdominal aortic aneurysm was 4.7 percent. Fifteen of the 16 cases were male; isolated iliac aneurysms had significantly higher preponderance for the male. Six of the cases were presented with ruptured aneurysms, giving a rupture rate of 37.5 percent. This rupture rate was significantly higher than that of abdominal aortic aneurysms of 11.1 percent. Operation was performed on 15 patients; the remaining one died before surgery. Although there was no operative death among the elective cases, three patients in the ruptured group died postoperatively giving a mortality rate of 60 percent. The least diameter of the ruptured aneurysms was 3.5 centimeter. Among the 16 patients 5 presented with a ruptured aneurysm and 3 had no symptoms related to the aneurysm. Five patients complained of a pulsatile abdominal mass. Two of the ruptured aneurysms were associated with an iliac arteriovenous fistula. Both of them involved the common iliac artery. Although emergency operation was performed on one of them, he died of acute renal failure due to preoperative dehydration and hypovolemia. The another one was operated on electively after intensive medical treatment for heart failure and the patient survived.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Isolated iliac aneurysms]. 650 53

Only 40 years ago infectious endocarditis (IE) was lethal in most cases. Due to the development of numerous antibiotics and continuous improvements in heart valve surgery, a wide range of possibilities for therapy and prophylaxis of IE are available. The prognosis depends essentially on rapid and relevant diagnosis, which should be followed by immediate and adequate therapy consisting of general measures for treatment of septicaemic disease and specific antibiotic therapy. As multiple complications may develop during IE, careful follow-up by clinical, laboratory and mechanical examinations is necessary to decide whether surgical intervention is urgently indicated or not. In case of complications such as myocardial failure, septicaemic embolism or acute renal failure, as well as septicaemia persisting for more than 72 hours in spite of antibiotic treatment, immediate valve replacement is usually indispensable. Furthermore, large vegetations found by echocardiography, or infections caused by staphylococci, gramnegative bacteria or fungi are arguments for early surgery. For most of the IE pathogens the antibiotic treatment concept is nowadays widely acknowledged. Penicillin-sensitive streptococci are treated with a combination of penicillin S and an amino-glycoside (streptomycin). If the penicillin-MBK is very low, combined treatment can usually be abandoned. In patients allergic to penicillin, treatment with lincomycin has advantages over vancomycin or cephalosporins. In enterococcal IE, ampicillin plus aminoglycoside is the combination of choice. Streptomycin has preference over gentamicin here only if the enterococci are not streptomycin-resistant. If penicillin allergy is evident, the new beta-lactam antibiotic imipenem offers a way out of the present therapy dilemma. For penicillin-sensitive staphylococci a combination of penicillin-G with gentamicin given over 6 weeks is recommended. In case of penicillin allergy, cefazolin or vancomycin may provide a substitute for penicillin. In penicillin-resistant staphylococci the combination of oxacillin or flucloxacillin with gentamicin is established. Fungal endocarditis can be treated with a combination of amphotericin-B and flucytosin. Cure without surgery, however, is rare. For the large remaining number of pathogens which are less frequently responsible for IE, antibiotic management depends on sensitivity test in vitro, as the sensitivity of pathogens may vary widely. Though not only groups of patients with high infection rates are widely known, but also the events provoking the infections, the prophylaxis of IE continues to be inadequate.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Therapy and prevention of infectious endocarditis]. 651 54

Prosthetic valve endocarditis (PVE) was shown in 46 patients out of a group of 2163 carrying prosthetic heart valves. The cumulative rate of early PVE was 1.4% and 1.5% for PVE occurring between the 60th day and 10 years after surgery. In 37% of all cases this was caused by staphylococci, 20% by streptococci, and 13% Gram negative species. Fungi were found in 9% and mixed infections in 21%. The incidence of staphylococci, Gram negative pathogens and fungi was significantly higher in early PVE. In 5 patients, valve involvement consisted in echocardiographically shown vegetations and/or obstructive thromboendocarditis. In 90% of 37 patients who developed paravalvular leakages, there was high intravascular haemolysis uncharacteristic of the type of prosthesis implanted. In 70% fluoroscopy revealed disproportionate tilting of the prosthetic annulus, and in 75% there was a distinct echocardiographic pattern in the closing movement of the valve poppet. The cumulative survival rate after six months was 31% for the conservatively treated, and 66% for the medically plus surgically treated patients. Survival rates at the end of a maximum follow-up of 20 years was 15% with conservative treatment and 51% after primary surgical therapy. The prognosis was worse (P less than 0.01) in patients who, during aortic PVE, developed heart failure refractant to therapy due to haemodynamically significant prosthetic valve dysfunction, to sepsis that persisted for more than 72 h despite antibiotic therapy, to major septic embolism or to acute renal failure. The retrospective prognosis was more favourable for patients with early aortic (P less than 0.02) or mitral (P less than 0.05) valve re-replacement than for patients who had been treated medically only.
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PMID:Prosthetic valve endocarditis: clinical findings and management. 651 77

Acute renal failure occurred in 21 patients after 311 cardiac operations with cardiopulmonary bypass in adults (6,75%). It was non oliguric in 20 cases. It is related to per and postoperative hemodynamic depression. Patients operated for valvular replacement seemed most at risk if severe cardiac failure existed with or without preoperative renal dysfunction. Similarly those operated upon for mechanical complications of myocardial infarction were often affected. The prognosis depends on the degree of cardiac failure. Strict patient selection, myocardial protection during bypass and measures to increase low cardiac output are recommended. Intra-aortic balloon pump for patients with myocardial infarction and dopamine in the early postoperative period seem helpful.
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PMID:[Incidence and prognosis of acute renal failure after cardiac surgery with extracorporeal circulation]. 652 72

The essential and critical role of inorganic phosphate has been known in veterinary medicine and experimental research on animals for decades. However, only recently has the phosphate depletion syndrome found widespread attention by clinicians. Hypophosphatemia is usually observed in the following clinical situations:chronic alcoholism, recovery phase of diabetic ketoacidosis, administration of phosphate-free solutions in parenteral nutrition, severe respiratory alkalosis, and infusion of fructose. Disturbed organ function in hypophosphatemia is the result of a depletion of inorganic phosphate in the cytoplasm of somatic cells. Such phosphate depletion may be due to either of the following mechanisms or a combination of both. (1) Negative external phosphate balance resulting from phosphate loss in urine or feces or (2) translocation of phosphate from the extracellular into the intracellular space with or without concomitant negative external phosphate balance. In principle, phosphate depletion interferes with the function of all somatic cells. In acute phosphate depletion, the clinically most important disturbances are observed in striated muscle (rhabdomyolysis with myoglobinuric acute renal failure), heart muscle (acute heart failure), and hematological systems (hemolysis, disturbed leukocyte and thrombocyte functions). In contrast, in chronic phosphate depletion skeletal abnormalities (osteomalacia) predominate. Organ disturbances are thought to result from diminished synthesis of ATP and other organic phosphate esters and/or from hypoxia secondary to changes in erythrocyte 2,3-DPG.
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PMID:[Phosphate-depletion (author's transl)]. 676 28

Acute renal failure (ARF) was observed in 6 patients under indomethacin treatment. Before receiving the drug 3 patients had normal, and the other 3 slightly elevated plasma creatinine levels. All patients were also treated with diuretics. ARF developed within the first 48 hours of therapy. Four patients had clear-cut oliguria. The renal disorders proved completely and rapidly reversible after treatment was discontinued, except in one female patient who had to undergo peritoneal dialysis for 12 days and in whom moderate aggravation of the pre-existing renal insufficiency persisted on follow up. The ARF was attributed to a sudden fall in renal blood flow due to the inhibitory effect of indomethacin on prostaglandin synthetase. This complication occurs exclusively in patients with renal hypoperfusion secondary to hypovolaemia, with cardiac insufficiency or with intrarenal vascular lesions. Sodium depletion induced by previous or concomitant diuretic treatment increases the risks. The possibility of ARF warrants careful monitoring of urinary output and renal function at the onset of non-steroidal anti-inflammatory therapy in patients with altered or precarious haemodynamics.
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PMID:[Acute renal failure during indomethacin treatment. 6 cases (author's transl)]. 678 Dec 8


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