Impairment of digoxin clearance by coadministration of quinidine

Seven healthy volunteers received a single 1.0-mg dose of intravenous digoxin in a drug-free control trial and again during concurrent therapy with therapeutic doses of quinidine. Digoxin kinetics were determined from multiple serum digoxin concentrations measured during 72 hours after dosage. Compared to the control state, quinidine coadministration reduced mean digoxin volume of distribution (15.1 vs. 12.4 l./kg), prolonged its elimination half-life (47.7 vs. 75.7 hours), and significantly reduced total clearance (6.06 vs. 2.18 ml/min.kg). Both renal and extrarenal digoxin clearances were impaired by quinidine. In nine cardiac patients receiving long-term digoxin therapy (0.25 mg twice daily), quinidine coadministration elevated mean morning digoxin levels from 1.37 to 2.0 ng/ml (P less than 0.001) and evening levels from 1.44 to 1.97 ng/ml (N.S.). If digoxin concentrations at the site of action are increased by quinidine, the interaction is likely to be of clinical importance in many patients.     

Renal clearance of ifosfamide

Nephrotoxicity is an important clinical side effect of the chemotherapeutic agent ifosfamide. This medication is activated by the hepatic cytochrome P450 system with potentially toxic metabolites produced through both ring hydroxylation and chloroethyl side chain oxidation pathways. Using an isolated perfused rat kidney preparation, we examined the possibility that renal metabolism of ifosfamide also occurs. Renal function before and after addition of ifosfamide to perfusate was not significantly different. After addition of ifosfamike to the perfusate, the metabolites N2-dechloroethylifosfamide, N3-dechloroethylifosfamide, and isophasphoramide mustard were recovered from urine and renal venous effluent. These results provide the first demonstration of ifosfamide metabolism by the kidney and suggest the possibility that intrarenal metabolism may contribute to nephrotoxicity.     

Magnesium homeostasis in premature and full-term neonates

Renal handling of magnesium (Mg) has not been comprehensively studied in the newborn period due to the difficulty, until recently, of measuring the diffusible fraction of plasma Mg (UfMg). In the present study this methodology was used to assess Mg homeostasis in 84 newborn infants of different postconceptional age (26-42 weeks), weight (720-4,830 g) and postnatal age (1-72 days). Very premature infants (postconceptional age less than 35 weeks) had significantly higher values of plasma Mg than mature newborn infants. Plasma Mg related inversely to postconceptional age, weight, plasma total protein and plasma calcium, and directly to plasma potassium. Stepwise multiple regression analysis revealed that postconceptional age was the unique factor contributing to variations in plasma Mg. Plasma values of UfMg were the same in preterm as in term infants but, when expressed as a fraction of total plasma Mg (UfMg/Mg), they were significantly lower in very preterm infants. Fractional excretion of Mg and the ratio of urine Mg to urine creatinine did not vary as a function of postconceptional age. These results indicate that plasma UfMg is kept constant at different gestational ages despite variations in total plasma Mg; furthermore, no functional immaturity is present for renal tubular reabsorption of Mg, even in very low birth weight infants.     

No latent chromosome damage in oxygen-exposed premature neonates

BACKGROUND: Benign intracranial hypertension is due to an increased intracranial pressure of unknown cause. The initial symptoms, complications and associations with medical conditions are discussed. CASE REPORT: A 6-year-old girl developed symptoms of benign intracranial hypertension following reduction of oral corticosteroid therapy. Laboratory studies and head-computed tomographic scan were normal. Examination of the optic discs showed bilateral papilledema and the cerebrospinal fluid pressure was increased. The patient was given prednisone therapy 1 mg/kg daily initially, associated with acetazolamide, and removal of 25 mL of cerebrospinal fluid. All the symptoms resolved and the treatment was gradually decreased. The child developed no further visual failure. CONCLUSION: Benign intracranial hypertension with the risk of permanent visual loss is a complication underrecognized in children. All patients receiving large doses of the corticosteroids who complain of headache or blurring vision, particularly following a reduction of corticosteroid dosage, should have an ophtalmoscopic examination to exclude this complication.     

Renal clearance of domoic acid in the rat

The renal clearance (Clr) of the seafood toxin domoic acid (DA) was investigated in the rat. Following cannulation of the right femoral artery, the left femoral vein and the bladder of anaesthetized rats, a single bolus injection of either [3H]DA, [14C]p-aminohippuric acid (PAH) or [3H]inulin was administered through the venous cannula. Blood samples were taken from the arterial cannula at 1, 2, 10, 30, 50, 70, 90, 110 and 130 min following injection, and urine samples were collected at 20-min intervals starting from the time of bolus injection. Based on plasma concentration-time profiles, the total clearances (Clt) for DA, PAH and inulin were 9.12, 33.17 and 7.50 ml/min/kg body weight, respectively. The Clr calculated from urinary excretion rates were not significantly different from the Clt. Probenecid significantly reduced the Clr of PAH but did not affect that of DA. When DA was given at doses of 0.5 ng, 0.5 mg and 2.0 mg/kg body weight, the pharmacokinetic parameters Clt, Clr, elimination-rate constant and apparent volume of distribution at steady state were not statistically different between doses. The entire dose of 3H was recovered in the urine by 160 min after dosing, and analysis of urine samples by HPLC confirmed that the radiolabel (3H) was associated predominantly with the parent form of DA. The results of the present study demonstrate that DA is cleared from plasma primarily through the kidneys. DA clearance occurs primarily by renal glomerular filtration since its Clt is comparable with that of inulin, is less than that of PAH and is not affected by probenecid.     

Renal sugar transport in the winter flounder. I. Renal clearance studies

The renal handling of several sugars was examined using clearance techniques in the winter flounder Pseudopleuronectes americanus. The nonmetabolizable sugar alpha-methyl-D-glucoside was extensively reabsorbed, with consequent accumulation in renal tissue to nearly twice plasma concentration. Both glucose and phlorizin abolished reabsorption and reduced tissue-to-plasma ratios (T/P). D-Galactose was reabsorbed. However, the T/P for free galactose was only 0.6 (total sugar was 1.7). Glucose and phlorizin produced only a transient decrease in reabsorption and no change in T/P. 2-Deoxy-D-glucose showed neither net reabsorption nore secretion. Nevertheless, kidney T/P were inexcess of 6 for total sugar and 1.2 for free sugar, indicating entry through the peritubular face of the tubule. Neither glucose nor phlorizin altered 2-deoxy-D-glucose clearance, but both reduced T/P for total sugar (2.4) and free sugar (0.7). Thus, several systems govern the handling of these sugars at the luminal membrane of the renal tubule, just as has been previously demonstrated at the peritubular membrane in this species.     

The pharmacokinetics and physiological effects of buprenorphine infusion in premature neonates

Whereas some people appear to cope after learning that they have human immunodeficiency virus (HIV) infection, others experience depression and suicidal ideation. In this study, 142 persons with HIV infection were administered the Center for Epidemiological Studies Depression Scale (CES-D). High levels of depression were predicted by lower perceived social support, attributions that health was influenced more by chance, high-risk sexual behavior practices, and greater number of HIV illness symptoms and greater duration of time knowing of one's own positive serostatus. Ongoing high-risk sexual behavior practices were predicted by higher levels of recreational drug use and of depression. These findings highlight the need for improved mental health services for persons with HIV conditions.     

Renal handling of carnitine in ill preterm and term neonates

BACKGROUND/AIMS: A prospective study was performed to evaluate the incidence of bile leak after T-tube removal, using 99mTc labelled BULIDA scintigraphy. PATIENTS AND METHODS: Thirty seven patients with choledocholithiasis underwent choledocholithotomy and T-tube drainage. T-tubes were removed on 9--26 postoperative day (mean 13.4 days). RESULTS: Six (16%) patients had scintigraphic evidence of bile leak; 4 patients had leak demonstrated in the early phase only. One patient each had partial persistent leak and complete bile leak. All patients were managed nonsurgically; conservative treatment: (4), percutaneous drainage (PCD) of intra-abdominal collection (1) and endoscopic sphincterotomy and PCD of intra-abdominal collection (1). There was no significant difference in the leak rate when T-tubes were removed at < 2 weeks versus later than 2 weeks (P=.97). CONCLUSIONS: T-tubes should be removed with extreme caution and treatment of symptomatic patients should be guided by clinical and scintigraphic findings.     

Assessment of perinatal pathologies in premature neonates using a syllable discrimination task

OBJECTIVE: To determine the preferred treatment of clinically localized prostate cancer. DESIGN: Cancer grade, patient age, and comorbidities are considered in a Markov model with Monte Carlo sensitivity analyses. Large and recent pooled analyses and patient-derived utilities are included. RESULTS: Principal findings suggest benefit for radical prostatectomy relative to watchful waiting for men under 70 years of age with low to moderate comorbidity. Men older than 70 with high comorbidity and disease of low to moderate grade do better with watchful waiting. CONCLUSIONS: Cohort-level sensitivity analyses suggest a quality-based treatment benefit for radical prostatectomy for younger men and treatment harm for older men. Tailored patient and clinician decisions remain necessary, especially for men older than 70 in good health but with aggressive cancers.     

Antenatal glucocorticoids modulate the amplitude of pulsatile cortisol secretion in premature neonates

We hypothesized that antenatal exposure to glucocorticoids influences subsequent pulsatile cortisol (F) secretion in premature neonates. To test this hypothesis, blood was sampled for plasma F determination via indwelling arterial lines at 15-min intervals for 6 h in 26 clinically stable neonates whose gestational ages were 25-33 wk. Deconvolution analysis was used to characterize F secretion and elimination. Pulsatile F secretion was observed in all neonates. Deconvolution estimates in eight neonates exposed to antenatal glucocorticoids (ANG group) were compared with those of 18 neonates not or only remotely exposed to ANG (No/RG group). The median amplitude of the F secretory burst of the ANG group was significantly less than that of the No/RG group [4.3 nmol/Lv x min and 9.2 nmol/Lv x min, respectively; p = 0.026 (Lv is liter of F distribution volume)]. The number and duration of F secretory bursts was similar for both groups: 5 bursts per 6 h, and 23 versus 16 min. By univariate linear regression analysis, mean arterial blood pressure correlated positively with F secretory burst frequency and F production rate (p = 0.0035, r = 0.55 and p = 0.0067, r = 0.52, respectively). We propose that ANG treatment modulates the amplitude of pulsatile F secretion in premature neonates.     

Bacillus cereus pneumonia in premature neonates: a report of two cases

The first publication to summarize the occupational diseases of musicians was Ramazzini's Diseases of Tradesmen in 1713. While there was sporadic interest in performing arts medicine during the 1800s, the first book devoted to the subject, Singer's Diseases of the Musical Profession, was published in 1932. During the 1960s and 1970s, both physicians and performers became more interested in arts medicine. When pianists Gary Graffman and Leon Fleisher publicly discussed their career-ending hand problems in the early 1980s, a huge, previously unknown group of injured musicians was brought to light. Since that time, publication in the field has dramatically increased, numerous conferences have been held, and clinics catering to the needs to performers have been set up in various large cities. Although we still do not have all the answers to the problems faced by performing artists, arts medicine is now a recognized discipline, reaching out to performers, arts educators, arts administrators, and instrument manufacturers.     

Two kinds of cytokine gene expression in umbilical cord blood of premature and mature neonates

OBJECTIVE: To study the immunological function of premature and mature neonates. METHOD: By means of in situ hybridization technique, mRNA expression of interleukin-1 (IL-1) beta and IL-1r alpha in umbilical cord blood of 34 cases was analyzed. RESULTS: It showed that mRNA expression of IL-1 beta and IL-1r alpha were significantly lower in the group of preterm vaginal delivery resulting from premature rupture of membranes than that of preterm cesarean section with the indication of pregnancy induced hypertension and than that of full term delivery (P < 0.001). No significant difference was found between the latter 2 groups. CONCLUSIONS: It indicated that gene expression of IL-1 beta and IL-1r alpha probably related to the fetal maturity.     

Colonization with group B streptococci in neonates and premature infants from selected neonatal departments

Group B streptococci are considered an important etiological agent of sepsis and meningitis in neonates and, particularly, in premature infants. There is a close correlation between colonization with these bacteria and the frequency of symptomatic infection. It is estimated that symptomatic infections occur in 1.0% of colonised neonates. The purpose of this work was to investigate the frequency of neonate colonization with group B streptococci for determination of the risk of symptomatic infection.     

Effects of furosemide on glomerular filtration rate and clearance of practolol, digoxin, cephaloridine, and gentamicin

Furosemide was shown to decrease inulin clearance in 20 of 27 normal subjects. The depression in inulin clearance occurred in both water-loaded and non-water-loaded subjects. The renal clearance of practolol, but not digoxin, was reduced when furosemide was given. The average total plasma clearances of gentamicin and of cephaloridine over a 6-hr period were decreased after furosemide. The reduced clearances of the antibiotics were associated with higher plasma levels, the increase in antibiotic concentration being as much as 100% at 1 hr after an intravenous bolus injection.     

Correlation between urinary epidermal growth factor excretion and serum thyroid hormone in premature and term neonates

We investigated a possible causal relation between exposure to organic solvents in Danish workers (housepainters, typographers/printers, carpenters/cabinetmakers) and onset of multiple sclerosis. Data on men included in the Danish Multiple Sclerosis Register (3,241 men) were linked with data from the 1970 census from the National Bureau of Statistics in Denmark, which has data on occupational status for 1,768,846 men between 15 and 74 years of age. From this census, we ascertained a group of 124,766 "solvent-exposed" men and an "unexposed" group of 87,501 male electricians, bricklayers, and butchers. Over a follow-up period of 20 years, we observed no increase in the incidence of multiple sclerosis among men presumed to be exposed to organic solvents. It was not possible to obtain data on potential confounders, and the study design has some potential for selection bias. Nevertheless, the study does not support existing hypotheses regarding an association between occupational exposure to organic solvents and multiple sclerosis.     

Immunoassay of digoxin in hair

Digoxin analysis in blood is an essential tool for therapeutic drug monitoring in cardiology because compliance with the treatment is a critical issue for the patient. Unfortunately, in postmortem cases blood digoxin concentration is of poor quality because there is a possible drug redistribution in the corpse and because of digoxin-like factors present in some people's blood. On the other hand, no biological fluid can be obtained at the autopsy. The aim of the present study was to evaluate the ability of an immunological method to determine digoxin in hair, in order to confirm that hair analysis can provide information on digoxin use before death. We studied 35 elderly patients who had been taking digoxin (60-250 micrograms/day) for 1-5 years. Two decontamination procedures were tested: washing by dichloromethane or by water and methanol. Three extraction procedures were compared: crushing in a ball mill and chloroform/acetone: crushing and methanol; enzymatic digestion. Immunoassays were performed by a microparticulate enzyme immunoassay. Serum digoxin levels were also assayed when sampling hair. The best results were obtained after decontamination with water and methanol followed by enzymatic digestion. Hair digoxin concentrations range from 3.6 to 11.4 pg/mg. Those very low concentrations are probably due to low and narrow range serum digoxin levels (0.3-1.4 ng/ml). No correlation was found between hair and blood digoxin. A forensic case is presented with 5 pg/mg digoxin in hair.     

Therapeutic digoxin level in chylous drainage with no detectable plasma digoxin level

A patient receiving digoxin for long-standing congestive heart failure developed a chylothorax following removal of an infected aortic graft. Drainage of the chylothorax resulted in plasma digoxin concentrations which were near zero while the digoxin levels in the chylous drainage fluid were therapeutic. The sequestration of even low lipid-soluble drugs, such as digoxin, in chyle should be recognized to prevent subtherapeutic plasma levels in patients undergoing chylothorax drainage.     

Renal clearance, tissue distribution, and CA-125 responses in a phase I trial of suramin

Exposure of human spermatozoa to nicotinamide adenine dinucleotide phosphate (NADPH) resulted in the dose dependent generation of reactive oxygen species (ROS) which, at a critical level of intensity, induced lipid peroxidation, DNA damage and a dramatic decline of sperm motility. This system was then used as a model for screening the ability of different antioxidants to combat oxidative stress created through the excessive intracellular generation of toxic oxygen products of metabolism. A variety of antioxidants that has previously been shown to be protective against extracellularly derived oxidants (e.g. superoxide dismutase, catalase, vitamin E, hypotaurine) were ineffective in this system. Albumin, however, could provide complete protection against NADPH induced oxidative stress via mechanisms that did not involve the suppression of the lipid peroxidation cascade but rather the inactivation of lipid peroxides generated during this process. Albumin did not protect against DNA damage induced by NADPH but was extremely effective at preventing DNA fragmentation arising from the suppression of glutathione peroxidase activity with mercaptosuccinate. These studies emphasize that the design of clinically effective antioxidant treatments will depend, critically, upon the source of the oxidative stress. For cases involving excessive intracellular ROS generation, albumin appears to be an important means of neutralizing lipid peroxide-mediated damage to the sperm plasma membrane and DNA.