Argatroban therapy in pediatric patients requiring nonheparin anticoagulation: an open-label, safety, efficacy, and pharmacokinetic study.

BACKGROUND: An increasing number of pediatric patients suffer from thrombotic events necessitating anticoagulation therapy including heparins. Some such patients develop heparin-induced thrombocytopenia (HIT) and thus require alternative anticoagulation. As such, studies evaluating the safety, efficacy, and dosing of alternative anticoagulants are required. PROCEDURE: In this multicenter, single arm, open-label study, 18 patients ≤ 16 years old received argatroban for either a suspicion of or being at risk for HIT, or other conditions requiring nonheparin anticoagulation. Endpoints included thrombosis, thromboembolic complications, and bleeding. RESULTS: Patients (ages, 1.6 weeks to 16 years) received argatroban usually for continuous anticoagulation (n = 13) or cardiac catheterization (n = 4). One catheterization patient received a 250 µg/kg bolus only; 17 patients received argatroban continuous infusion (median (range)) 1.1 (0.3-12) µg/kg/min (of whom four received a bolus) for 3.0 (0.1-13.8) days. In patients without bolus dosing, typically argatroban 1 µg/kg/min was initiated, with therapeutic activated partial thromboplastin times (aPTTs) (1.5-3× baseline) achieved within 7 hr. Within 30 days, thrombosis occurred in five patients (two during therapy). No one required amputation or died due to thrombosis during therapy. Two patients had major bleeding. Pharmacometric analyses demonstrated the optimal initial argatroban dose to be 0.75 µg/kg/min (if normal hepatic function), with dose reduction necessary in hepatic impairment. CONCLUSIONS: In pediatric patients requiring nonheparin anticoagulation, argatroban rapidly provides adequate levels of anticoagulation and is generally well tolerated. For continuous anticoagulation, argatroban 0.75 µg/kg/min (0.2 µg/kg/min in hepatic impairment), adjusted to achieve therapeutic aPTTs, is recommended.

The effect of low-dose cimetidine (200 mg twice daily) on the pharmacokinetics of theophylline.

The potential for nonprescription cimetidine (200 mg twice daily) to affect the pharmacokinetics of sustained-release (SR) theophylline was assessed in 26 male subjects, 13 smokers and 13 nonsmokers. This was a concentration-controlled drug interaction study in which the subjects were administered a dose of SR theophylline every 12 hours to provide a mean steady-state concentration between 8 and 15 micrograms/ml. To determine individual theophylline dose, a test dose of aminophylline was administered, and baseline theophylline pharmacokinetics were determined. Subjects remained on SR theophylline for 23 days and were treated in the following sequence: run-in phase (4 days), treatment 1 (7 days), washout (5 days), and treatment 2 (7 days). During the treatment phases, subjects received cimetidine (200 mg at approximately 08:00 and 12:00) or placebo for 7 days in a randomized crossover fashion. Theophylline pharmacokinetics were determined on days 1, 4, and 7 of both treatment phases. A large day-to-day variability in the oral clearance of theophylline was evident for the theophylline-placebo treatment and the theophylline-cimetidine treatment. Nonprescription strength cimetidine resulted in a mean 5% decrease in theophylline oral clearance on day 1 and a mean 12% decrease on days 4 and 7 combined. There were no significant differences in the cimetidine-theophylline interaction between smokers and nonsmokers. Oral clearance during the nighttime dosing interval was 13% greater than the daytime oral clearance for nonsmokers and 22% greater for smokers, showing a greater circadian rhythm for smokers. In summary, nonprescription doses of cimetidine (400 mg/day) have the potential to produce small changes in theophylline concentrations during steady-state dosing with SR theophylline; however, this effect appears less than changes that occur as a consequence of theophylline's intrasubject variability.

The pharmacokinetics of carvedilol and its metabolites after single and multiple dose oral administration in patients with hypertension and renal insufficiency.

INTRODUCTION: Carvedilol, a chiral compound possessing nonselective beta- and alpha1-blocking activity, is used for the treatment of hypertension and congestive heart failure (CHF). The enantiomers of carvedilol exhibit similar alpha1-blocking activity; only S-carvedilol possesses beta-blocking activity. Carvedilol is primarily hepatically metabolized, with less than 2% of the dose excreted renally as unchanged drug. METHODS: The pharmacokinetics of carvedilol, R-carvedilol, and S-carvedilol were studied in hypertensive patients (control; n = 13) versus patients with hypertension and advanced renal insufficiency not yet on dialysis [GFR < or = 30 ml x min(-1) (CRI, chronic renal insufficiency), n = 12] following single (12.5 mg, Day 1) and multiple (25 mg once daily, Days 2 9) dosing. RESULTS: Mean with (SD) AUC(0-24h) (ng x h x ml(-1)) for carvedilol was 220 (120) and 618 (335) in CRI compared with 165 (83.5) and 413 (247) in controls on Days 1 and 9, respectively, primarily due to higher R-carvedilol concentrations. Mean with (SD) Cmax (ng x ml(-1)) for carvedilol were 53.4 (31.4) and 128 (63.3) in CRI compared with 46.7 (23.3) and 104 (58.9) in controls on Days 1 and 9, respectively. The difference in group mean values was characterized by considerable overlap in individual AUC(0-24h) and Cmax values between groups. There was no apparent difference in mean terminal elimination half-life for carvedilol between groups on each study day. Less than 1% of the dose was excreted in urine as unchanged carvedilol in both groups. Blood pressure and heart rate declined in both groups to a similar degree. CONCLUSION: Compared with controls, average AUC(0-24 h) values for carvedilol were approximately 40% and 50% higher on study Days 1 and 9 in patients with renal insufficiency, primarily due to higher R-carvedilol concentrations with only a small change (<20%) in S-carvedilol concentrations, the isomer possessing beta-blocking activity. These changes in pharmacokinetics are modest in view of the large interindividual variability. Carvedilol was well tolerated in both groups. Although the present study cannot provide a final conclusion, based on the results of the present study, no changes in dosing recommendations for carvedilol are warranted in patients with moderate/severe renal insufficiency.

Lymphoma at the extremes of age.

OBJECTIVES: To provide a review of the unique features of both Hodgkin's and non-Hodgkin's lymphoma in pediatric and geriatric patient populations. Treatment approaches and nursing care interventions at the extremes of age will be discussed. DATA SOURCES: Review articles, research studies, and book chapters. CONCLUSIONS: Lymphoma is a highly heterogeneous malignancy whose classification and management have undergone significant evolution. Of particular concern has been lymphoma's prevalence and treatment at the extremes of age. Appropriate treatment by age and subtype remains controversial. IMPLICATIONS FOR NURSING PRACTICE: The nursing care of pediatric and geriatric patients with lymphoma presents numerous challenges in education, symptom management, and supportive care.

Effect of ranitidine on the pharmacokinetics of orally administered eprosartan, an angiotensin II antagonist, in healthy male volunteers.

OBJECTIVE: To assess the effect of ranitidine on the pharmacokinetics of eprosartan in healthy male volunteers. DESIGN: Single-center, randomized, open-label, two-period, period-balanced, crossover study. PATIENTS: Seventeen healthy men aged 19 to 43 years. INTERVENTION: In each period (separated by a > or = 7 d washout), subjects received a single 400-mg oral dose of eprosartan alone, or a single oral dose of eprosartan 400 mg and ranitidine 150 mg on day 4 after 3 days of ranitidine 150 mg twice daily. Serial pharmacokinetic samples were obtained for up to 24 hours following eprosartan dosing. MAIN OUTCOME MEASURES: Plasma and urine eprosartan concentrations during each treatment session. RESULTS: Eprosartan maximum concentration (Cmax), the AUC from time-zero to the last quantifiable concentration (AUC0-t), and renal clearance (Cl(r)) values were approximately 7%, 11%, and 4% lower, respectively, when administered with ranitidine compared with eprosartan alone. The 95% CIs for the ratio of eprosartan plus ranitidine compared with eprosartan alone were 0.81 to 1.07, 0.77 to 1.03, and 0.64 to 1.43, for Cmax, AUC0-t, and Cl(r), respectively, indicating no statistically significant difference between regimens. CONCLUSIONS: Repeated doses of ranitidine did not have a marked effect on the single-dose pharmacokinetics of eprosartan.

A review of paclitaxel (Taxol) administration, stability, and compatibility issues.

The purpose of this article is to review information relative to the administration, stability, and compatibility of paclitaxel (Taxol, Mead Johnson Oncology Products, Princeton, NJ). The unique formulation used to solubilize paclitaxel has led to an increased awareness of plasticizer-leaching issues, paclitaxel stability in solution, and paclitaxel compatibility with other medications. Particularly with longer paclitaxel infusion schedules (greater than 48 hours), both drug stability in solution and pump apparatus congruence require careful consideration to minimize plasticizer-leaching problems and to ensure optimum drug delivery. Despite knowledge of the physical compatibility of paclitaxel with numerous drugs, a paucity of research has documented the specifics of paclitaxel's chemical compatibility with other medications.

Keratomycosis in a Percheron cross horse caused by Cladorrhinum bulbillosum.

This report describes an infection of a horse's cornea caused by Cladorrhinum bulbillosum. Minor surgery and treatment with antibiotics successfully resolved the infection. The only previous reported case involving this fungus was an Argentinian boy who was infected while working with horses.

Disseminated opportunistic fungal disease in dogs: 10 cases (1982-1990).

Medical records of 10 dogs in which fungal infection was diagnosed between 1982 and 1990 were reviewed. In each dog, infection was determined to be caused by a single species of fungus, either Aspergillus terreus, Penicillium sp, Paecilomyces sp, Chrysosporium sp, or Pseudallescheria boydii. Nine dogs were German Shepherd Dogs; 1 was a German Shepherd Dog cross, and 9 were females. The most common clinical signs were signs of neck or back pain (9 dogs), weight loss (7 dogs), anorexia (6 dogs), pyrexia (6 dogs), paresis (3 dogs), and paralysis (3 dogs). All 10 dogs had evidence of multiple sites of diskospondylitis. Urine sediment was examined in 6 dogs, and all 6 had fungal hyphae. Urine samples from these dogs produced a medium to heavy pure growth of fungi when placed on Sabaraud's medium. Predisposing causes were not identified in any of the dogs. Four dogs were euthanatized immediately after diagnosis because of paralysis or paresis. The other 6 dogs were treated, and 4 of the 6 received itraconazole. One dog was euthanatized for an unrelated problem after 21 months of treatment; 1 dog was still alive after 4 years of continuous treatment with itraconazole. The other 4 dogs were euthanatized because of eventual paralysis or paresis. Our results suggest that German Shepherd Dogs are predisposed to infection with opportunistic fungi, possibly because of a specific inability to mount an effective response. This predisposition needs to be further studied.

Effects of long-term oral carvedilol on the steady-state pharmacokinetics of oral digoxin in patients with mild to moderate hypertension.

The effect of multiple oral doses of carvedilol on steady-state plasma digoxin pharmacokinetics was evaluated in 12 patients with mild to moderate hypertension. Area under the curve (AUC), mean maximum plasma concentration (Cmax), mean time to maximum concentration (Tmax), concentration at 24 hours after the dose (C24), creatinine clearance, renal digoxin clearance, and urinary digoxin excretion were determined after patients took oral digoxin 0.25 mg once/day for 2 weeks. Carvedilol was added to the regimen, and digoxin pharmacokinetics were assessed after 2 weeks of concurrent treatment. The AUC and Cmax for digoxin increased by 14% and 32%, respectively (p < 0.05), with no change in Tmax. The 24-hour urinary digoxin excretion and 24-hour renal digoxin clearance increased by 45% and 26%, respectively (p < 0.05), with no change in creatinine clearance. Carvedilol appears to increase digoxin's oral bioavailability as well as renal elimination. The absolute change in digoxin pharmacokinetics was small and not clinically significant. The significance of the interaction in other patient populations remains to be studied.

Preclinical and clinical pharmacology of carvedilol.

Carvedilol is a novel multiple-action cardiovascular drug that has recently been introduced to the market for the treatment of mild to moderate hypertension. Clinical studies have demonstrated that once daily therapy with carvedilol is efficacious and has a favourable side-effect profile. Clinical studies are in progress to establish the utility of carvedilol in angina and congestive heart failure. Carvedilol is a beta-adrenoceptor antagonist and a vasodilator, with the vasodilating activity resulting primarily from alpha 1-adrenoceptor blockade and possibly also from calcium channel blockade. The reduction in BP produced by carvedilol results from the vasodilating activity of the drug because peripheral vascular resistance is significantly reduced. The reduction in BP produced by carvedilol is not associated with reflex tachycardia owing to the beta-adrenoceptor blocking activity of the compound. Throughout its antihypertensive dose range, carvedilol has been a renal-sparing antihypertensive agent in animals and also in humans, inasmuch as renal blood flow, glomerular filtration rate and sodium excretion are all maintained. In preclinical experimental models of acute myocardial infarction, carvedilol has produced marked reductions in infarct size in the pig, rat and dog. The cardioprotection observed with carvedilol is greater than that provided by beta-adrenoceptor antagonists alone, suggesting that the additional activities of carvedilol may provide benefit in the setting of myocardial ischaemia.

The effect of food on pharmacokinetics and pharmacodynamics of fenoldopam in class III heart failure.

Eighteen patients with New York Heart Association class III congestive heart failure were given single 100 mg oral doses of fenoldopam with food or fasting in a random-order single-blind crossover trial. Before and after each fenoldopam dose, thermodilution cardiac output, right atrial pressure, pulmonary artery pressure, and pulmonary capillary wedge pressure (PCWP) were measured with a balloon-tipped pulmonary artery catheter, and heart rates and blood pressures were recorded with an automated sphygmomanometer. Compared with fasting, bioavailability of fenoldopam was decreased significantly when administered with food: mean peak plasma fenoldopam level decreased from 26.5 (+/- 4.1 SEM) ng/ml to 10.9 (+/- 1.7 SEM) ng/ml (p = 0.0004) and mean area under the concentration-time curve was decreased from 44.7 (+/- 5.8 SEM) ng.hr/ml to 26.8 (+/- 4.1 SEM) ng.hr/ml (p = 0.0001). Fenoldopam administration to fasting patients resulted in decreases in mean arterial pressure, systemic vascular resistance, and PCWP and significant increases in cardiac index without change in heart rate. The maximum changes in mean cardiac index, systemic vascular resistance, and PCWP were greatest 1 hour after oral administration and did not persist beyond 3 hours after administration. In fasting patients, changes in cardiac index were correlated with plasma fenoldopam levels, whereas changes in PCWP and mean arterial pressure did not correlate significantly with the observed fenoldopam level.

Evaluation of a Bayesian regression program for predicting warfarin response.

The ability of a Bayesian regression program (Warfcalc) to predict warfarin response was evaluated retrospectively in 48 inpatients and prospectively in 10 inpatients. The prothrombin ratio (PR) on the last day of inpatient therapy was predicted using zero (naive) to five sequential, daily PR feedbacks. Bias and precision were measured using mean error (ME) and mean absolute error (MAE), respectively. Root mean squared error (RMSE) was used as a combined measure of bias and precision. In the retrospective group, the use of five PR feedbacks yielded the lowest ME, MAE, and RMSE (0.22, 0.30, and 0.45, respectively). The use of two and three daily PR feedbacks resulted in larger prediction errors compared with the use of naive parameters. Further evaluation of the retrospective patient data indicated that deletion of PR feedbacks associated with an activated partial thromboplastin time greater than 100 s and exclusion of metabolic inhibitors in the estimation of warfarin clearance resulted in more reliable predictions (ME = 0.07, MAE = 0.20, RMSE = 0.28). Similarly, deletion of such PR feedbacks and metabolic inhibitors from the prospective data and use of PRs for the first 5 days of therapy yielded ME, MAE, and RMSE values of 0.07, 0.21, and 0.27, respectively. The variance for prothrombin complex activity (PCA) as a function of the variance in the prothrombin time (PT) was investigated using Monte Carlo simulation assuming four different random error models for the PT measurements. These error models yielded functions that exhibit a maximum coefficient of variation at PCA values of 40-70%.(ABSTRACT TRUNCATED AT 250 WORDS)

Absolute bioavailability and dose proportionality of betaxolol in normal healthy subjects.

The absolute bioavailability and dose proportionality of betaxolol [(+/-)-1-(p-[2-cyclopropylmethoxy)ethyl]phenoxy]-3- (isopropylamino)-2-propanol hydrochloride], a cardioselective beta-adrenergic antagonist effective in the treatment of angina and hypertension, was studied in 12 healthy male subjects using a four-way crossover Latin Square design. Each subject received a 10-mg iv dose administered by constant-rate infusion over a period of 30 min and three oral doses (10, 20, and 40 mg). Blood and urine were collected over a 48-h period and analyzed for betaxolol using gas-liquid chromatography with electron capture detection. Maximum concentrations occurred 3-4 h after the dose. The maximum mean (+/- SD) blood concentrations normalized to the 10-mg oral dose were 21.6 +/- 3.7, 21.1 +/- 3.7, and 22.5 +/- 4.0 micrograms/L following the 10-, 20-, and 40-mg doses, respectively. A significant lag time of 10-80 min was observed after oral doses but was not related to dose size. The terminal slope (ts), absolute bioavailability (F), and renal clearance (CLr) were likewise not affected to an important degree by dose (ts: 0.043 +/- 0.006, 0.044 +/- 0.005, 0.046 +/- 0.006 h-1; F: 0.88 +/- 0.08, 0.82 +/- 0.06, 0.84 +/- 0.07; CLr: 0.68 +/- 0.22, 0.69 +/- 0.19, 0.65 +/- 0.22 mL/min kg). Unlike many beta-adrenergic antagonists, betaxolol has a long half-life (13-20 h) and high and consistent bioavailability (70-90%), and its disposition is independent of the size of the administered dose.

Factors affecting the survival of Salmonella and Escherichia coli in anaerobically fermented pig waste.

The survival of Salmonella typhimurium was investigated in acidogenic, anaerobically fermented pig wastes and in synthetic media, each containing volatile fatty acids (VFA). Salm. typhimurium survived at pH 6.8, but not at pH 4.0, when incubated at 37 degrees C for 24 h in either fermented or synthetic medium containing VFA. The minimum inhibiting concentration of VFA for Salm. typhimurium after 48 h incubation at 30 degrees C at pH 4.0 was 0.03 mol/l and for Escherichia coli it was 0.09 mol/l. Fermented pig wastes in a digester, maintained at pH 5.9, were inoculated with Salm. typhimurium and then incubated at 37 degrees C for 24 h. The pH was adjusted to either 4.0 or 5.0 and after a further 48 h at 30 degrees C, Salm. typhimurium survived at pH 5.0 but not at pH 4.0. It was concluded that pH is critical in determining the survival of this organism in acidogenic anaerobically fermented pig waste.

Experimental Salmonella anatum infection in horses.

Salmonella anatum was given orally to 8 horses on 11 occasions in doses ranging from 9.5 X 10(6) to 8.8 X 10(11) organisms. Four distinct syndromes were induced based upon clinical, laboratory and pathological findings: (1) asymptomatic; (2) moderate clinical signs with or without changes in faecal consistency; (3) fever, depression, anorexia with unstructured or diarrhoeic faeces; and (4) septicaemia with or without diarrhoea, and peripheral circulatory failure. All animals excreted the organism. The peak temperature preceded the onset of diarrhoea by 1 or 2 days. Changes in faecal consistency were associated with direct isolation of the organism. The degree of neutropaenia increased with the dosage. Blood cultures were unsatisfactory, only 1 of 33 samples being positive. The serological responses were not significant although one animal displayed a significant seroconversion consistent with the clinical reaction. Indomethacin was not of value in moderating intestinal fluid secretion in one animal. The distribution and quantitation of positive cultures at autopsy closely reflected the type of syndrome induced. The invasiveness of the organism was confirmed by frequent direct recoveries from intestinal wall and draining lymph node samples. S. anatum appears to be of similar pathogenicity to S. typhimurium in the horse, at least under experimental conditions.

The prevalence and epizootiology of salmonellosis among groups of horses in south east Queensland.

Over a 3-year period, 1178 faecal samples were cultured from 462 horses admitted to the equine clinic of the University of Queensland; 185 samples were positive for salmonella yielding 213 isolations consisting of 21 serotypes. S. anatum was the predominant serotype isolated (54%) followed by S. ohio (11.27%) and S. typhimurium (9.4%). One hundred and ten horses (23.81%) were positive on one or more occasion, and 42 (9.09%) on more than one occasion. S. anatum was the most common serotype isolated (71.43%) from the main drains in the stable block (33.57% positive samples). The prevalence of salmonella excretors among a large non-clinic population of horses in south east Queensland was 1.65%. Acute salmonellosis did not occur in the hospitalised animals. However, salmonellas were incriminated in 6 cases of chronic diarrhoea, which all yielded S. anatum, although the most severe involved both S. anatum and S. typhimurium, and these serotypes were isolated from multiple locations at the subsequent autopsy of 3 cases.