Twice-daily Infusion Research Articles

Eficácia da terapia antimicrobiana associada à vacinação na cura bacteriológica de mastite subclínica causada por Staphylococcus aureus em vacas em lactação

ABSTRACT: The objective of this study was to evaluate the efficacy of the antibiotic therapy associated with vaccination on the microbiological cure rate of subclinical mastitis caused by Staphylococcus aureus in lactating dairy cows. A total of five herds, from which 72 cows (120 mammary quarters - MQ) were diagnosed with S. aureus subclinical mastitis, were included in this study. Cows were randomly allocated to one of three treatment groups: a) Control (no treatment); b) ATB (antibiotic therapy); and c) ATB+VAC (antibiotic therapy plus vaccination against S. aureus). Intramammary treatment consisted of twice-daily infusion of ampicillin 75mg + cloxacillin 200mg, for 5 days. Parenteral treatment was done by injection of a single dose (7.5mg/kg) of enrofloxacin, on the first day of the treatment protocol. Vaccinated cows received three doses of a commercial vaccine 14 days before treatment (d-14), on the first day of treatment protocol (d1), and 14 days after the treatment protocol (d+14). Non-treated cows had a lower cure rate (0.06) than cows treated with ATB (0.84) and ATB+VAC (0.85). No difference in cure rate was observed between cows treated with ATB and ATB+VAC. On the other hand, vaccinated cows had lower somatic cell count (SCC) after 28 days of the treatment protocols (4.76 log10) than non-treated cows (5.37 log10). In conclusion, treatment with intramammary ampicillin and cloxacillin, associated with intramuscular enrofloxacin presented a high cure rate for SCM caused by S. aureus during lactation. The use of vaccination against S. aureus in association with antibiotic therapy did not increase the cure rate of MQ during lactation, but it was effective in reducing the SCC when compared to non-treated MQ. Although to ensure that the decrease of the SCC in ATB+VAC group was associated with the vaccination, the study should have included an additional group of only vaccinated cows, without antimicrobial therapy, with was not done in the present study, and therefore is one of the limitations of the experimental protocol used.

Pharmacokinetics of Cyclosporine a Conversion From Twice-Daily Infusion to Oral Administration in Allogeneic Hematopoietic Stem Cell Transplantation

Twice-daily administration of cyclosporine A (CyA) has often been used for prophylaxis of acute graft versus host disease in allogeneic hematopoietic stem cell transplantation (allo-HSCT). But there have not been any reports that calculated the conversion ratio of the switch from twice-daily intravenous infusion to oral administration of CyA in adult patients. To establish the conversion ratio and the best strategy of twice-daily administration of CyA, the authors investigated the serial changes in the blood CyA concentration during the switch from twice-daily intravenous infusion to oral administration while maintaining high-peak concentration (over 1000 ng/mL) and calculated the bioavailability of Neoral, a micro emulsion cyclosporine, in 11 patients. All the patients underwent allo-HSCT with graft versus host disease prophylaxis consisting of CyA at a high-peak concentration of twice-daily infusion with short-term methotrexate and oral administration. Neoral was started at an oral dose, 2 times daily, at twice the latest dose of intravenous dose according to the bioavailability of healthy volunteers. Micafungin, a mild inhibitor of CYP3A4, was administered for prophylaxis against fungal infection. The total area under the concentration-time curve during oral administration (AUCpo) was nearly the same as AUC during intravenous infusion (AUCiv) (mean ± SD, 7206 ± 1557 ng·h·mL and 7783 ± 897.7 ng·h·mL, respectively). The bioavailability of Neoral, defined as F = AUCpo × DOSEiv/AUCiv × DOSEpo was 0.58 ± 0.15 (mean ± SD, range: 0.41-0.94). When patients were switched from twice-daily infusion to oral administration, the dose conversion ratio of 1:2 seemed to be appropriate. At that time, the target trough level of Neoral was nearly the same as that of the infusion.

Pharmacokinetics of cyclosporine A at a high-peak concentration of twice-daily infusion and oral administration in allogeneic haematopoietic stem cell transplantation

The most appropriate immunosuppressive strategy with calcineurin inhibitors for the prevention of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT) has not yet been established. To estimate the safety and efficacy of a new strategy, we investigated the pharmacokinetics of cyclosporine A (CyA) delivered by twice-daily infusion and oral administration maintained with a peak level above 1000 ng/mL to keep 24 h area under the concentration-time curve (AUC0-24) higher than 10 000 ng·h/mL in 12 patients. Cyclosporine A was started as a twice-daily infusion at 1·5 mg/kg and then orally administered at twice the infusion dose to maintain the trough blood concentration between 200 and 500 ng/mL, and with a peak level above 1000 ng/mL. Serial blood samples were collected at 0, 1, 2, 3, 5, 8 and 12 h after CyA dosing (C0, C1, C2, C3, C5, C8 and C12) on days 14-21 after transplantation and on days 7-14 after switching to oral administration, and the AUC was calculated. In all patients, the AUC0-24 for both twice-daily infusion and oral administration was higher than 10 000 ng·h/mL. Two close relationships were observed between AUC0-12 and the C3 for infusion and between AUC0-12 and the C8 for oral administration. None of the patients had grades 3-4 aGVHD or other serious complications. This strategy was well tolerated, and the C3 for twice-daily infusion and the C8 for oral administration were the optimal points for monitoring of CyA concentration in the early phase of transplantation.

Optimal Post-Dose Levels of Cyclosporine A at a Higher Peak Concentration Are Correlated with the Area Under the Concentration-Time Curve of Twice-Daily Infusion and Oral Administration in Allogeneic Hematopoietic Stem Cell Transplantation.

Abstract 4656 IntroductionCyclosporine A (CyA), a calcineurin inhibitor, is widely used as an immunosuppressor for the prevention of acute graft-versus-host disease (aGVHD) in allogeneic hematopoietic stem cell transplantation (alloHSCT). However, the optimal regimen of CyA has not yet been unequivocally established. Among liver transplant patients, it is important to maintain a peak CyA concentration and to monitor area under the concentration-time curve (AUC) and 2 h after CyA dosing (C2) for prophylaxis against graft rejection. We investigated the pharmacokinetics of CyA delivered by twice-daily infusion and oral administration maintained with a peak level above 1000 ng/ml to keep AUC 0-24 higher than 10000 ng-h/ml in 10 patients with hematological malignancy who underwent alloHSCT. MethodsCyA was started as a twice-daily infusion at 1.5 mg/kg and then orally administered at twice the infusion dose in order to maintain the trough blood concentration between 200 and 500 ng/ml and with a peak level above 1000 ng/ml. Serial blood samples were collected at 0, 1, 2, 3, 5, 8, and 12 h after CyA dosing (C0,C1,C2,C3,C5,C8,C12) on days 14-21 after transplantation and on days 7-14 after switching to oral administration, and the AUC was calculated. ResultsThe mean AUC0-12 for twice-daily infusion and oral administration was 7443±998.5 ng-h/ml and 7185±1714 ng-h/ml, respectively. Among all the patients, the AUC0-24 for both CyA twice-daily infusion and oral administration was higher than 10000 ng-h/ml. Two close relationships were observed between AUC0-12 and the C3 level for infusion and between AUC0-12 and the C8 level for oral administration. Engraftment was achieved in all cases, and two patients suffered from grade 2 aGVHD. None of the patients had grades 3-4 aGVHD or other serious complications. ConclusionThis strategy was well tolerated, and the C3 level for twice-daily infusion and the C8 level for oral administration were the optimal points for monitoring of CyA concentration in the early phase of alloHSCT. Disclosures:No relevant conflicts of interest to declare.

Decreased incidence of acute graft‐versus‐host disease by continuous infusion of cyclosporine with a higher target blood level

Cyclosporine A (CsA) is the mainstay of pharmacologic prevention of acute graft-versus-host disease (GVHD). We previously reported that continuous infusion of CsA with a target blood level between 250 and 400 ng/ml significantly increased the incidence of acute GVHD compared to twice-daily infusion with a target trough level between 150 and 300 ng/ml. Thus, we raised the target level of CsA continuous infusion to 450-550 ng/ml. We treated 33 patients with the higher target level (CsA500) and compared the efficacy and toxicity with those in the 33 historical control patients (CsA300 group). Other transplantation procedures were not changed. The patients' characteristics were equivalent. The average CsA concentration was adjusted around 500 ng/ml and the actual daily dose was maintained at the initial dose (CsA 3mg/kg/day). Toxicities were equivalently observed among the two groups. The incidence of grades II-IV acute GVHD was significantly lower in the CsA500 group (27 vs. 52%, P = 0.033). The target level of CsA was identified as an independent significant risk factor for grades II-IV acute GVHD (P = 0.039), adjusted for the presence of HLA mismatch. The incidence of chronic GVHD was also decreased in the CsA500 group (47 vs. 73%, P = 0.016). We conclude that the toxicity of the continuous CsA infusion with a target level of 450-550 ng/ml is acceptable and the efficacy to prevent acute GVHD is significant. A larger comparative study is warranted to confirm these findings.

Population Pharmacokinetics and Proton Pump Inhibitory Effects of Intravenous Lansoprazole in Healthy Japanese Males

A total of 56 healthy Japanese males were enrolled in single- or multiple- dose pharmacokinetic trials of intravenous lansoprazole administration. The population pharmacokinetics of the drug was evaluated using nonlinear mixed effects model (NONMEM) software. In addition, the effect of CYP2C19 polymorphism on proton pump inhibition by lansoprazole was investigated using 24-h intragastric pH monitoring in the 32 subjects. Time course of serum lansoprazole concentration following intravenous short infusion was well described by a 2-compartment model. The mean volume of the central and peripheral compartments was 0.110 and 0.201 l/kg, respectively. The mean inter-compartment clearance was estimated to be 0.0882 l/h/kg. The population mean value of systemic clearance in the homoEM (CYP2C19 1/ 1), heteroEM (CYP2C19 1/2 and 1/3), and PM (CYP2C19 2/2, 2/3, and 3/3) groups was 0.179, 0.109, and 0.038 l/h/kg, respectively. The mean intragastric pH following twice-daily doses of 30 mg lansoprazole was approximately 6, 5, and 4 in the PM, heteroEM, and homoEM groups, respectively. These findings indicate that large interindividual variability exists in the pharmacokinetics of intravenously administered lansoprazole, but that twice-daily infusion of a 30 mg dose leads to significant and sustained proton pump inhibition, even in the homoEM group, despite the short elimination half-life of the drug.

Phase I dose escalation clinical trial of phenylbutyrate sodium administered twice daily to patients with advanced solid tumors

Phenylbutyrate (PBA), and its metabolite phenylacetate (PAA), induce growth inhibition and cellular differentiation in multiple tumor models. However, despite their potential anti-cancer properties, several pharmacodynamic aspects remain unknown. We conducted a dose escalating trial to evaluate twice-daily intravenous PBA infusions for two consecutive weeks (Monday through Friday) every month at five dose levels (60-360 mg/kg/day). Twenty-one patients with the following malignancies were treated: colon carcinoma 4, non-small cell lung carcinoma 4; anaplastic astrocytoma 3, glioblastoma multiforme 3, bladder carcinoma 2, sarcoma 2, and ovarian carcinoma, rectal hemangiopericytoma, and pancreatic carcinoma 1 each. Conversion of PBA to PAA and phenylacetylglutamine (PAG) was documented without catabolic saturation. Plasma content of PBA > or =1 mM was documented for only 3 h following each dose at the top two dosages. The therapy was well tolerated overall. Common adverse effects included grade 1 nausea/vomiting, fatigue, and lightheadedness. Dose limiting toxicities were short-term memory loss, sedation, confusion, nausea, and vomiting. Two patients with anaplastic astrocytoma and a patient with glioblastoma remained stable without tumor progression for 5, 7, and 4 months respectively. Administration of PBA in a twice-daily infusion schedule is safe. The maximum tolerated dose is 300 mg/kg/day. Study designs with more convenient treatment schedules and specific molecular correlates may help to further delineate the mechanism of action of this compound. Future studies evaluating PBA's ability to induce histone acetylation and cell differentiation alone or in combination with other anti-neoplastics are recommended.

Pharmacokinetics of foscarnet after twice-daily administrations for treatment of cytomegalovirus disease in AIDS patients.

The pharmacokinetics of foscarnet were evaluated in 11 AIDS patients with cytomegalovirus disease after twice-daily infusion of 90 mg/kg of body weight for 2 weeks. All patients were hydrated during foscarnet infusion. Blood and urine samples were collected on days 1, 7, and 14 of therapy. Foscarnet concentrations were measured by high-pressure liquid chromatography. Despite large interindividual variations, no significant differences were seen between day 1, day 7, and day 14 concentrations in plasma. Mean peak and trough concentrations on day 14 of therapy were 605 +/- 118 and 52 +/- 59 microM, respectively. In all patients, peak concentrations were well above those necessary to inhibit cytomegalovirus. Pharmacokinetic parameters remained stable throughout the study. On day 14, the mean half-life was 3.4 h, total and renal clearances were 118 and 92 ml/min, respectively, and the volume of distribution was 0.6 liter/kg. These data and previous clinical trials demonstrate that this more convenient dosage regimen can be safely used for patients with cytomegalovirus disease. The side effects were comparable to those reported with other dosage regimens, although no renal impairment was seen in this study, probably because of the hydration.