Pharmaceutical care needs of patients with angina.

OBJECTIVE: The aim of this study was to evaluate patient knowledge and assess the management of angina for patients receiving sublingual glyceryl trinitrate (GTN) METHOD: Prospective data collection and patient interview was undertaken in 17 community pharmacies. RESULTS: During the study 488 angina patients presented to the participating pharmacies. Data were collected for 347 patients receiving sublingual GTN. Problems with administration technique were identified for 108 patients (31%) and knowledge of when to seek medical help appropriately after failed GTN use was unsure for 134 patients (39%) or poor for 88 patients (25%). Eighty five patients (24%) were not receiving regular symptomatic therapy. Aspirin was prescribed or purchased by 253 patients (73%). Seven pharmacies participated in GP referral (data collected for 201 patients); 31 patients (15%) were referred usually with a recommendation to add aspirin. The outcome of 20 of these referrals was assessed; advice was taken for 13 patients, 3 patients failed to attend GP, aspirin was contraindicated for 3 patients and one patient already attended pharmacist medication review. CONCLUSION: This study demonstrated the potential contribution community pharmacists could make at the time of dispensing to the management of patients with angina.

The effects of age and chemotherapy on gentamicin pharmacokinetics and dosing in pediatric oncology patients.

We attempted to determine the effects of prior antineoplastic chemotherapy and age on gentamicin pharmacokinetics in children (age 1-18 yrs) with cancer and in controls, and to establish a protocol for gentamicin dosing and monitoring to ensure rapid attainment of therapeutic serum concentrations in these patients. In a prospective controlled study, patients with fever who were receiving empiric gentamicin for confirmed or suspected infections were separated into three groups: 29 with cancer who were receiving a continuing chemotherapy protocol with nonnephrotoxic antineoplastic agents; 23 with cancer who were receiving a continuing chemotherapy protocol with nephrotoxic antineoplastic agents; and 25 control patients who did not have cancer. Three blood samples (one predose, two postdose concentrations), collected between the third and sixth gentamicin doses from each patient, were analyzed by the Emit assay. Pharmacokinetic parameters were calculated and gentamicin dosages recommended based on the Sawchuk-Zaske method of serum level interpretation. When normalized by body weight, there was no significant difference in clearance, volume of distribution, and half-life between the control group and either group of patients with cancer. However, when normalized by body surface area, patients receiving prior nephrotoxic chemotherapy appeared to have a lower mean clearance (98.2 ml/min/1.73 m2) than those exposed to nonnephrotoxic chemotherapy (117.4 ml/min/1.73 m2) and controls (113.3 ml/min/1.73 m2; ANCOVA p = 0.033). When kinetic parameters were normalized by body weight, the effect of advancing age yielded a decrease in both clearance (p < 0.001) and volume of distribution (p = 0.02), and an increase in gentamicin half-life (p < 0.001). When normalized by body surface area, age had no significant effect on clearance (p = 0.579). There was no significant difference in gentamicin daily dose requirements (mg/kg) between the chemotherapy groups, which may be due to the lack of significant effects of chemotherapy on gentamicin's volume of distribution and clearance normalized by body weight. The final maintenance doses (mg/kg/day, mean +/- SD) for patients with cancer were 10.8 +/- 1.8 for those age 1-5 years, 8.9 +/- 1.1 for those age 6-12 years, and 7.9 +/- 1.9 for those age 13-18 years. However, when normalized by body surface area, the age-dependent doses became remarkably similar for children in all three age groups (ANOVA p = 0.932), approximately 250 mg/m2/day. We recommend that pediatric patients with cancer who require treatment for fever and neutropenia be given higher than standard gentamicin dosages to achieve therapeutic serum concentrations promptly. In particular, initial empiric doses of 10 mg/kg/day are appropriate for those age 1-5 years.

Challenges in comparing treatment outcome from a prospective with that of a retrospective study: assessing the merit of gentamicin therapeutic drug monitoring in pediatric oncology.

The objectives of this study were: (a) to assess whether treatment outcome with gentamicin in pediatric oncology patients could be improved by a pharmacy based therapeutic drug monitoring (TDM) service that included pharmacokinetic interpretation; and (b) to describe the challenges in comparing treatment outcome from a prospective to a retrospective study when the merit of gentamicin therapeutic drug monitoring (TDM) was assessed in pediatric oncology patients. Two groups of pediatric oncology patients, aged 1-18 years, received empiric gentamicin therapy for fever and for confirmed or suspected infection, with the same inclusion and exclusion criteria. Group 1 consisted of patients from a prospective gentamicin pharmacokinetic study with a formalized pharmacy-based TDM service (n = 52). Group 2 consisted of patients admitted to the oncology units who had gentamicin levels analyzed in the TDM Laboratory without the formalized TDM Service (n = 25). Gentamicin dosage adjustments were recommended based on three blood samples (one pre- and two postdose concentrations) collected between the third and sixth doses from each patient in the TDM group, utilizing pharmacokinetic principles and the Sawchuk-Zaske method. In the non-TDM group, dosage adjustments based on two routine blood samples (one pre- and post-gentamicin dose) were performed by physicians without the help of the formalized TDM Service. Multiple regression analysis showed that time periods (TDM, non-TDM), duration of neutropenia, intravenous methotrexate, and types of cancer, e.g., hematologic malignancy vs. solid tumor, had significant effects on duration of fever. Initial absolute neutrophil count, insertion of central venous line, intravenous cloxacillin administration, bacteriologic cultures, and initial post gentamicin levels > or = 5 mg/ml had no significant effects on the duration of fever. Mean duration of fever in the TDM group (2.8 +/- 2.4 days) was significantly shorter than that in the non-TDM group (9.0 +/- 8.8 days) (p < 0.001). Therapeutic serum concentrations were achieved more promptly in the TDM group, with significantly fewer patients requiring dose changes and fewer sets of serum concentrations required. One patient from each group had a > 100% increase in serum creatinine on day 5 compared to baseline. No apparent nephrotoxicity was observed in other patients. Although there was an association of shorter duration of fever with prompt achievement of therapeutic gentamicin serum concentrations with the TDM Service, there were several unresolved factors that affected duration of fever. A randomized prospective and controlled study would be required to substantiate the merit of TDM in shortening the duration of fever in pediatric oncology patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Polyvinylchloride containers do not influence the hemodynamic response to intravenous nitroglycerin.

In-vitro evidence of sorption of nitroglycerin (NTG) to polyvinylchloride (PVC) containers suggests that these containers may deliver less nitroglycerin to the patient than glass containers. Sorption of NTG to the PVC container may result in hemodynamic changes in the patient when a fresh solution of NTG is prepared and administered from a PVC container. This study was designed as a prospective, randomized trial to measure the hemodynamic response in patients receiving NTG in glass or PVC containers, during the first hour after a container exchange. Patients admitted to the coronary care unit in a University hospital with chest pain considered to be due to unstable angina or acute myocardial infarction were eligible. Patients who received other vasoactive drugs within one hour of container exchanges were excluded. Systolic and diastolic blood pressures, and heart rate were measured at baseline and at intervals for one hour following a container exchange. Twenty patients completed the study. There were no significant changes with time in either group (ANOVA, p > 0.05) with respect to systolic, diastolic, or mean arterial blood pressure or heart rate. No chest pain occurred during the 60 minutes following the container exchange in either group. We conclude that NTG can be administered safely and effectively in PVC containers to patients with unstable angina or acute myocardial infarction. However, it remains possible that changes in hemodynamic status could occur in patients on NTG if a change in container type (i.e., from PVC to glass or vice versa) is made during the course of therapy.

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.

Evaluation of bayesian forecasting for individualized gentamicin dosage in infants weighing 1000 g or less.

We evaluated the use of Bayesian forecasting for gentamicin therapy in outborn infants weighing 1000 g or less irrespective of postnatal age. Dosages were individualized using a computer program, guided by early serum gentamicin assays after a loading dose and a database of population kinetics. Steady-state gentamicin levels achieved were compared with those from a regimen based on guidelines. A total of 26 gentamicin courses were individualized in 19 infants of 22 to 33 weeks' gestation, weighing 500 to 1000 g at 1 to 41 days of age. All steady-state trough levels were between 1 and 2.4 mg/L; peak levels were between 4.4 and 9.3 mg/L. The 95% confidence intervals were in almost identical ranges. The prevalence of toxic and suboptimal trough levels was less when compared with that of 23 gentamicin courses based on guidelines in 17 control infants. We conclude that early individualized gentamicin dosage over a range of postnatal age is a practical alternative and serum level distributions appear superior.

Therapeutic monitoring and pharmacokinetic evaluation of procainamide in neonates.

Past experience with the disposition of procainamide hydrochloride (PA) in neonates is restricted to a single case study involving placental transfer. We studied aspects of PA pharmacokinetics in three neonates who received constant-rate infusion therapy. Results indicated that the total serum clearance of PA is similar to the adult value, but elimination half-lives of both PA and N-acetylprocainamide (NAPA) were slightly prolonged and volume of distribution was variable. Pharmacokinetic evaluations in a renally compromised neonate confirmed that total PA clearance and the renal clearance of both PA and NAPA were reduced, although not to the extent expected for the degree of renal impairment. Peritoneal dialysis was used concurrently and may have contributed to the elimination process. We believe that our experience provides important preliminary guidelines for the management of PA therapy in neonates.

Therapeutic monitoring of cyclosporine following pediatric bone marrow transplantation: problems with sampling from silicone central venous lines.

Blood concentrations are commonly used to guide dosing requirements of cyclosporine, due to large variations in pharmacokinetics both between and within individuals. Bone marrow transplant patients at The Hospital for Sick Children are prescribed intravenous cyclosporine as part of the posttransplant immunosuppression protocol. Sampling for blood concentration measurement is generally done via a single-lumen central venous line (CVL). Cyclosporine concentrations sampled by this route were compared with concentrations in peripheral capillary samples taken concurrently. Results from the CVL blood were substantially higher despite appropriate flushing of the CVL between the end of the infusion and the time of sample collection. This discrepancy disappeared once the patient was converted to oral cyclosporine. We conclude that the sampling error is due to drug adsorbed to the silicone CVL catheters during intravenous administration and displaced during blood sample collection.

Caffeine overdose in an adolescent male.

A 16 year old male who ingested an estimated 6-8 grams of caffeine is described. Caffeine is commonly thought to be harmless, but its wide availability has promoted abuse. This patient manifested many of the adverse effects seen in acute caffeine ingestion including hypokalemia, elevated blood glucose, tachycardia, bigeminy and agitation. Respiratory alkalosis and chest pain, which have not been previously reported to our knowledge in caffeine overdose, were also noted in this patient. Three serum caffeine levels were analyzed and an abnormally long elimination half-life of approximately 16 hours was calculated from the results.

Comparison of a Bayesian forecasting technique with a new method for estimating phenytoin dose requirements.

A simple, novel approach to phenytoin dose adjustment recently proposed by Wagner has been compared with an established Bayesian method. A data set comprising a minimum of two steady-state concentration/dose pairs from each of 43 adult epileptic patients was used. Prediction error analysis demonstrated that the two methods were equally precise but that the Wagner method tended to underpredict concentrations. The slope of the semilogarithmic relationship between concentration and dose was found to be 54% higher than originally reported by Wagner. It may therefore be necessary to adjust Wagner's equation for different patient populations before this method is used in routine clinical practice.

Population pharmacokinetics of gentamicin in neonates.

The influence of a number of clinical characteristics on the population pharmacokinetics of gentamicin were examined using routine drug-monitoring data from a group of 113 neonates. The data were analyzed using the programme NONMEM. Clearance was 0.053 litres.h-1.kg-1 and was reduced in neonates with postconceptional age less than or equal to 34 weeks (X 0.83) and 5-min Apgar score less than 7 (X 0.82). Volume of distribution was 0.47 litres.kg-1. These population mean parameter estimates were used to generate dosage regimens to achieve concentrations within the therapeutic range.

Pharmacokinetics of high-dose metoclopramide in cancer patients.

The introduction of new cytotoxic drug regimens has been associated with an increase in the incidence and severity of adverse effects. This in turn has highlighted the need for more effective adjuvant therapy. The use of metoclopramide for the prophylaxis of nausea and vomiting, in high intravenous doses (50 to 1000 mg), has become established since 1981. As a lipid-soluble drug, metoclopramide has a large volume of distribution. The reported mean values after high doses range between 2.8 and 4.6 L/kg. The mean values for total body clearance and terminal half-life range from 0.31 to 0.69 L/kg/h and from 4.5 to 8.8 hours, respectively. The values of these pharmacokinetic parameters are essentially similar to those obtained after conventional doses (less than 50mg). Pharmacokinetic parameters appear unaffected by age, although no high-dose study has been conducted in children. Bodyweight is apparently correlated with clearance. An influence of renal function indices on terminal half-life and clearance has been shown, which is rather surprising since renal clearance accounts for only 20% of the total clearance. No thorough investigations exist which examine the influence of hepatic disease, cancer type and cytotoxic drug regimen on the disposition of metoclopramide. A relationship between dose (or concentration) and therapeutic or adverse effects of metoclopramide is outlined. The therapeutic benefit of high doses (up to 14 mg/kg) may be dependent on age, and on the combination of cytotoxic drugs. The advantages of high doses of metoclopramide are most apparent when the drug is used as protection against the adverse effects of high doses of cisplatin (greater than 60 mg/m2). Despite considerable pharmacokinetic variability, intravenous administration of high doses of metoclopramide is relatively safe due to its large therapeutic index.

Disopyramide in acute myocardial infarction: problems with changing pharmacokinetics.

In the acute phase of myocardial infarction it is recognized that serum disopyramide concentrations may be lower than expected. This has generally been attributed to reduced oral bioavailability. This report describes data obtained routinely from 6 patients with acute myocardial infarction and cardiac dysrhythmias treated initially with intravenous disopyramide. Serum disopyramide concentrations were consistently lower than expected, on average by 2.6 micrograms/ml. This was interpreted as being due to relatively high drug clearance, calculated as 6.7 +/- 1.5 l/h, compared to expected values of 3-4 l/h. Dosage schedules determined on the basis of the acute phase pharmacokinetics subsequently produced higher than predicted concentrations at later times on average by 2.8 micrograms/ml. Clearance at this time was calculated to be 3.1 +/- 0.6 l/h. Thus even with intravenous disopyramide therapy there are problems with changing pharmacokinetic parameters after myocardial infarction.

The pharmacokinetics of high dose metoclopramide in patients with neoplastic disease.

High dose metoclopramide infusions (10 mg/kg) were administered to nineteen patients with bronchial carcinoma who were receiving intravenous cyclophosphamide as single agent chemotherapy. Considerable interindividual variability in metoclopramide disposition was observed. Mean clearance was 0.33 +/- 0.13 (s.d.) l h-1 kg-1, mean volume of distribution at steady state was 3.8 +/- 1.2 (s.d.) l/kg and mean elimination half-life was 8.3 +/- 4.4 (s.d.) h. These results were significantly different from mean values previously reported for young healthy volunteers given conventional doses (0.70 l h-1 kg-1, 2.2 l/kg and 2.6 h respectively). Significant correlations were found between serum urea, serum creatinine and metoclopramide clearance. The metoclopramide regimens were well tolerated and, with the exception of two patients, were completely effective in the prevention of nausea and vomiting. To achieve and maintain target serum metoclopramide concentrations of 1 microgram/ml, we now administer a loading infusion of 3.61 mg/kg over 30 min followed by a maintenance infusion of 0.36 mg kg-1 h-1 for 10 h. Cyclophosphamide is normally administered concurrently with the second infusion. For patients with evidence of mild renal impairment, the maintenance infusion rate of metoclopramide hydrochloride should be adjusted according to the predicted individual clearance value; CL (l h-1 kg-1) = 0.57 - [0.036 X urea (mmol/l)].

Estimation of gentamicin clearance and volume of distribution in neonates and young children.

Gentamicin therapy should be guided by serum level monitoring in all age groups, dosage adjustments depending on age related changes in pharmacokinetics. Population data analysed from two centres (43 infants from Glasgow and 100 infants and children from Manchester) by the computer program NONMEM showed that volume of distribution was related to body weight by a proportionality factor that decreased from the region of 0.41-0.46 l/kg in children less than 3 months to 0.25-0.32 l/kg in older children, a value which merges with that accepted for adults (0.25 l/kg). In both young and older children, clearance was also found to be dependent on body weight. Renal function (creatinine concentrations) provided no further explanatory power. When these results were used prospectively to forecast gentamicin concentrations with a Bayesian kinetic parameter estimation program, trough concentrations were more precisely predicted than peaks when a single concentration measurement was used. In clinical practice, however, two concentration measurements are usually routinely available and these should lead to greater precision of both peak and trough predictions. These results have been incorporated into a simple nomogram which can be used to determine a dose of gentamicin which will achieve target peak concentrations in infants, assuming that troughs should not exceed 2 micrograms/ml.

Evaluation of a high pressure liquid chromatographic technique for metoclopramide analysis.

High-dose metoclopramide has found an established place in the prophylaxis of nausea and vomiting which may be induced by cancer chemotherapy. A simple reliable high pressure liquid chromatographic technique for the measurement of this drug in serum has been developed and evaluated. The methodology will find application in the study of metoclopramide pharmacokinetics and in the monitoring of high-dose metoclopramide therapy in individual patients with neoplastic disease.

Clinical pharmacokinetics: a comprehensive system for therapeutic drug monitoring and prescribing.

Clinical pharmacokinetics is an expanding scientific discipline which can make an impact on treatment in coronary care, intensive care, paediatrics, general medicine and surgery, and general practice. The aim of this study was to establish a rapid system of drug assay, to report the result, to assess the influence of pathological and clinical factors on the pharmacokinetics of certain drugs, and to use a computer to determine the optimum dosage of drugs. The clinical pharmacokinetics laboratory in Stobhill is available to all clinical departments and to general practitioners in the area. Digoxin, theophylline, and phenytoin have been assessed. Initial samples of these drugs showed that only about a third were in the therapeutic range; samples obtained after the issue of the laboratory report showed an improvement. The predictive performance of the computer program improved with feedback of one or two drug concentrations. Dosages of drugs chosen on an empirical basis may not lead to optimum treatment, and by testing samples early the dosage of the drug can be adjusted. It is hoped that the results achieved will encourage other clinical, pharmaceutical, and scientific colleagues to develop laboratories along similar lines.