Annals of Pharmacotherapy

To assess the effects of recombinant human DNase (rhDNase) therapy on the cost of treating respiratory tract infections (RTIs) in patients with cystic fibrosis.

We prospectively documented the use of healthcare services among 968 patients with cystic fibrosis who participated in a recent Phase III double-blind, multicenter, clinical trial in which patients were assigned randomly to receive either rhDNase 2.5 mg once daily, rhDNase 2.5 mg twice daily, or placebo. All patients were followed for 24 weeks. Data from secondary sources were used to estimate a total cost of RTI-related care (excluding the cost of study therapy) for each trial participant, based on observed levels of resource use.

Number of RTI-related hospital admissions, days of RTI-related outpatient antibiotic therapy (intravenous and oral), and total costs of RTI-related care (excluding the cost of study therapy).

Patients randomized to receive rhDNase once daily averaged 0.15 fewer RTI-related hospital admissions (0.41 vs 0.56 for placebo; p < 0.05) and 1.5 fewer days of RTI-related outpatient intravenous antibiotic therapy (2.9 vs 4.4; p < 0.05). Patients randomized to receive rhDNase twice daily had 0.14 fewer hospital admissions (p < 0.01), but no reduction in outpatient intravenous antibiotic therapy. Compared with placebo, the cost of treating RTIs over 24 weeks was $814–1682 less among patients receiving rhDNase.

rhDNase therapy reduced the costs of treating RTIs in patients with cystic fibrosis; assuming once-daily dosing, these savings would offset about one-third of the cost of such therapy.

To compare the administration pharmacokinetics of a 30-minute intravenous piggyback (ivpb) infusion of tobramycin with those of controlled-release infusion system (CRIS) using a 20-mL vial at rates of 60 and 120 mL/h.

Randomized, controlled, crossover, prospective, open-label trial.

Medical college-affiliated hospital.

Eight healthy volunteer men between the ages of 22 and 24 years weighing between 60 and 90 kg.

Volunteers received, in random order, tobramycin sulfate 2 mg/kg iv on 3 occasions separated by 1 week. The drug was administered using a 50-mL ivpb infusion at 100 mL/h for 30 minutes, and with the CRIS using a 20-mL vial with flow rates of 60 mL/h for 1 hour (slow) and 120 mL/h for 1 hour (fast).

Primary endpoints were area under the time–concentration curve (AUC), time to reach maximum concentration (t_max), and maximum concentration (C_max). Secondary endpoints were elimination rate constant (k_e), clearance (Cl), and half-life (t_1/2).

Six volunteers successfully completed the trial. The t_max values observed following fast CRIS and ivpb were 28 ± 8 and 32 ± 4 minutes, respectively, and not significantly different from each other. Both occurred significantly earlier than the t_max associated with slow CRIS (44 ± 7 min). The C_max values observed following ivpb (11.2 ± 1.5 mg/L) and slow CRIS (10.9 ± 0.9 mg/L) administration were not significantly different from each other, but both were significantly lower than that of fast CRIS (13.4 ± 1.5 mg/L). The AUCs of slow and fast CRIS were 29.8 ± 4.8 and 31.2 ± 3.8 mg/L•h, respectively, and were not significantly different from each other. The AUC of fast CRIS was significantly greater than that observed with ivpb (27.4 ± 4.3 mg/L•h). No significant difference in k_e (fast CRIS 0.32 ± 0.03 h^-1; slow CRIS 0.33 ± 0.04 h^-1; ivpb 0.34 ± 0.0 h^-1) was observed among any of the methods.

CRIS administration of tobramycin resulted in higher AUCs than did ivpb administration. Compared with ivpb, fast CRIS resulted in a higher C_max, but the t_max values of fast CRIS and ivpb administration were not statistically different. Compared with ivpb, slow CRIS resulted in a more delayed t_max, but the C_max values of slow CRIS and ivpb were not statistically different.

To compare the predictive performance of 2 equations that estimate unbound (free) phenytoin plasma concentrations when valproic acid (VPA) and phenytoin are administered concurrently.

Eighty-eight adults receiving VPA and phenytoin concurrently were included in the study. Steady-state plasma concentration measurements of total phenytoin, total VPA, and unbound phenytoin were collected prospectively in the inpatient group (group 1) and retrospectively in the outpatient group (group 2). Using the equations developed by Haidukewych and May, unbound phenytoin concentrations were calculated. The mean predicted unbound phenytoin concentrations then were compared with mean actual unbound phenytoin concentrations measured in the laboratory. Identical assays were performed to measure unbound phenytoin, total phenytoin, and VPA from each patient group.

Antiepileptic drug concentration measurements were collected from 43 inpatients (mean age 34.8 y) from the epilepsy unit at Abbott Northwestern Hospital and 45 outpatients (mean age 37.3 y) at the MINCEP Epilepsy Care clinic, Minneapolis, MN.

Mean prediction error (MPE) and mean squared error (MSE) were calculated to determine which equation was the least biased and most precise in predicting unbound phenytoin when total VPA and phenytoin concentrations are known. Linear regression of predicted unbound phenytoin on measured unbound phenytoin values determined the correlation coefficients (r). A paired Student's t-test also was performed comparing mean predicted unbound phenytoin concentration with mean actual unbound phenytoin concentrations in both groups.

The MPE from May's equation was -0.49 and -0.45 for groups 1 and 2, respectively; using the Haidukewych equation, MPE was -0.02 and 0.08 for groups 1 and 2, respectively. The MSE using May's equation was 0.34 for both groups. Using the Haidukewych equation, group 1 MSE was 0.07, and for group 2, 0.12. Correlation coefficients were more than 0.91 (p < 0.001) from each equation in both patient groups. In group 1, mean actual unbound phenytoin concentration was 2.02 μg/mL; May's equation predicted 1.52 μg/mL (p < 0.001) and the Haidukewych equation predicted 2.00 μg/mL (p = 0.64). In group 2, mean actual unbound phenytoin concentration was 2.10 μg/mL; May's equation predicted 1.65 μg/mL (p < 0.001) and the Haidukewych equation predicted 2.18 μg/mL(p = 0.11).

Haidukewych's equation predicts unbound phenytoin concentrations with the least bias and most precision with statistical significance. May's equation consistently underpredicted unbound phenytoin concentrations. Because unbound phenytoin fraction is not constant (and usually more than the expected 10%) in patients comedicated with VPA, unbound phenytoin concentrations cannot be predicted even though total VPA and phenytoin concentrations are known. If unbound phenytoin concentrations cannot be readily measured, Haidukewych's equation is a reliable predictor of unbound phenytoin concentrations.

To characterize and evaluate hematopoietic colony-stimulating factor (CSF) use, including cost implications, in US academic health centers.

An observational study of patients who received granulocyte colony-stimulating factor (G-CSF) or granulocytemacrophage colony-stimulating factor (GM-CSF) from September 1 to October 15, 1993.

Thirty academic health centers in the US.

Five hundred sixty-five patients were evaluated.

The appropriateness of CSF use was assessed, based on consensus-derived indication guidelines and the Food and Drug Administration-approved product labeling. Indication, type of CSF, and dosage were considered in determining the appropriateness of CSF therapy.

Based on indication evaluation criteria, 71% of CSF use was appropriate, 7% was inappropriate, and 22% was unproven, although the majority of unproven use was deemed promising by the expert panel. Based on dosage evaluation criteria, 51% of CSF use was appropriate, 27% was inappropriate, and 22% was for promising and other unproven indications. More than 90% of the patients studied received G-CSF. Approximately 3.4% of patients who received G-CSF had an adverse event, compared with 22% of those who received GM-CSF. Approximately $791 000 was spent on CSF therapy in the 565 patients: $401 000 (51%) on appropriate indications and doses, $160 000 (20%) on inappropriate doses for appropriate indications, $124 000 (16%) on promising indications, and $106 000 (13%) on unproven or inappropriate indications.

Substantial costs are incurred currently for CSF therapy without adequate literature support. Further studies are warranted to justify promising but unproven uses of CSFs, as well as to clarify proper dosing, monitoring, and relative safety of CSFs.

To report the loss of therapeutic control in 2 hypothyroid patients and remind clinical pharmacists and other healthcare professionals to remain cognizant of possible product quality differences within or bioequivalency differences between levothyroxine products.

Two patients with stable hypothyroidism experienced symptoms of hypothyroidism with increased serum thyroid-stimulating hormone (TSH) concentrations after switching from 1 levothyroxine product to another. One tablet from 1 of the patient's levothyroxine prescriptions was assayed, and its levothyroxine content was 74.5% of the label claim, a value outside of the United States Pharmacopeia requirements of 90–110%.

Two patients with hypothyroidism had remained euthyroid and stable while receiving 1 levothyroxine product, but became symptomatic with dramatically increased serum TSH concentrations while receiving what were thought to be comparable dosages of another levothyroxine product. Therapeutic control was reestablished in both patients after therapy with the original levothyroxine product was reinstated.

Clinical pharmacists and other healthcare professionals should remain cognizant of possible product quality differences within or bioequivalency differences between levothyroxine products. These differences necessitate close monitoring of hypothyroid patients, counseling these patients about the clinical signs of sub- and supratherapeutic levothyroxine dosages, and prudence when switching patients with stable hypothyroidism to alternative levothyroxine products. If there are inconsistencies between levothyroxine products, resultant deleterious effects on the therapeutic stability of patients with hypothyroidism may undermine cost savings that might be incurred by such a change. If these patients are switched to alternative levothyroxine products, it is recommended that thyroid function tests be repeated after equilibration to the new product.

Clarithromycin is a macrolide antibiotic very similar to erythromycin in structure and spectrum of activity. It has gained increasing use since its release in Canada in May 1992, partly because it is promoted as having less potential for drug interactions and adverse effects. However, as with all new medications, a high degree of vigilance for unreported adverse effects is advisable.

A healthy 53-year-old lawyer was receiving long-term fluoxetine 80 mg hs and nitrazepam 10 mg hs for depression and mild sleep apnea. Subsequent to initiation of treatment with clarithromycin for a respiratory infection, he rapidly developed delirium, which cleared quickly after stopping all 3 medications. The delirium and psychosis did not recur when the infection was treated with erythromycin alone or after restarting fluoxetine and nitrazepam therapy at previous dosages in the absence of antibiotics.

This man's delirium is consistent with fluoxetine intoxication, which appears to have resulted from inhibition of hepatic cytochrome P450 metabolism by clarithromycin. Undiagnosed, this serious drug reaction could have lead to serious medical and social consequences.

As the use of clarithromycin increases, the potential for interactions with other drugs metabolized by the P450 enzyme system may be realized. Clinicians should consider which other medications a patient is receiving before prescribing clarithromycin or any macrolide antibiotic with potential to influence the P450 system.

To report 2 cases in which oral propantheline reduced the discomfort associated with sweating related to spinal cord injury (SCI), and to review the literature on the management of SCI-related sweating.

Case 1: A 27-year-old quadriplegic man with an American Spinal Injury Association (ASIA) Frankel class C injury to C5/C6 experienced profuse sweating and requested propantheline. He stated that he had received the medication previously and reported that propantheline 15 mg tid had controlled his sweating. Propantheline bromide was reinstituted, and within 24 hours, the patient's episodes of profuse sweating had decreased markedly in number and frequency. Case 2: A 35-year-old quadriplegic woman had an ASIA class D lesion at C3. Since her injury, she had experienced profuse sweating that worsened when she became cold and at night. She stated that her sweating was under control as long as she took propantheline. Propantheline therapy was continued and no further sweating episodes have occurred.

A MEDLINE search was used to identify pertinent literature including reviews. Standard texts and texts referenced in the pertinent literature also were examined.

All available sources of information were reviewed.

The earliest case reports of systemic therapy for hyperhidrosis described the use of the anticholinergic methantheline bromide. Methantheline in combination with ergoloid mesylates also was suggested for the treatment of congenital hyperhidrosis. Local topical therapy for hyperhidrosis, such as aluminum chlorohydrate and aluminum chloride, the active ingredients in some antiperspirants, have been tried with some success. Talc, starch, and other powders have been suggested to absorb excessive sweat. Formalin and glutaraldehyde also have been used. Topical propantheline bromide has been used successfully in treating palmar and plantar hidrosis. Clonazepam has been used successfully in a case of unilateral localized hyperhidrosis. Systemic phenoxybenzamine has been used with some success and there have been attempts at other systemic therapy using mecamylamine, atropine, propoxyphenel, and methenamine. Scopolamine patches also have been used successfully in a small number of patients. Other agents that have been used include dibenamine, piperoxan, and phentolamine. Systemic propantheline also has been listed as an agent with potential efficacy in treating the profuse sweating associated with SCI, but was not recommended primarily because of adverse effects and difficulty in titrating to the lowest effective dosage. However, studies or case reports specific to the use of propantheline in patients with SCI appear to be lacking, as are reports of direct comparison between propantheline and other agents.

Concerning the mechanism of action of propantheline bromide for hyperhidrosis, it seems reasonable to attribute its effects to the drug's well-documented anticholinergic/antimuscarinic actions. At dosages used to effectively treat neurogenic bladder, propantheline bromide also should block the muscarinic receptors responsible for sweat gland stimulation. Central nervous system adverse effects should be minimal at usual clinical dosages, as propantheline does not cross the blood–brain barrier.

It would appear that in some patients with SCI who are subject to incidental episodes of profuse sweating, oral propantheline may offer some relief and may, in fact, be well tolerated, as in the cases described. Additionally, propantheline would seem a good therapeutic choice in SCI patients with excessive sweating and neurogenic bladder dysfunction who may derive dual benefit from the agent.

To describe the beneficial effects of low-dose dopamine infusion (2-5 μg/kg/min) in a patient with severe cor pulmonale complicating chronic obstructive pulmonary disease (COPD).

A 53-year-old woman with severe cor pulmonale and generalized edema complicating COPD received low-dose dopamine to stabilize blood pressure and, perhaps, improve cardiac output. Low-dose dopamine also improved her renal function and enhanced the diuretic response to furosemide therapy.

Previous studies of dopamine in such patients were reviewed. Both dopamine infusion (4 μg/kg/min) and oral administration of its precursor, l-dopa, can increase the cardiac output, decrease pulmonary vascular resistance, and enhance oxygen delivery in patients who are stable with cor pulmonale secondary to COPD. In patients with COPD during acute respiratory failure, high-dose dopamine (10 μg/kg/min) has been shown to increase the diaphragmatic blood flow and contraction. Low-dose dopamine also has been reported to be useful in patients with congestive heart failure or cirrhosis of the liver.

Low-dose dopamine is useful in the acute management of patients with severe cor pulmonale complicating COPD because of the drug's beneficial effects on blood pressure, cardiac output, renal perfusion, natriuresis, and diuresis. Low-dose dopamine also may enhance the natriuretic and diuretic response to loop diuretics, decrease pulmonary vascular resistance, and enhance oxygen delivery.

To report a patient with intolerance to amphotericin B reversed by preparing the antifungal in fat emulsion 20% and to review the medical literature on innovative formulations of amphotericin B.

A 51-year-old man diagnosed with acute myelogenous leukemia was treated with standard induction chemotherapy. Empiric antibiotic therapy was initiated 2 days postchemotherapy; however, the patient continued to be febrile until day 7. At this time amphotericin B 35 mg/250 mL D5W over 4 hours was administered. Despite premedication, the patient experienced severe rigors, chills, and fever. As the result of continuing infusion-related adverse events, the patient refused further therapy after the third daily dose. In an attempt to reduce the infusion-related events, a trial of amphotericin B 35 mg/35 mL of fat emulsion 20% was administered over 2 hours after patient consent was obtained. Premedication was administered and the patient tolerated therapy without adverse events. Amphotericin B dosage escalations to 50 and 70 mg were tolerated similarly. During this treatment the patient became afebrile and the serum creatinine concentration decreased to normal.

Despite significant toxicities and the development of newer antifungal agents, amphotericin B remains the drug of choice for the empiric coverage of suspected fungal infection in neutropenic patients. Amphotericin B often exacerbates the nephrotoxicity of other agents characteristically prescribed in these patients. Furthermore, infusion-related events, if not intolerable, can dramatically reduce the patient's quality of life. For these reasons, novel means of amphotericin B administration are being explored.

The delivery of amphotericin B in a lipid diluent may have substantial benefit in reducing the nephrotoxicity and infusion-related events associated with the antifungal. Prospective clinical trials comparing lipid-complexed amphotericin B with liposomal and approved formulations of amphotericin B are essential to define potential differences in toxicity and efficacy.

To discuss the antimicrobial activity, pharmacokinetics, clinical efficacy, and adverse effect profile of piperacillin/tazobactam, a new beta-lactam/beta-lactamase inhibitor combination.

Literature was identified by MEDLINE search of the medical literature, review of selected references, and data provided by the manufacturer.

In vitro susceptibility data were surveyed from studies following the methods of the National Committee for Clinical Laboratory Standards. Data evaluating clinical efficacy were selected from all published trials and abstracts. Additional information concerning safety, chemistry, and pharmacokinetics was reviewed.

The antimicrobial activity of piperacillin is enhanced by addition of tazobactam against gram-positive, gram-negative, and anaerobic bacteria. Tazobactam is active against a broad spectrum of plasmid and chromosomally mediated enzymes and has minimal ability to induce class I chromosomally mediated beta-lactamase enzymes. Piperacillin/tazobactam's expanded activity appears encouraging in the treatment of mixed aerobic and anaerobic infections. Direct comparisons of ticarcillin/clavulanate and piperacillin/tazobactam for the treatment of lower respiratory tract infections showed piperacillin/tazobactam to be clinically superior, and in the treatment of skin and soft tissue infections the 2 agents were comparable. For the treatment of intraabdominal infections, piperacillin/tazobactam was at least as effective as imipenem/cilastatin and clindamycin plus gentamicin.

The combination of tazobactam with piperacillin results in an antimicrobial agent with enhanced activity against most beta-lactamase–producing organisms. Preliminary data indicate that piperacillin/tazobactam has proven clinical efficacy in the treatment of a variety of infections, especially polymicrobic infections.

To review medications currently being used or investigated for the treatment of preterm labor. Adverse effects, pharmacoeconomic issues, and therapeutic controversies are included.

A MEDLINE search, limited to English-language articles and publication years of 1989–1994, was used to identify pertinent literature. Additional references were identified from articles retrieved in the search.

Studies were chosen on drugs that are available or whose approval is anticipated in the US: ritodrine, terbutaline, hexoprenaline, and magnesium sulfate. Several studies comparing indomethacin and nifedipine with currently used medications are also included. Oxytocin antagonists, now in Phase II clinical trials, are discussed. Studies focusing on adverse reactions were included because of serious concerns that these reactions raise.

Part of the controversy surrounding tocolytic agents involves the difficulty in comparing data from different trials, particularly because the criteria for diagnosis of preterm labor vary significantly. Therefore, no attempt was made to directly compare data from different sources; individual study data are presented.

Most studies reviewed using the beta-agonists showed each to be comparable in effectiveness when given parenterally during early preterm labor. These drugs usually delay delivery for 24–48 hours. There is less evidence that they are consistently effective in the long-term treatment of preterm labor. The adverse effects vary somewhat, but all beta-agonists have been reported to cause pulmonary edema, which is the most serious adverse effect associated with the use of these medications to inhibit labor. Indomethacin and nifedipine may be alternative choices for tocolytic therapy, but each has different adverse reactions that also make them less than ideal agents. Oxytocin antagonists may provide more specific therapy and are currently being investigated.

The beta-agonists are effective in delaying delivery for 24–48 hours in most patients; however, there are potential risks involved. Magnesium sulfate, prostaglandin synthetase inhibitors, calcium-channel blockers, and oxytocin antagonists may provide alternative choices for the treatment of preterm labor associated with neonatal morbidity and mortality. Each of the medications has advantages and disadvantages at different stages of gestation.

To review the data examining the use of rapid infusion of amphotericin B in dextrose infusions.

A MEDLINE search of the English-language literature and review of pertinent references' bibliographies was used to identify articles evaluating the effect of amphotericin B infusion rates on the incidence of adverse reactions.

Controlled and uncontrolled studies involving humans are reviewed; emphasis is placed on recent comparative trials. Pertinent information, as judged by the authors, was selected for discussion.

Amphotericin B, a polyene antifungal agent with significant toxicity, remains the agent of choice for many serious fungal infections. The potential benefits of rapid administration of amphotericin B in reducing the incidence and/or severity of adverse reactions were noted soon after its introduction. Recent studies have examined the tolerability of rapid (0.75–1 h) amphotericin B infusions. Results of studies assessing the tolerability of rapid amphotericin B infusions suggest that tolerance to infusion-related reactions develops during therapy. Comparative trials have obtained variable results. The comparative trials supporting rapid amphotericin B infusion have generally used crossover designs, enrolled small numbers of patients, and excluded patients with significant renal or cardiovascular dysfunction.

Rapid amphotericin B infusions should be avoided during initiation of therapy when infusion-related reactions tend to be most problematic, and in patients with cardiovascular disease, renal dysfunction, and potassium disorders because of the potential risk for cardiac arrhythmias. The literature currently available is conflicting and insufficient to support the routine use of rapid amphotericin B infusion.