Effect of gastrointestinal inflammation and age on the pharmacokinetics of oral microemulsion cyclosporin A in the first month after bone marrow transplantation.

Cyclosporin A (CsA) absorption is highly variable in BMT patients. Neoral, a new microemulsion formulation of CsA, permits increased absorption with less variable pharmacokinetic parameters in non-BMT patients. We evaluated the pharmacokinetics of CsA after BMT in patients received microemulsion CsA. Two oral doses of 3mg/kg were given 48 h apart between 14 and 28 days after allogeneic BMT in 20 adults, and one dose in seven children, while subjects were receiving a continuous i.v. infusion of CsA. Whole blood samples were taken throughout the dosing interval to calculate the incremental CsA exposure using maximum concentration (Cmax), time to Cmax (tmax), concentration at 12 h after the dose (C12), the area under the concentration-time curve (AUC), and to establish inter- and intra-patient pharmacokinetic variability. Drug exposure was substantially lower in children than adults, with an AUC of 861+/-805 vs 2629+/-1487 micromg x h/l (P = 0.001), respectively, and absorption was delayed and diminished in both groups by comparison with solid organ recipients. Intra-patient variability in adults for AUC was high at 0.59+/-0.34, while inter-patient variability, measured as the coefficient of variation (c.v.), was 0.55 for the first and 0.54 for the second dose. In adults, gastrointestinal (GI) inflammation due to either mucositis or GVHD resulted in a higher AUC of 3077+/-1551 microg x h/l compared to 1795+/-973 microg x h/l (P = 0.02), and a similar trend was observed in children. AUC seemed little affected by the CsA formulation (liquid or capsule), or co-administration with liquids or food. Trough (12 h) CsA levels correlated poorly with incremental AUC. Sparse sample modeling of the AUC using two-point predictors taken at 2.5 and 5 h after dosing accurately approximated AUC in adults (r2 = 0.94), while 1.5 and 5 h was superior in children (r2 = 0.98). These data suggest that 12 h postdose trough measurements of CsA may not be the most appropriate way to evaluate CsA blood concentrations in order to establish therapeutic efficacy in BMT patients. Based on this study, the dose of microemulsion CsA should be adjusted based on recipient age, and the presence of GI inflammation secondary to mucositis or GVHD. These data would suggest that sparse sampling at time points earlier than the trough more accurately reflects the AUC and may correlate more closely with therapeutic efficacy early post-BMT.

Pharmacist's management of drug-related problems: a tool for teaching and providing pharmaceutical care.

During the development of education and practice models based on the philosophy of pharmaceutical care (PC), six pharmacists worked with the University of Toronto Faculty of Pharmacy to implement the PC model in their practice sites. These pharmacists found it necessary to modify existing tools to create one that explicitly guided them through the PC process, including the phase of monitoring patients for desired outcomes. This resulted in the development of the Pharmacist's Management of Drug Related Problems. This tool requires pharmacists to collect patient drug and medical data and write responses to specific questions about the data to interpret their significance. As proficiency in providing PC is attained, the questions and space for written responses can be eliminated, leaving a comprehensive documentation system of patient outcomes and the data collected, recommendations made, and monitoring completed by the pharmacist. This tool has been adopted by the University of Toronto Faculty of Pharmacy and is being used in various continuing education programs and by practicing pharmacists across Canada.

Acute acyclovir neurotoxicity in a hemodialyzed child.

A 5-year-old girl with a kidney transplant developed post-transplant Epstein-Barr virus-induced lymphoproliferative disease. She was treated with acyclovir, alpha-interferon, and gamma globulin. A transplant nephrectomy was performed on day 4 due to acute rejection and she was started on hemodialysis. The acyclovir dose was decreased at this time. However, 6 days following the start of acyclovir she developed progressively worsening neurological symptoms resulting in a coma on day 8. Fourteen days after acyclovir was begun pre- and post-dose serum concentrations were 7.02 microM and 182.5 microM, respectively. Acyclovir was then discontinued and 2 days later the child's neurological status began to improve. We conclude that acyclovir in children with end-stage renal failure may lead to severe and reversible neurotoxicity, despite acyclovir dosage adjustment based on renal impairment.

Focus and impact of pharmacists' interventions.

All pharmacists' interventions were collected over a two-week period and were assessed for type and impact on patient care and medication costs. A total of 361 interventions were collected with a physician acceptance rate of 95.8 percent. Eighty-two of the 361 interventions were reviewed by seven physicians with 93 percent of those being judged to have had a positive effect on patient outcome, 7 percent were judged to have had no effect, while none reviewed were judged to be detrimental. Life-saving interventions were judged to have occurred in 8.5 percent of interventions, while 90 percent of the interventions were perceived to have resulted in improved quality of care and/or physician education. Cost analysis was performed comparing the difference of total medication costs (drug, pharmacy, nursing and drug assay costs) for a 24 hour period prior to and after the intervention occurred. The cost-avoidance over the two week period was calculated to be $679, representing a conservative estimate of an annual cost-avoidance of $17,654. Costs not evaluated were those avoided due to increased quality of care, decreased adverse drug effects and decreased length of hospital stay. Pharmacists' interventions which represent only a portion of a pharmacist's responsibilities, improve the quality of patient care and result in cost avoidance.

Amantadine neurotoxicity in a pediatric patient with renal insufficiency.

Amantadine hydrochloride, a dopamine agonist with antiviral and antiparkinsonism properties, is used for the prevention and treatment of influenza A respiratory infections in high-risk populations. The occurrence of amantadine-induced hallucinations and tremors is described in a young, renal transplant patient with declining renal function. Following discontinuation of amantadine, plasma amantadine concentrations were correlated with central nervous system toxicity. In view of the usage of amantadine in renal transplant recipients and the elderly, clinicians must be alert to the possibility of amantadine-induced neurotoxicity in patients with changing renal function.

Tissue plasminogen activator for the treatment of thromboembolism in infants and children.

We report our experience with the use of tissue plasminogen activator to treat 12 infants and children with various thromboembolic states after conventional thrombolytic agents had failed. The dosage range was between 0.1 to 0.5 mg/kg per hour. Complete clot dissolution occurred in seven cases after 2 hours to 3 days of therapy. Partial clot dissolution and clinical improvement were noted in another four patients. Bleeding complications were noted in 6 of the 12 patients and included bruising, oozing from various venipuncture sites, and bleeding; these complications were controlled by clinically available means. In all cases with bleeding the dose rate was in the higher range (0.46 to 0.50 mg/kg per hour). In one patient, restlessness, agitation, and screaming were noted during administration of tissue plasminogen activator and when it was reinstituted. We conclude that tissue plasminogen activator is effective in inducing clot lysis in children. Because the effective dose appears to overlap with those causing bleeding, we recommend that a dose of 0.1 mg/kg per hour be started and increased gradually if clot dissolution does not occur, with close monitoring for bleeding.

Pharmacist intervention in prescribing of cefuroxime for pediatric patients.

A targeted drug review of cefuroxime use in pediatric patients is described. Because of a 65% increase in cefuroxime costs over one year, pharmacists assessed the appropriateness of cefuroxime therapy from October 13 to December 20, 1987. This assessment was done within 48 hours after the prescription was written and again after 72 hours of cefuroxime therapy, when bacteriology and susceptibility data were available. When a drug order was inappropriate, a pharmacist intervened with the prescribing physician. For comparison, data collection forms were completed for patients who had received cefuroxime before and after the study period. Before the study period, 42% of the cefuroxime orders were inappropriate with respect to dosage or indication at the time of the initial order; this rate fell to 26% during the study period and increased to 33% after the study period. After 72 hours of therapy, the rates of inappropriate prescribing were 48% (before study period), 32% (during study period), and 40% (after study period). During the study period, pharmacists intervened in only half of the 51 cefuroxime orders initially deemed to be inappropriate, and only 26% of these interventions resulted in an order change. Although pharmacists met with some success in increasing the appropriateness of cefuroxime prescribing, both pharmacists and physicians resumed their previous monitoring and prescribing habits after the study period had ended.

Modification of M-FC medium by eliminating rosolic acid.

Eliminating rosolic acid from M-FC medium improves the MFC procedure by allowing higher fecal coliform colony recoveries with greater ease in counting. Samples of unchlorinated and chlorinated domestic sewage, creek, lake, and river water were analyzed for fecal coliforms by standard procedures. Results of 200 comparisons of fecal coliform counts on M-FC medium without and with rosolic acid showed that higher counts were obtained 71% of the time when rosolic acid was excluded without an overgrowth of background colonies. Results from analyzing chlorinated sewage showed that eliminating rosolic acid improved the recovery of fecal coliform bacteria by 49%. A total of 1,675 blue colonies and 766 nonblue colonies were verified. Of the 1,675 blue colonies, 1,566 were confirmed as fecal coliform bacteria, for a verification of 93.5%. The percent verification of nonblue colonies as noncoliform bacteria was 84.2% (644/766).