Determination of mean valproic acid serum level by assay of a single pooled sample.

Determinations of single serum drug concentrations are useful in monitoring drug therapy. A mean serum level would supply more information but is expensive and laborious because of the multiple blood samples and assays, calculation of area under the curve (AUC) by the trapezoidal rule, and division of the AUC by the time interval during which the samples were drawn. A method was devised that pools aliquots from individual serum samples taken during the testing period to form on composite sample. A single assay of this sample provides the mean serum level of the testing period. The method was successfully tested with amaranth and then applied to valproic acid serum levels. AUC and mean serum levels were determined by the standard procedure of assays of multiple samples and the trapezoidal rule. Mean serum level was also determined by the pooled sample technique. The correlation coefficient for the comparison of the mean serum levels determined by the two techniques is 0.907 (p less than 0.001). There was no difference between the estimates of the mean serum levels by Student's paired t test (t = 0.693, p greater than 0.2). The good correlation and lack of difference between the conventional method and the pooled sample method indicates that the method is valid.

The absolute bioavailability and pharmacokinetics of butorphanol nasal spray in patients with hepatic impairment.

OBJECTIVE: The objective of the study was to investigate the effects of hepatic impairment on the absolute transnasal bioavailability and pharmacokinetics of butorphanol. STUDY DESIGN: Twelve (eight men and four women) healthy subjects and 12 (eight men and four women) patients with hepatic impairment received a 1 mg dose of butorphanol by intravenous or transnasal administration on two separate occasions. Hepatic function was assessed by antipyrine and indocyanine green clearance tests. Serial blood and urine samples were collected after each dose. Plasma samples were analyzed for butorphanol, and urine samples were analyzed for butorphanol and its metabolites. RESULTS: No statistical difference in maximum plasma concentration (Cmax) for butorphanol was observed between the two groups of volunteers after transnasal administration. However, total plasma clearance (CL), steady-state volume of distribution, area under the concentration-time curve [AUC(0-infinity)], and elimination half-life of butorphanol in patients with hepatic impairment were significantly altered (approximately twofold to threefold). The absolute transnasal bioavailability of butorphanol was significantly higher (approximately 20%) in patients with hepatic impairment. A greater fraction of the administered dose was recovered from the urine in hepatically impaired patients compared to that in healthy subjects (23% to 31% versus 10% to 11%). There was a significant reduction in CL of indocyanine green and antipyrine in hepatically impaired patients. The percentage of reduction in butorphanol CL was highly correlated to the estimated degree of portosystemic shunts in the patients with hepatic impairment. CONCLUSION: Based on the comparable Cmax but the increased AUC in patients with liver dysfunction, the initial dose of butorphanol nasal spray may not need to be adjusted. However, the subsequent dosing intervals for butorphanol should be prolonged.

Safety and tolerance of multiple doses of intramuscular fosphenytoin substituted for oral phenytoin in epilepsy or neurosurgery.

BACKGROUND: Safety, tolerability, and pharmacokinetics of fosphenytoin sodium, a water-soluble phenytoin prodrug, were investigated after a temporary substitution of intramuscular fosphenytoin for oral phenytoin sodium in 240 epileptic or neurosurgical patients taking oral phenytoin sodium (100-500 mg/d). METHODS: Patients were randomly assigned to 1 of 2 parallel groups. During screening and follow-up, patients were maintained on a regimen of oral phenytoin at an individualized dose. During treatment, the phenytoin-treated patients received intramuscular placebo and their prescribed dose of oral phenytoin; the fosphenytoin-treated patients received oral placebo and intramuscular fosphenytoin equimolar to their phenytoin dose. RESULTS: Both groups had similar types and frequencies of mild to moderate adverse events. Fosphenytoin was as well tolerated as intramuscular placebo at the injection site. Intramuscular fosphenytoin equimolar to a patient's oral phenytoin dose produced equal or greater plasma phenytoin concentrations. CONCLUSIONS: Dosing adjustments are not required when intramuscular fosphenytoin is temporarily substituted or oral phenytoin therapy is resumed. Intramuscular fosphenytoin is a safe and well-tolerated alternative to oral phenytoin when oral administration is not feasible.

The effects of storage and shaking on the settling properties of phenytoin suspension.

Phenytoin suspension (PHY-S) is reported to settle, resulting in uneven drug distribution and variable patient dosing. We designed this study to determine the rate of settling and the amount of agitation needed to resuspend the preparation. To determine the rate of settling, we thoroughly shook three bottles of PHY-S and then left them undisturbed. We took samples from the top and bottom of each bottle with a microsyringe at 15 minutes, 1, 6, 12, 24, 48, and 72 hours, and 1, 2, 3, 4, and 5 weeks. We simulated patient administration with daily doses that were measured under good, fair, and poor shaking techniques. We analyzed samples after every tenth dose. After complete resuspension the active ingredient in PHY-S settles at a very slow rate. We found no differences in concentration between the top and bottom until the fifth week in the bottles thoroughly shaken and left undisturbed. Minimal agitation is required to resuspend PHY-S. The well-shaken and poorly shaken bottles in the patient simulation phase exhibited no differences in concentrations whereas the unshaken bottle had differences throughout the study period. Problems thought to be associated with PHY-S may be related to compliance and inaccurate measuring devices.

Six-month evaluation of Carbatrol (extended-release carbamazepine) in complex partial seizures.

We evaluated the use of a new, controlled-release capsule form of carbamazepine, Carbatrol capsules, in an open-label, multicenter study of 124 patients with complex partial seizures. Ninety-one percent of the patients successfully completed the 6-month trial with good seizure control, with a significant improvement in quality of life. We conclude that switching patients with complex partial seizures from multiple daily-dose carbamazepine to twice-daily Carbatrol on a milligram-to-milligram basis is relatively safe.

Pharmacokinetic effects of fluvastatin in patients chronically receiving digoxin.

A double-blind, randomized, crossover study assessed the effects of a single 40-mg dose of fluvastatin on the steady-state pharmacokinetics of digoxin in chronically treated patients. After demonstrating consistent digoxin serum concentrations as part of the inclusion criteria, 18 patients received a single dose of either fluvastatin or placebo, with a 1-week washout period between crossover to the other treatment. For each patient, 14 serum samples were drawn and urine collected over 24 hours; all samples were assayed for digoxin using a fluorescence polarization immunoassay. The following pharmacokinetic parameters were determined using noncompartmental techniques: area under the curve for 24 hours (AUC24); time to maximum concentration after digoxin (tmax); maximum concentration after digoxin dosing (Cmax); concentration at 24 hours after fluvastatin or placebo (Cmin); total amount excreted in the urine over 24 hours (U24); and urinary clearance (Clren). The pharmacokinetic data were analyzed for sequence, patient nested with sequence, and period and treatment differences using ANOVA, Schuirmann's two one-sided testing approach, confidence intervals, and power analysis. The AUC24, Cmax, and tmax for digoxin were considered bioequivalent with the two treatments. The differences in Cmax, U24, and Clren were statistically significant but were not considered to be clinically relevant due to the low magnitude of the difference (< 20%). There were no clinically significant adverse reactions attributable to either digoxin or fluvastatin.

A review of current clinical findings with fluvastatin.

Fluvastatin, the newest member of the class of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, is structurally different from the fungal metabolites (lovastatin, pravastatin, and simvastatin) and is wholly synthetic. Fluvastatin has a distinct biopharmaceutical profile, including a short systemic exposure time (half-life of 1.2 hours) and virtually no active circulating metabolites. Fluvastatin is targeted to the liver, where it is rapidly metabolized; 98% of fluvastatin is protein bound. Double-blind, placebo-controlled studies have demonstrated that fluvastatin at daily dosages of 20-40 mg produces significant decreases from baseline in low-density lipoprotein (LDL) cholesterol on the order of 22-31% in patients with severe primary hypercholesterolemia (mean baseline LDL cholesterol 227 mg/dL) and decreases of 19-25% in patients with familial hypercholesterolemia (mean baseline LDL cholesterol 270 mg/dL). Interim results of a titrate-to-goal, 20-week study in patients with moderate hypercholesterolemia (LDL cholesterol >= 160 mg/dL and triglycerides <= 350 mg/dL) demonstrate that fluvastatin, 20 mg/day, lowers LDL cholesterol by 21% within 6 weeks. Long-term results indicate that the lipid-lowering effects of fluvastatin are sustained for 96 weeks. Further, 1 study has shown that the combination of low-dose fluvastatin plus niacin decreased LDL cholesterol levels 40% without untoward adverse events, suggesting that this combination is effective and safe for patients needing intensive lipid-lowering therapy. Asymptomatic, reversible increases in hepatic transaminase levels occur in fluvastatin-treated patients at a frequency comparable to that reported for other HMG-CoA reductase inhibitors. The 20-30% reduction in LDL cholesterol required by the majority of patients with hypercholesterolemia can be achieved with fluvastatin at 20 or 40 mg/day as well as with the other available HMG-CoA reductase inhibitors at their most commonly prescribed doses. Fluvastatin, priced 40% lower than other statins, provides the most cost-effective means of safely achieving goal LDL cholesterol levels in these patients.

Monitoring digoxin therapy in two long-term facilities.

Digoxin monitoring was examined according to 13 criteria in two nursing homes: 1) an intermediate care facility (ICF) with private physicians, and 2) a skilled care (SCF) plus ICF with 3 housestaff physicians from a identify all patients receiving digoxin, 2) evaluate dosage patterns, 3) evaluate monitoring patterns, and 4) detect possible toxic reactions and determine whether management was appropriate. The calculated correct dosage of digoxin in both ICFs. More frequent monitoring of serum creatinine and potassium levels was associated with fewer symptoms of toxicity. Possible toxicity occurred in 46 percent of the SCF and in 68 and 71 percent of patients in the ICFs. Documented toxicity occurred in 18 percent of the SCF patients and in 16 and 10 percent of the ICF patients. Eighty percent of patients who had symptoms of digoxin toxicity were not examined or managed appropriately in the SCF, and 43 and 33 percent in the ICFs. Often standing orders had been assigned for drugs to treat nausea, vomiting or diarrhea. A number of possible drug interactions with digoxin were discovered. The participation of the pharmacist in nursing home care is discussed.

Cardiovascular effects of H2-receptor antagonists.

The type II histamine receptor antagonists, cimetidine and ranitidine, widely used in treatment of peptic ulcer disease have been reported to cause bradycardia. To evaluate the cardiovascular effects of H2 antagonists nineteen healthy volunteers were entered into a double-blind crossover comparison of cimetidine 300 mg qid, ranitidine 150 mg bid, and placebo. Subjects ingested study medicine for 7 days prior to being tested by the Bruce Exercise Test. Heart rate, blood pressure, oxygen consumption, expiratory volume, and fractional expiration of CO2 and O2 were measured at rest, exercise and recovery. A plasma sample for determination of cimetidine and ranitidine levels were obtained prior to the exercise period. Multivariate analysis and paired t test revealed no significant differences for the cardiovascular or pulmonary variables. However, in 5 subjects, the heart rate at 25% maximum VO2 was depressed 8% (P less than or equal to 0.03). This effect in a small percentage of the population suggests that further studies are needed to determine if subpopulations are affected.

The effect of everyday exercise on steady state digoxin concentrations.

The purpose of this study was to evaluate the effect of 1 hour of everyday exercise (walking at patient's own pace) on serum digoxin concentrations. Nine white male subjects (ages 58-74) who had been taking the same digoxin dose for greater than 1 month participated. There were three continuous phases: 1 hour of rest, 1 hour of exercise, and a final hour of rest. Serum digoxin concentrations were drawn every 20 minutes. During the first rest period, serum digoxin concentrations rose 30% from the first concentration drawn in the study. After 1 hour of exercise, serum digoxin concentrations fell 26.8% from the last concentration of the first rest period. At the end of the second hour of rest, serum digoxin concentrations increased by 36.6% from the last concentration. Repeated measures analysis of variance demonstrated a significant (P less than .01) change in serum digoxin concentrations. Significant (P less than .01) differences were found between sampling times 0 and 60, 60 and 80, 60 and 100, 60 and 120 and 180 minutes using a paired t-test with Bonferroni correction. A weak correlation (r = 0.74, r2 = 0.55) between percent change in concentrations and age during the exercise phase was found, but there was no correlation between the percent change in concentrations and age during the two immobilization phases. Because significant changes in concentrations occurred during each phase of the study, we conclude that the influence of everyday exercise should be taken into account when interpreting serum digoxin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of effect of tacrine administration on the anticoagulant activity of warfarin.

The effect of tacrine administration on prothrombin time was studied in 13 patients receiving prolonged warfarin therapy. After a 3-week baseline period and 5 days of placebo administration, patients received 20 mg tacrine four times daily for 5 days. Prothrombin times were determined during baseline, daily before the morning doses of placebo and tacrine, and 14 days after the last tacrine dose (closeout). Mean (+/- SD) prothrombin times were 16.2 +/- 2.8 seconds at baseline, 15.1 +/- 2.6 seconds during the placebo phase, 15.8 +/- 3.6 seconds during the tacrine phase, and 15.3 +/- 3.6 seconds at closeout, indicating that tacrine has no effect on the anticoagulant activity of warfarin. Alteration of warfarin dosage should not be required in patients receiving concurrent tacrine therapy.

Ranitidine accumulation in patients undergoing chronic hemodialysis.

Ranitidine accumulation was assessed in 20 patients undergoing chronic hemodialysis following oral daily doses of 150 mg ranitidine for 10 days. Serum ranitidine concentrations prior to dialysis were 191 +/- 115 mcg/l and 207 +/- 172 mcg/l for patients dialyzed three and two times per week, respectively. The amount of ranitidine recovered in the dialysate during the final dialysis session of the study was negligible and ranged from 308-3036 mcg, representing less than 3% of the administered dose. Clearance by hemodialysis was 3.0 +/- 1.1 l/hr. Once daily dosing of 150 mg ranitidine does not result in excessive accumulation, and drug loss during hemodialysis is small. These data suggest that supplemental dosing after hemodialysis is not indicated.

Clinical implications of drug interactions with coxibs.

Nonsteroidal antiinflammatory drugs (NSAIDs) often are prescribed to patients who are taking concomitant drugs. Cyclooxygenase (COX)-2 inhibitors (coxibs) rofecoxib and celecoxib are highly selective inhibitors of COX-2, differentiating them from nonselective NSAIDs, which substantially inhibit both COX-1 and COX-2. Like nonselective NSAIDs, coxibs are hepatically metabolized: rofecoxib primarily by reduction by cytosolic enzymes and celecoxib by the cytochrome P450 (CYP) enzyme system. Because rofecoxib is not significantly metabolized by CYP, it has fewer confirmed or potential drug interactions than celecoxib. However, potent inducers of CYP, such as rifampin, may decrease rofecoxib concentrations because of induction of general hepatic metabolic activity. Celecoxib is metabolized by CYP2C9 and may be increased or decreased by CYP2C9 modifiers. It also inhibits CYP2D6 and may affect concentrations of CYP2D6 substrates. Similar to NSAIDs, many pharmacodynamic interactions involving coxibs are related to inhibition of production of renal prostaglandins. However, coxibs have no antiplatelet activity and may be preferred to NSAIDs in patients receiving antithrombotic therapy. Nonetheless, when a potential for an interaction exists, standard monitoring is recommended when starting or discontinuing a coxib. Due to lack of data to support these interactions, which are primarily theoretical, additional studies are necessary to establish the drug interaction profiles of coxibs.

Antiepileptic drug treatment: outcomes and adherence.

The goal in treating patients with epilepsy is a cost-effective approach to the elimination of seizures or a reduction in their number and frequency while avoiding drug interactions and side effects, so as to achieve the best possible quality of life. Among the desirable outcomes are an enhanced understanding of epilepsy by patients, caregivers, and society, and a lessening of the psychosocial risks of this disease. Patients fail to achieve their goals and outcomes when they fail to adhere to the drug regimen or when a less-than-adequate drug regimen is prescribed. To help improve adherence, once- or twice-daily formulations should be used. New antiepileptic drugs (AEDs) increase the possibility of effective treatment for a patient who initially fails therapy. Working together, patients and clinicians can maximize the effectiveness of AED therapy and the potential for achieving desired goals and outcomes.

Identification, diagnosis, and treatment of acid-related diseases in the elderly: implications for long-term care.

Acid-related disorders such as peptic ulcer disease and gastroesophageal reflux disease occur frequently in the elderly and are associated with a high frequency of morbidity and mortality. The proton pump inhibitors lansoprazole and omeprazole produce faster rates of healing and greater symptomatic relief in patients with acid-related disorders than histamine2-receptor antagonists, are well tolerated, and are associated with few adverse events. Compared with omeprazole, which interacts with diazepam, warfarin, and phenytoin, lansoprazole produces only a minor increase in theophylline clearance. Proton pump inhibitors in combination with antibiotic therapy can eradicate Helicobacter pylori, the main risk factor in the recurrence of peptic ulcer disease, obviating the need for maintenance therapy. Long-term acid suppression with proton pump inhibitors may be necessary to prevent the recurrence of gastroesophageal reflux disease. The safety and efficacy profile of these agents makes them ideal for the treatment of acid-related diseases in elderly patients.

The effect of age and everyday exercise on steady-state plasma digoxin concentrations.

Age-related physiologic changes may significantly alter the disposition and pharmacologic characteristics of many drugs. The elderly are the most frequent users of digoxin because of increased prevalence of atrial fibrillation and congestive heart failure. This study was conducted to confirm the decrease in digoxin concentrations during exercise, to determine if age is a factor in this decrease, and to explore the difference between chronologic age and physiologic age. Eighteen men age 50-85 years were treated with digoxin for more than 1 month before enrolling and had serum digoxin concentrations of 0.4-2.0 micrograms/L. They were evaluated during a 3-hour period in the morning (A.M. dose withheld). Blood samples were obtained every 10 minutes during sequential 60-minute periods of rest (phase I), walking (phase II), and rest (phase III). There were no significant differences in mean concentration between phases II and I (p < 0.76), phases III and phase I (p < 0.70), or phases II and III (p < 0.37). The effect of age was positively correlated with the mean concentration of phase II but was not statistically significant (p < 0.62). Statistically significant correlations were seen only between the exercise phase and serum albumin and Mini-Mental Status Examination scores. We conclude that exercise has minimal, if any, clinically relevant effects on plasma digoxin concentrations. Increasing chronologic age has no influence on a decrease in the concentrations with exercise; a younger physiologic age may play a role.

Intramuscular fosphenytoin (Cerebyx) in patients requiring a loading dose of phenytoin.

Fosphenytoin (Cerebyx), is a water soluble prodrug that is rapidly and completely converted to phenytoin. This study reports the injection-site tolerance and safety of intramuscular fosphenytoin (> 10 mg/kg doses) in 60 patients requiring a phenytoin loading dose. Patients received injections at single or multiple sites with volumes ranging from 4 to 30 ml per injection site. The majority of patients had no irritation (erythema, swelling, tenderness, bruising) or complaints of discomfort related to fosphenytoin injection either after injection (95%) or at follow-up (88%). Irritation, when reported, was mild in all cases. Forty of 60 patients (67%) reported transient side effects, primarily involving the central nervous system, such as nystagmus, dizziness or ataxia, which are commonly associated with phenytoin therapy. All patients received prescribed doses; no patient had an injection(s) stopped due to intolerance or side effects. No serious adverse events occurred with intramuscular fosphenytoin. In this study, intramuscular fosphenytoin was demonstrated to be a safe and well tolerated, and in many instances, a preferable alternative to other means of phenytoin loading.

Pharmacokinetics and safety of lamotrigine (Lamictal) in patients with epilepsy.

In a double-blind parallel study, patients with epilepsy on stable regimen of antiepileptic drugs (AEDs) were given lamotrigine (8 pts) or placebo (3 pts). Patients were sequentially dosed with 100, 200 and 300 mg/day given as a b.i.d. regimen. After steady state was achieved, timed plasma lamotrigine levels were obtained post dose. No medical, psychogenic, neurologic, or hematologic changes were observed and no subjective effects were detected as a result of treatment with lamotrigine. No changes in heart rhythm or blood pressure were observed related to lamotrigine. Pharmacokinetic parameters were calculated using 1-compartment and non-compartment models. The results were similar using both models. Area under the plasma concentration vs. time curves increased linearly with dose. Mean half life (13.5 h), volume of distribution (1.36 l/kg) and clearance (1.27 ml/min/kg) were similar to previously reported results and did not change with increasing dose. These findings indicate that lamotrigine pharmacokinetics can be described by the 1-compartment model, has linear kinetics, and does not induce its own metabolism in patients on concomitant AEDs.

Lamotrigine: pharmacokinetics.

The pharmacokinetics of lamotrigine have been studied in single and multiple dose studies in animals, normal volunteers, and patients with epilepsy. Lamotrigine exhibits first-order linear pharmacokinetics. Lamotrigine is well absorbed with bioavailability approaching 100%. The absorption is unaffected by food and there is no first-pass metabolism. The volume of distribution is between 1.25 and 1.47 L/kg and protein binding is about 55%. The half-life of lamotrigine is between 24.1 and 35 hours in drug naive adults but may be altered by enzyme inducing and inhibiting drugs. Clinical trials demonstrated no evidence of autoinduction or saturable metabolism. Younger children (0.17 to 5 years) eliminate lamotrigine faster than older children (5 to 10 years). Children may be more prone to enzyme induction than adults.

Considerations for long-term use of proton-pump inhibitors.

The safety of proton-pump inhibitors (PPIs) for long-term use is reviewed. PPIs are being used with increasing frequency to inhibit secretion of gastric acid in order to treat acid-related disorders such as gastroesophageal reflux disease and peptic ulcer disease. Some patients may require long-term acid suppressive treatment to control the symptoms of their disease, which raises questions about the long-term safety of PPIs. A thorough literature search was conducted, and the clinical consequences of sustained hypergastrinemia induced by all antisecretory therapy, the consequences of atrophic gastritis in patients infected with Helicobacter pylori, the effects of hypochlorhydria on bacterial overgrowth and nutrient absorption, and possible interactions of PPIs with other drugs were identified as areas of concern with long-term use of PPIs. Short- and long-term studies showed that PPIs have a wide safety margin and a favorable adverse-event profile with few drug interactions. Available data support the short- and long-term safety of PPIs.