Serum itraconazole and hydroxyitraconazole concentrations and interaction with digoxin in a case of chronic hypertrophic pachymenigitis caused by Aspergillus flavus.
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A patient treated with itraconazole (ITCZ) under the diagnosis of Aspergillus flavus-induced chronic hypertrophic pachymeningitis is presented. The reason for the successful cure of this patient was investigated by the pharmacokinetic analysis of serum levels of ITCZ. Concurrently administered digoxin was also investigated for its drug-drug interaction. The patient (a 75-year-old male) developed ophthalmopathy, and was diagnosed as having A. flavus hypertrophic pachymeningitis by pachymeninx biopsy. After admission, he was treated with FLCZ, AMPH, 5-FC and MCZ. The infection tended to subside with the AMPH administration. Since renal insufficiency was induced by AMPH and the other antifungal drugs were ineffective, daily administration of 200 mg of ITCZ was initiated, and the inflammatory signs and symptoms gradually subsided. The symptoms did not recur during the 36 months of itraconazole treatment after discharge, and it was concluded that ITCZ was effective for A. flavus hypertrophic pachymeningitis. Pharmacokinetic parameters of ITCZ and OH-ITCZ as follows: ITCZ: Cmax 93.2 ng/ml, T1/2 beta 11 hours, AUC0-24 999 ng.h/ml, OH-ITCZ: Cmax 159.4 ng/ml, T1/2 beta 16. 2 hours, AUC0-24 of 1391 ng.h/ml. Both ITCZ and OH-ITCZ reached steady states seven days after administration began. The ITCZ and OH-ITCZ levels in serum collected 36 months after the initiation of administration were 452.9 ng/ml and 1233.6 ng/ml, respectively. Cmax and AUC0-24 of ITCZ and OH-ITCZ on the second day were markedly lower than those in healthy adults reported by Oguchi et al., and hypoalbuminemia observed at administration on that day was considered the most probable cause. It was assumed that the most plausible reason for a successful cure even at a low dose of ITCZ was the increase of distribution to tissue by the increase of the unbound form. Digoxin was concurrently given to this patient at 0. 125 mg/day, but the blood digoxin level was not elevated. Consideration of the blood level of albumin is believed to be important for evaluating the blood concentration of ITCZ. (+info)
Interleukin-13 prevents diaphragm muscle deterioration in a septic animal model.
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The effects of an intravenous injection of Interleukin-13 (IL-13) after endotoxin administration on diaphragm muscle were studied using Wistar rats. Two treatment groups, a control (saline+endotoxin) group and an IL-13 (IL-13+endotoxin) group were studied. E. coli endotoxin (10 mg/kg) was injected intraperitoneally 5 minutes after saline or IL-13 (0.25 microg) injection. The force-frequency curves, twitch kinetics and fatigability were measured at 0 and 4 hours after endotoxin injection. The force-frequency curves and twitch tension in the control group were significantly lower at 4 hours than those at 0 hour due to endotoxin. On the other hand, IL-13 prevented the decrement of the force-frequency curves and twitch tension induced by endotoxin. Nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry showed positive staining at 4 hours due to endotoxin in the control group; however, IL-13 also blocked NADPH diaphorase staining at 4 hours. Furthermore, the positive muscle fibers detected by the NADPH diaphorase staining were classified as type I (slow twitch) muscle fibers by ATPase staining. We conclude that IL-13 prevents the deterioration of contraction induced by endotoxin by inhibiting nitric oxide production in the diaphragm muscle, mainly the type I muscle fibers. (+info)
Atrial flutter in the perinatal age group: diagnosis, management and outcome.
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OBJECTIVES: The aim of this retrospective study was to evaluate perinatal atrial flutter (AF) and the efficacy of maternally administered antiarrhythmic agents, postpartum management and outcome. BACKGROUND: Perinatal AF is a potentially lethal arrhythmia, and management of this disorder is difficult and controversial. METHODS: Forty-five patients with documented AF were studied retrospectively. RESULTS: Atrial flutter was diagnosed prenatally in 44 fetuses and immediately postnatally in 1 neonate. Fetal hydrops was seen in 20 patients; 17 received maternal therapy, 2 were delivered and 1 was not treated because it had a severe nontreatable cardiac malformation. In the nonhydropic group of 24 patients, 18 were treated and the remaining 6 were delivered immediately. In the hydropic group, 10 received single-drug therapy (digoxin or sotalol) and 7 received multidrug therapy. In the nonhydropic group, 13 received a single drug (digoxin or sotalol) and 5 received multiple drugs. One patient with rapid 1:1 atrioventricular conduction (heart rate 480 beats/min) died in utero and another died due to a combination of severe hydrops because of the AF, sotalol medication, stenosis of the venous duct and hypoplastic placenta. Of the 43 live-born infants, 12 were in AF at birth. Electrical cardioversion was successful in eight of nine patients. No recurrences in AF have occurred beyond the neonatal period. Four patients with fetal flutter and hydrops showed significant neurological pathology immediately after birth. CONCLUSIONS: Fetal AF is a serious and threatening rhythm disorder, particularly when it causes hydrops, it may be associated with fetal death or neurological damage. Treatment is required and primarily aimed at reaching an adequate ventricular rate and preferably conversion to sinus rhythm. Digoxin failed in prevention of recurrence at time of delivery in a quarter of our patients, whereas with sotalol no recurrence of AF has been reported, suggesting that class III agents may be the future therapy. Once fetuses with AF survive without neurological pathology, their future is good and prophylaxis beyond the neonatal period is unnecessary. (+info)
Systematic review of the management of atrial fibrillation in patients with heart failure.
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AIMS: To systematically review the management of atrial fibrillation (AF) in patients with heart failure. METHODS: Studies investigating the management of AF in patients with heart failure published between 1967 to 1998 were identified using MEDLINE, the Cochrane register and Embase databases. Reference lists from relevant papers and reviews were hand searched for further papers. RESULTS: Eight studies pertaining to acute and twenty-four pertaining to chronic AF were identified. For patients with acute AF ventricular rate control, anticoagulation and treatment of heart failure should be pursued simultaneously before cardioversion is attempted. Digoxin is relatively ineffective at controlling ventricular response and for cardioversion. Intravenous diltiazem is rapidly effective in controlling ventricular rate and limited evidence suggests it is safe. Amiodarone controls ventricular rate rapidly and increases the rate of cardioversion. There are insufficient data to conclude that immediate anti-coagulation, trans-oesophageal echocardiography to exclude atrial thrombi followed by immediate cardioversion is an appropriate strategy. Patients with chronic AF should be anti-coagulated unless contra-indications exist. It is not clear whether the preferred strategy should be cardioversion and maintenance of sinus rhythm with amiodarone or ventricular rate control of AF combined with anticoagulation to improve outcome including symptoms, morbidity and survival. Electrical cardioversion has a high initial success rate but there is also a high risk of early relapse. Amiodarone currently appears the most effective and safest therapy for maintaining sinus rhythm post-cardioversion. Digoxin is fairly ineffective at controlling ventricular rate during exercise. Addition of a beta-blocker reduces ventricular rate and improves symptoms. Whether digoxin is required in addition to beta-blockade for the control of AF in this setting is currently under investigation. If pharmacological therapy is ineffective or not tolerated then atrio-ventricular node ablation and permanent pacemaker implantation should be considered. CONCLUSION: There is a paucity of controlled clinical trial data for the management of AF among patients with heart failure. The interaction between AF and heart failure means that neither can be treated optimally without treating both. Presently treatment should be on a case by case basis. (+info)
Therapy of heart failure.
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The incidence and prevalence of heart failure is on the rise. It has become the single most expensive health care item in the United States and the number one discharge diagnosis in the elderly. The goals of therapy include both prevention and treatment of heart failure. In recent years research studies and randomized clinical trials have revolutionized the understanding of the pathophysiology and treatment of this disease. This article focuses on the medical management of chronic systolic heart failure based on the pathophysiology of the disease. Systolic heart failure is characterized by a decrease in left ventricular function and cardiac output, which results in activation of several neurohormonal compensatory systems. The long term effects of this neurohormonal activation leads to further deterioration of cardiac function. The use of hydralazine and nitrates to reduce the systemic vascular resistance was the first to show an improvement in mortality and morbidity. Then angiotensin converting enzyme inhibitors, by inhibiting the renin angiotensin system, demonstrated a greater improvement in mortality and morbidity. More recently the inhibition of the sympathetic stimulation with beta-blockers has been shown to have an additive effect on morbidity and mortality in combination with angiotensin-converting enzyme inhibitors. Digoxin and diuretics remain important for improving symptoms and decreasing hospitalizations but have not been shown to decrease mortality. The most recent advance in the treatment of cardiac failure is the demonstration that the aldosterone antagonists, spironolactone decreases morbidity and mortality. (+info)
Photoaffinity glycoprobes-a new tool for the identification of lectins.
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One of the proposed functions for the carbohydrate structures on glycoconjugates is the transfer of information through interaction with specific lectin receptors. However, the number of elucidated functional lectin-carbohydrate interactions is still relatively small, largely due to the lack of adequate methods to identify lectin activity in complex biological samples. Aiming to solve this problem, we have developed a method based on the novel group of compounds we named glycoprobes. The glycoprobe consists of three vital parts: (1) glycan, (2) digoxin tag, and (3) photoreactive crosslinker. When incubated in dark, oligosaccharide part of the glycoprobe forms a complex with lectin. After illumination, covalent link between the probe and the lectin is formed resulting in a digoxin-tagged lectin. Using antibodies against digoxin, this complex can easily be identified immuno/cytochemically, or by Western blots. To demonstrate the applicability of glycoprobes we have used Man(9)-glycoprobe (containing Man(9)oligosaccharide) and YEE(ahGalNAc)(3)-glycoprobe (containing a synthetic neoglycopeptide with three terminal N-acetyl-galactosamine residues; Lee and Lee, Glycoconjugate J., 1987,4, 317) to identify lectins in bovine serum and rat liver membranes. The simplicity of the method enables its application in routine monitoring of changes in lectin activity during various developmental or pathological processes. An example of GalNAc-binding analysis in human serum is shown. (+info)
Characterization of the major metabolites of verapamil as substrates and inhibitors of P-glycoprotein.
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Verapamil is subject to extensive oxidative metabolism mediated by cytochrome P450 enzymes with less than 5% of an oral dose being excreted unchanged in urine. Furthermore, verapamil is known to be a potent inhibitor of P-glycoprotein function. There is evidence from in vivo investigations that some verapamil metabolites might be actively transported. The aim of the present study was to investigate P-glycoprotein-mediated transport and inhibition properties of verapamil and its metabolites norverapamil, D-620, D-617, and D-703. Polarized transport of these compounds was assessed in P-glycoprotein-expressing Caco-2 and L-MDR1 cells (LLC-PK1 cells stably transfected with human MDR1-P-glycoprotein). Inhibition of P-glycoprotein-mediated transport by these compounds was determined using digoxin as P-glycoprotein substrate. At concentrations of 5 microM, significant differences between basal-to-apical and apical-to-basal apparent permeability coefficients were observed for D-617 and D-620 in all P-glycoprotein-expressing cell monolayers, indicating that both are P-glycoprotein substrates. In contrast, no P-glycoprotein-dependent transport was found for verapamil, norverapamil, and D-703 in Caco-2 cells and for D-703 in L-MDR1 cells. Moreover, verapamil, norverapamil, and D-703 inhibited P-glycoprotein-mediated digoxin transport with IC(50) values of 1.1, 0.3, and 1.6 microM, respectively, whereas D-617 and D-620 did not (at concentrations up to 100 microM). We conclude that verapamil phase I metabolites exhibit different P-glycoprotein substrate and inhibition characteristics, with the N-dealkylated metabolites D-617 and D-620 being P-glycoprotein substrates and norverapamil and D-703 being inhibitors of P-glycoprotein function, which may influence P-glycoprotein-dependent drug disposition and elimination. (+info)
Interference of iodine-125 ligands in radioimmunoassay: evidence implicating thyroxine-binding globulin.
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Although there is abundant published evidence that radioiodinated antigens interfere in digoxin radioimmunoassays, other radioimmunoassays are similarly affected. We investigated the relationship of radioiodinated antigen structure to its function in the immunoassay. Carrier-free 125I-labeled iodotyrosine and iodohistamine derivatives were incubated with human serum, and the bound and free fractions were separated. We demonstrated that diiodotyrosyl analogs bind avidly to serum proteins. Because protein binding could be reduced with competitors that inhibit thyroxine-binding globulin, such as 1,8-anilinonaphthalene sulfonate and thyroxine, thyroxine-binding globulin was clearly implicated. Diiodotyrosyl compounds also bound to solutions of purified thyroxine-binding globulin, and this binding was inhibited by the same two competitors. We postulate that thyroxine-binding globulin is the major source of the heretofore unexplained interference of radioiodinated haptens. We present recommendations for eliminating or minimizing such interference. (+info)