Pharmacokinetics of a 503B outsourcing facility-produced theophylline in dogs.

Theophylline is an important drug for treatment of canine chronic bronchitis and bradyarrhythmias, but new products require validation since pharmacokinetics in dogs can vary by formulation. A new, 503B outsourcing facility-produced theophylline product (OFT) is available for veterinary use. Outsourcing facilities have many advantages over traditional compounding sources including current good manufacturing practice compliance. The purpose of this study was to establish the pharmacokinetics of OFT in dogs. Eight healthy dogs received 11 mg/kg intravenous aminophylline and 10 mg/kg oral OFT followed by serial blood sampling in a two-way, randomized, crossover design with 7-day washout. Plasma theophylline concentrations were quantified by liquid chromatography-mass spectrometry. Bioavailability, maximum concentration, time to maximum concentration, half-life and area under the curve were: 97 ± 10%, 7.13 ± 0.71 µg/mL, 10.50 ± 2.07 h, 9.20 ± 2.87 h, and 141 ± 37.6 µg*h/mL, respectively. Steady-state predictions supported twice daily dosing of the OFT, but specific dosage recommendations are hindered by lack of a canine-specific therapeutic range for plasma theophylline concentration. These findings suggest that the OFT is well absorbed and can likely be dosed twice daily in dogs, but future pharmacodynamic and clinical studies are needed to establish a definitive therapeutic range for theophylline in this species.

Impact assessment of tail-vein injection in mice using a modified anaesthesia induction chamber versus a common restrainer without anaesthesia.

Intravenous (IV) administration in mice is predominantly performed via the lateral tail veins. The technique requires adequate training before it can be used safely and routinely. A novel anaesthesia induction chamber has been developed to simplify the treatment and to facilitate IV injection in mice, particularly for untrained personnel. We have assessed the benefits of the chamber in refining IV injection in isoflurane-anaesthetized mice in direct comparison with the common restrainer method on conscious animals. The body weight, nesting behaviour and concentrations of faecal corticosterone metabolites were taken as indicative of distress induced by the various procedures. The results suggest that both methods of tail-vein injection induce similar levels of momentary stress in the animals, revealed by a short-term increase in the levels of stress hormone metabolites in faeces. A temporary reduction of body weight was observed after IV injection under isoflurane anaesthesia but not for conscious mice injected in the common restrainer. We conclude that the severity of tail-vein injection in mice is 'mild' for both methods. There was no evidence that refining the procedure by using isoflurane anaesthesia in the induction chamber was associated with any benefit.

Well-defined hydroxyethyl starch-10-hydroxy camptothecin super macromolecule conjugate: cytotoxicity, pharmacodynamics research, tissue distribution test and intravenous injection safety assessment.

10-Hydroxy camptothecin (10-HCPT) is an antitumor agent effective in the treatment of several solid tumors but its use is hampered by poor water solubility, low lactone stability, short plasma half-life and dose-limiting toxicity. These limits of 10-HCPT had been overcome by our group through preparing super macromolecule prodrug: 10-HCPT-hydroxyethyl starch (HES) conjugate. In this study, we mainly evaluated in vitro and in vivo behavior of the prodrug, containing cytotoxicity assay, pharmacodynamics study, vascular irritation test, hemolysis experiment and tissue distribution test of rats. The irritation test results achieved much lower irritation than the commercial injection. The tissue distribution results showed that HES-10-HCPT conjugate increased significantly the 10-HCPT concentration in the tumor, liver and spleen site, whereas decreased the drug concentration in the heart and kidney. The hemolysis effect of the prepared conjugate was not obvious. The pharmacodynamics results indicated that HES-10-HCPT prodrug had a better antitumor efficiency against mice with H22 tumor than the commercial injection, and the inhibition ratio of tumor was 85.2% and 31.1%, respectively at the same dosage. These findings suggest that HES-10-HCPT prodrug is a promising drug delivery system providing improved good injection safety, greater tolerance and antitumor effect.

Prevention of peritonitis in newly-placed peritoneal dialysis catheters: efficacy of oral prophylaxis with cefuroxime axetil - a preliminary study.

BACKGROUND: Peritonitis is one of the causes of early peritoneal dialysis (PD) failure in newly-placed catheters. Antibiotic prophylaxis has been recommended to decrease the risk of infection after PD catheter placement. In this study, we compared the efficacy of parenteral versus oral prophylactic cefuroxime axetil for preventing peritonitis after placed PD catheters. METHODS: In total, 67 patients (F/M: 32/35; mean age: 46.6±13.2 years) undergoing 70 percutaneous PD catheter placement procedures were included (in three patients, placement was repeated). In 37 patients (parenteral group), we administered a single intravenous (IV) 750-mg dose of cefuroxime axetil, approximately 30 min before placement. In the oral group, 33 patients received a 500-mg dose of oral cefuroxime axetil 1 hour before the procedure and the patients continued that twice daily for 3 days. Patients were evaluated for peritonitis over the following 14 days. The costs of both oral and parenteral forms of cefuroxime axetil were calculated. RESULTS: The two groups were similar regarding age and gender. Three patients (9%) in the oral group and three (8.1%) in the parenteral group developed peritonitis (P=0.578). All were responded to therapy for peritonitis. The cost of parenteral prophylaxis was $US 7.58, while that of the oral form was $US 3.92. CONCLUSION: For patients undergoing percutaneous PD catheter insertion, a 3-day regimen of oral cefuroxime axetil for preventing early peritonitis was safe, equally effective, and had lower cost comparing with single intravenous dose of the same agent.

The influence of different contrast medium concentrations and injection protocols on quantitative and clinical assessment of FDG-PET/CT in lung cancer.

OBJECTIVES: To compare the effects of two different contrast medium concentrations for use in computed X-ray tomography (CT) employing two different injection protocols on positron emission tomography (PET) reconstruction in combined 2-(18)F-desoxyglucose (FDG) PET/CT in patients with a suspicion of lung cancer. METHODS: 120 patients with a suspicion of lung cancer were enrolled prospectively. PET images were reconstructed with the non-enhanced and venous phase contrast CT obtained after injection of iopromide 300 mg/ml or 370 mg/ml using either a fixed-dose or a body surface area adapted injection protocol. Maximum and mean standardized uptake values (SUV(max) and SUV(mean)) and contrast enhancement (HU) were determined in the subclavian vein, ascending aorta, abdominal aorta, inferior vena cava, portal vein, liver and kidney and in the suspicious lung lesion. PET data were evaluated visually for the presence of malignancy and image quality. RESULTS: At none of the sites a significant difference in the extent of the contrast enhancement between the four different protocols was found. However, the variability of the contrast enhancement at several anatomical sites was significantly greater in the fixed dose groups than in the BSA groups for both contrast medium concentrations. At none of the sites a significant difference was found in the extent of the SUV(max) and SUV(mean) increase as a result of the use of the venous phase contrast enhanced CT for attenuation. Visual clinical evaluation of lesions showed no differences between contrast and non-contrast PET/CT (P=0.32). CONCLUSIONS: Contrast enhanced CT for attenuation correction in combined PET/CT in lung cancer affects neither the clinical assessment nor image quality of the PET-images. A body surface adapted contrast medium protocol reduces the interpatient variability in contrast enhancement.

Intravenous recombinant tissue plasminogen activator therapy for stroke patients receiving maintenance hemodialysis: the Stroke Acute Management with Urgent Risk-Factor Assessment and Improvement (SAMURAI) rt-PA registry.

BACKGROUND: To examine the therapeutic effect of intravenous recombinant tissue plasminogen activator (rt-PA) therapy for stroke patients receiving maintenance hemodialysis (HD). methods: Of 600 stroke patients receiving intravenous rt-PA using 0.6 mg/kg alteplase who were enrolled in a multicenter observational study in Japan, 4 patients (3 men, 64-77 years old) on maintenance HD were studied. RESULTS: The primary kidney disease requiring HD was glomerulonephritis in 2 patients, diabetic nephropathy in 1, and undetermined in 1. The duration of HD ranged between 1.2 and 28 years. Three patients developed stroke on the day of HD, including 1 during HD and another just after HD. All patients had stroke in the carotid arterial territory. Pretreatment NIH Stroke Scale scores ranged between 4 and 20, and decreased by 2-5 points at 7 days. One patient needed intravenous antihypertensive therapy before rt-PA; he developed an ectopic cortical hematoma and intraventricular hemorrhage after rt-PA. The other 3 did not develop hemorrhagic complications. The modified Rankin Scale score at 3 months was 0 in 1 patient, 2 in 2 patients, and 4 in 1 patient. CONCLUSIONS: rt-PA therapy for stroke patients receiving maintenance HD might improve the stroke outcome. Ectopic hematoma was a unique complication in our case series.

Pharmacokinetics of intravenous and oral linezolid in adults with cystic fibrosis.

Linezolid is a treatment option for methicillin-resistant Staphylococcus aureus (MRSA) infections in cystic fibrosis (CF) patients. Little is known, however, about its pharmacokinetics in this population. Eight adults with CF were randomized to receive intravenous (i.v.) and oral linezolid at 600 mg twice daily for 9 doses in a crossover design with a 9-day washout. Plasma samples were collected after the first and ninth doses of each phase. Population pharmacokinetic analyses were performed by nonlinear mixed-effects modeling using a previously described 2-compartment model with time-dependent clearance inhibition. Monte Carlo simulation was performed to assess the activities of the linezolid dosing regimens against 42 contemporary MRSA isolates recovered from CF patients. The following pharmacokinetic parameter estimates were observed for the population: absorption rate constant, 1.91 h(-1); clearance, 9.54 liters/h; volume of central compartment, 26.8 liters; volume of peripheral compartment, 17.3 liters; and intercompartmental clearance, 104 liters/h. Linezolid demonstrated nonlinear clearance after 9 doses, which was reduced by a mean of 38.9% (range, 28.8 to 59.9%). Mean bioavailability was 85% (range, 47 to 131%). At steady state, 600 mg given twice daily produced 93.0% and 87.2% probabilities of obtaining the target pharmacodynamic exposure against the MRSA isolates for the i.v. and oral formulations, respectively. Thrice-daily dosing increased the probabilities to 97.0% and 95.6%, respectively. Linezolid pharmacokinetics in these adults with CF were well described by a 2-compartment model with time-dependent clearance inhibition. Standard i.v. and oral dosing regimens should be sufficient to reliably attain pharmacodynamic targets against most MRSA isolates; however, more frequent dosing may be required for isolates with MICs of ≥ 2 µg/ml.

Can oncology patients' central venous catheters be used for isotope assessment of glomerular filtration rate? An in-vitro study.

BACKGROUND: Isotope assessment of glomerular filtration rate (GFR) is frequently performed in patients with central venous catheters (CVCs). Use of the CVCs for administration of tracer and subsequent blood sampling would be less distressing for patients (particularly paediatric) and would reduce the frequency of failed samples due to poor venous access. However, the GFR test is quantitative and could be affected by incomplete tracer delivery due to adhesion to the CVC and also by contamination of blood samples due to adhered tracer leaching back into the sampled blood as it passes through the CVC. AIM: This in vitro study aimed to quantify the effects on GFR assessment of tracer adhesion and leaching, in single-lumen and dual-lumen CVCs. METHOD: New and clinically used single-lumen CVCs were injected with tracer (99mTc-DTPA and 51Cr-EDTA) and then flushed repeatedly with saline. The outflows were assayed in a gamma counter and, where possible, the CVCs were imaged on a gamma camera to take snap shots of tracer movement throughout a GFR assessment. In a separate experiment, a phantom patient was used to compare blood sampling through a dual lumen CVC with peripheral sampling. RESULT AND CONCLUSION: A CVC successfully delivers >99% of tracer. Subsequent blood samples can be taken through the other lumen of a dual-lumen CVC but not through a single-lumen as this significantly alters the GFR result due to contamination.

Home versus outpatient administration of intravenous steroids for multiple-sclerosis relapses: a randomised controlled trial.

BACKGROUND: Intravenous steroids are routinely used to treat disabling relapses in multiple sclerosis, and can be administered in an outpatient or home setting. We developed a rating scale that allowed us to compare the two strategies formally in a trial setting. METHODS: Patients who had a clinically significant multiple-sclerosis relapse within 4 weeks of onset were randomly assigned administration of a 3-day regimen of intravenous methylprednisolone either in an outpatient clinic (n=69) or at home (n=69). The MS relapse management scale (MSRMS) was developed to measure patients' experiences of relapse management as the primary outcome. Efficacy of the two treatment modalities was compared in terms of traditional measures and economic cost. A cost-minimisation analysis was also done. Analysis was by intention to treat. FINDINGS: Of 149 eligible patients, 138 consented to participate in the trial and were randomly assigned to a treatment group. Coordination of care was significantly better in the home-treatment group (median score 4.5 [IQR 3.0-11.4]) than in the hospital-treatment group (12.1 [3.0-18.6]; p=0.024). The other dimensions of the MSRMS did not differ between groups (p>0.10). Administration of steroids was equally safe and effective in either location, and cost was either the same or cheaper when delivered at home than when delivered in hospital. INTERPRETATION: Treatment of relapses in multiple sclerosis with intravenous steroids can be effectively and safely administered at home, from both patient and economic perspectives. Moreover, the trial indicates the importance of explicit and valid outcome measures of all aspects of service delivery when making decisions about health policy. This finding has implications for complex service delivery care models for long-term diseases.

Safety assessment of gadoversetamide (OptiMARK) administered by power injector.

PURPOSE: To evaluate the safety of OptiMARK (gadoversetamide injection) administered via power injector. MATERIALS AND METHODS: The study population included 144 healthy volunteers aged 18 years or older randomly assigned to one of seven treatment groups (N = 20/group). The safety assessment was based on changes in physical examination, vital signs, electrocardiograms (ECGs), standard clinical laboratory tests, and adverse events (AEs) through a 24-hour postinjection period. RESULTS: OptiMARK caused no serious AEs or unexpected changes in physical examinations or laboratory parameters. The changes observed in vital signs and ECG intervals did not vary with changes in injection rate and were not significantly (P < 0.05) different from those elicited by saline administration at the same rates. CONCLUSION: This study demonstrated the safety of OptiMARK when administered via a power injector at rates of 2, 4, and 6 mL/second.

Direct assessment and distribution of regional portal blood flow in the pig by means of fluorescent microspheres.

Measurement of regional organ blood flow by means of fluorescent microspheres (FM) is an accepted method. However, determination of regional portal blood flow (RPBF) cannot be performed by microspheres owing to the entrapment of the spheres in the upstream capillary bed of the splanchnic organs. We hypothesized that an adequate experimental setting would enable us to measure RPBF by means of FM and to analyze its distribution within the pig liver. A mixing chamber for the injection of FM was developed, and its capability to distribute FM homogeneously in the blood was evaluated in vitro. The chamber was implanted into the portal vein of six anesthetized pigs (23.5 +/- 2.9 kg body wt). Three consecutive, simultaneous injections of FM of two different colors into the chamber were performed. Reference portal blood samples were collected by means of a Harvard pump. At the end of the experiment, the liver was explanted and fixed in formalin before dissection. FM were isolated from the tissue samples by an automated process, and fluorescence intensity was determined. Comparison of 5,458 single RPBF values, determined by simultaneously injected FM, revealed good agreement (bias 2.5%, precision 12.7%) and high correlation (r = 0.97, r2 = 0,95, slope = 1.04, intercept = 0.05). Median RPBF was 1.07 +/- 0.78 ml x min(-1) x g(-1). Allocation of the blood flow values to the anatomic regions of the liver revealed a significantly higher RPBF (P = 0.01) in the liver tissue located close to the diaphragm compared with the rest of the organ and a significantly lower RPBF (P = 0.01) in the left liver lobe compared with the median and right lobes. The results show that the model presented makes it possible to measure RPBF by means of FM reliably and that RPBF is distributed heterogeneously in the porcine liver.

Reengineering intravenous drug and fluid administration processes in the operating room: step one: task analysis of existing processes.

BACKGROUND: A reengineering approach to intravenous drug and fluid administration processes could improve anesthesia care. In this initial study, current intravenous administration tasks were examined to identify opportunities for improved design. METHODS: After institutional review board approval was obtained, an observer sat in the operating room and categorized, in real time, anesthesia providers' activities during 35 cases ( approximately 90 h) into 66 task categories focused on drug/fluid tasks. Both initial room set-up at the beginning of a typical workday and cardiac and noncardiac general anesthesia cases were studied. User errors and inefficiencies were noted. The time required to prepare de novo a syringe containing a mock emergency drug was measured using a standard protocol. RESULTS: Drug/fluid tasks consumed almost 50 and 75%, respectively, of the set-up time for noncardiac and cardiac cases. In 8 cardiac anesthetics, drug/fluid tasks comprised 27 +/- 6% (mean +/- SD) of all prebypass clinical activities. During 20 noncardiac cases, drug/fluid tasks comprised 20 +/- 8% of induction and 15 +/- 7% of maintenance. Drug preparation far outweighed drug administration tasks. Inefficient or error prone tasks were observed during drug/fluid preparation (e.g., supply acquisition, waste disposal, syringe labeling), administration (infusion device failure, leaking stopcock), and organization (workspace organization and navigation, untangling of intravenous lines). Anesthesia providers (n = 21) required 35 +/- 5 s to prepare a mock emergency drug. CONCLUSIONS: Intravenous drug and fluid administration tasks account for a significant proportion of anesthesia care, especially in complex cases. Current processes are inefficient and may predispose to medical error. There appears to be substantial opportunity to improve quality and cost of care through the reengineering of anesthesia intravenous drug and fluid administration processes. General design requirements are proposed.

Ready-to-use injection preparations versus conventional reconstituted admixtures: economic evaluation in a real-life setting.

OBJECTIVE: To measure, in a real-life setting, the benefits of using ready-to-use (RTU) injection preparations compared with conventional reconstituted admixtures (Admix) in terms of cost savings. DESIGN AND PERSPECTIVE: An economic model was developed, based on a randomised study. The perspective of the economic evaluation was that of the hospital administration. A microcosting approach was used to determine costs. SETTING: Department of Cardiac Surgery at the Charleroi University Hospital in Belgium. STUDY PARTICIPANTS: Fifty-eight patients undergoing cardiac surgery under cardiopulmonary bypass were randomised to Admix dobutamine or to the RTU dobutamine group and were followed up during 24 hours after initiation of dobutamine therapy. MAIN OUTCOME MEASURES AND RESULTS: Nursing time was reduced by 32% in the RTU group compared with the Admix group. Material cost was also reduced and the overall cost savings in the RTU group amounted to a 60% reduction in the cost of the conventional Admix process (p<0.001). When drug cost was included in the equation, cost savings varied from 1.60 euros (EUR) to EUR21.40 per patient depending on dosage. There was no difference between the two groups in terms of safety and efficacy. A user satisfaction survey showed that medical staff especially welcomed improved ease of preparation and potential for prevention of errors and risks of handling. CONCLUSION: This study confirmed the potential for RTU forms to reduce nursing time associated with preparation and administration of intravenous admixtures and to enable overall cost savings.

Cost-effective adenosine dosing for the treatment of PSVT.

We reviewed our experience with adenosine for the conversion of paroxysmal supraventricular tachycardia (PSVT) to determine whether the recommended dosing strategy of 6 mg, followed by 12 mg, is cost-effective in actual practice. We observed a 65% conversion rate to sinus rhythm with the initial dosage of 6 mg adenosine (95% CI, 54% to 75%), and, based on subsequent cost analysis, conclude that the current strategy should not be replaced by a 12-mg-first strategy. If the packaging of adenosine was changed so that 12 mg cost less than twice 6 mg, this analysis should be revisited.

Preoperative assessment of gastric carcinoma: value of two-phase dynamic CT with mechanical iv. injection of contrast material.

OBJECTIVE: The purpose of this study was to evaluate the utility of two-phase dynamic CT performed with mechanical IV injection of a bolus of contrast medium after oral intake of water in the preoperative staging of gastric cancers. SUBJECTS AND METHODS: We performed incremental dynamic CT in 52 patients with pathologically proved gastric cancers. Dynamic CT findings were prospectively analyzed and correlated with surgical and histopathologic findings. A total of 150 ml of nonionic contrast medium was administered IV with a power injector at a flow rate of 5 ml/sec for 30 sec, and two-phase images were obtained at 30 sec (early phase) and 2 min (equilibrium phase) after the start of bolus injection. RESULTS: Forty-one advanced gastric carcinomas showed a moderate to marked degree of heterogeneous enhancement in the early phase and homogeneous enhancement of the entire lesion in the equilibrium phase of dynamic CT. The primary tumors were correctly detected with dynamic CT in five (56%) of the nine early gastric cancers and in 41 (95%) of the 43 advanced gastric cancers. The overall detection rate of gastric cancers was 88% (46 of 52 cases). The accuracies of dynamic CT according to TNM staging in determining the depth of tumor invasion, the degree of serosal invasion, and regional lymph node metastasis were 65% (34 of 52 cases), 83% (38 of 46 cases), and 70% (32 of 46 cases), respectively. CONCLUSION: Our findings show that two-phase incremental dynamic CT with mechanical IV injection of a bolus of contrast medium after oral intake of water improves the diagnostic accuracy of CT over that provided by conventional CT in the preoperative staging of gastric cancers.

Home chemotherapy for children with cancer.

A program was established in which the parents of children with cancer were trained to administer intravenous chemotherapy to the children in their homes. The main objectives of this program (Home Intravenous Chemotherapy by Parents [HICP]) were to improve the quality of life for children with cancer and their parents and to decrease the cost of medical care for these children by decreasing the number of clinic visits and hospital stays intended solely for the administration of chemotherapy. Twenty-four months of experience with this program indicates that with a close communication network and a good working relationship among a home care organization (HCO), the parents of the patient, a pediatric oncology nurse, and an attending pediatric oncologist, many chemotherapeutic agents can be safely administered to these children by their parents in their homes. The patients and their parents are enthusiastic about this program because of the valuable time saved and the increased participation in care. In addition, this program greatly decreased the cost of medical care for these children.

Determinants of needle sharing among intravenous drug users.

Data from 110 IV-drug abusing persons in methadone maintenance were analyzed to determine the correlates of needle sharing. Sharing was directly related to peer group behavior, attitudes conducive to sharing, economic motivation to share, not owning injection equipment, and fatalism about developing AIDS. Sharers were aware of their AIDS risk. Indicated measures to reduce needle sharing would be positive peer support groups to help resist pressures to share, legal and free access to fresh injection equipment, education on the utility of risk reduction, and increased treatment options for IV cocaine users.