Showing papers by "American Pharmacists Association published in 1998"

Torsade De Pointes Resulting from the Addition of Droperidol to an Existing Cytochrome P450 Drug Interaction

Abstract: OBJECTIVE:To report a case of QT prolongation associated with concomitant cyclobenzaprine and fluoxetine administration followed by torsade de pointes potentiated by droperidol.CASE SUMMARY:A 59-year-old white woman who had been receiving long-term fluoxetine and cyclobenzaprine therapy was admitted for Achilles tendon repair. Baseline QTc was prolonged at 497 msec. Prior to surgery, the patient received droperidol, an agent known to prolong the QT interval. During surgery the patient developed torsade de pointes, which progressed into ventricular fibrillation. On postoperative day 1, after cyclobenzaprine discontinuation, the QTc decreased toward normal (440 msec).DISCUSSION:Cyclobenzaprine shares anticholinergic effects, tachycardia, and dysrhythmic potential with the tricyclic antidepressants (TCAs). Fluoxetine is a known inhibitor of the CYP2D6 isoenzyme (along with CYP3A4 and CYP2C) and has been shown to increase TCA serum concentrations. The combination of cyclobenzaprine and fluoxetine resulted in ...

Physician and Staff Assessments of Drug Interventions and Outcomes in Swedish Nursing Homes

Abstract: OBJECTIVE: To describe the type and frequency of drug-related problems discussed in regular team meetings conducted in 15 Swedish nursing homes and report physician and staff assessments of these i ...

Multiple Congenital Malformations Associated with Topical Tretinoin

Abstract: 1. Mishima HK, Masuda K, Kitazawa Y, Azuma I, Araie M. A comparison of latanoprost and timolol in primary open-angle glaucoma and ocular hypertension. A 12-week open study. Arch Ophthalmol 1996;114:92932. 2. Kjellgren D, Douglas G, Mikelberg FS, Drance SM, Alm A. The shortterm effect of latanoprost on the intraocular pressure in normal pressure glaucoma. Acta Opthalmol Scand 1995;73:233-6. 3. Rulo AH, Greve EL, Hoyng PF. Additive effect of latanoprost, a prostaglandin F2 alpha analogue, and timolol in patients with elevated intraocular pressure. Br J Ophthalmol 1994;78:899-902. 4. Zaia N, Dolan JW, Kacere RD, Brubaker RF. The effects on aqueous dynamics of PhXA41, a new prostaglandin F2 alpha analogue, after topical application in normal and ocular hypertensive human eyes. Arch Ophthalmol 1993;111:1351-8. 5. Package insert. Xalatan (latanoprost). Woodstock, IL: Pharmacia & Upjohn, June 3, 1996. 6. McIntyre RC, Agrafojo J, Banerjee A, Fullerton DA. Pulmonary vascular smooth muscle contraction. J Surg Res 1996;61:170-4. 7. Troug WE, Norbeg M, Thibeault DW. Effects of 8-epi-prostaglandin F(2alpha) and U46,619 on pulmonary hemodynamics in piglets. Biol Neonate 1997;71:306-16. 8. Okazawa A, Kawikova I, Cui ZH, Skoogh BE, Lotvall J. 8-epi-PGF(2alpha) induces airflow obstruction and airway plasma exudation in vivo. Am J Respir Crit Care Med 1997;155:436-41. 9. Johnstone MA. Hypertrichosis and increased pigmentation of adjacent hair in the region of the ipsilateral eyelids of patients treated with unilateral topical latanoprost. Am J Ophthalmol 1997;124:544-7. 10. James S. Center for Drug Evaluation and Research: Xalatan adverse drug reaction information. File Number F97-15017. Rockville, MD: Food and Drug Administration, 1997. 11. Rang HP, Dale MM. Pharmacology. London: Churchill Livingstone, 1987. 12. Sodeman WA, Sodeman TM. Pathologic physiology: mechanisms of disease. Philadelphia: WB Saunders Co., 1985. 13. Quilley J, Bell-Quilley CP, McGiff JC. Eicosanoids and hypertension. In: Laragh JH, Brenner BM, eds. Hypertension: pathophysiology, diagnosis, and management. 2nd ed. New York: Raven Press, Ltd., 1995. 14. Olin BR, ed. Facts and comparisons. St. Louis: Facts and Comparisons, 1997:118j. 15. Kappus H, Diplock AT. Tolerance and safety of vitamin E: a toxicological position report. Free Radic Biol Med 1992;13:55-74. 16. Omaye ST. Safety of megavitamin therapy. Adv Exp Med Biol 1984; 177:169-203. 17. Roberts HJ. Prospective of vitamin E as therapy. JAMA 1981;246:12931. 18. Roberts HJ. Does vitamin E precipitate angina (letter)? Chest 1994;106: 1636-7. 19. Roberts HJ. Thrombophlebitis associated with vitamin E therapy with a commentary on other medical side effects. Angiology 1979;30:167-76.

Nicotine Replacement Therapy

Abstract: OBJECTIVE:To review the literature on nicotine dependence, nicotine pharmacology, health consequences associated with the use of nicotine, and nicotine replacement therapies used to aid smokers who are nicotine dependent.DATA SOURCES:A review of articles, book bibliographies, and published studies identified by a search of the MEDLINE database from 1982 to 1996 on nicotine dependence, nicotine addiction, nicotine withdrawal, smoking, smoking cessation, smoking intervention, nicotine pharmacology, nicotine pharmacokinetics, nicotine pharmacodynamics, and nicotine replacement therapies.STUDY SELECTION AND DATA EXTRACTION:Inclusion criteria were published randomized, double-blind trials of at least 12 weeks' duration, meta-analyses, and panel consensus guidelines.DATA SYNTHESIS:Cigarette smoking and tobacco use have met the surgeon general's primary criteria as well as additional criteria for drug dependence. Drug dependence requires that the drug produce psychoactive effects. Nicotine has been identified as...

Michigan Medicaid recipients' perceptions of medication counseling as required by OBRA '90.

Abstract: Objective To assess pharmacist counseling under OBRA '90 from the Medicaid recipient's perspective. Specifically, the study was designed to (1) assess pharmacists' compliance with counseling requirements, (2) assess recipients' level of satisfaction with the information provided during counseling and whether the information provided increased their comfort level in taking medication correctly, and (3) determine relationships between variables associated with pharmacist counseling and recipient satisfaction and comfort level. Design Cross-sectional telephone survey of Medicaid recipients. Medicaid recipient or caregiver was the unit of measure. Setting Michigan. Patients 408 recipients who received new prescriptions during a one-week period in November 1995. Interventions: Telephone survey. Main Outcome Measure Recipients' perception of whether an offer to counsel was made. Results Only 104 (25.5%) recipients indicated that someone offered counseling for their new prescription, and only 62 (15.2%) recipients indicated they knew olthe requirement; 163 (40.0%) indicated someone counseled them. Counseled recipients were satisfied with the amount, quality, and way the information was presented, and were more likely to assign a higher level of importance to pharmacist counseling. The majority of respondents indicated high levels of comfort in using their medications safely, with those who were counseled expressing a higher level of comfort. Conclusion From the perspective of the Medicaid recipient, pharmacies are failing to offer counseling for most new prescriptions. The results indicate that counseling improves measures of recipient comfort in using medications safely and enhances the level of importance patients assign to pharmacist counseling.

Pleurodesis with Iodized Talc for Malignant Effusions Using Pigtail Catheters

Abstract: OBJECTIVE:To assess the efficacy of using an iodized talc slurry as a sclerosing agent instilled into the pleural space via a 12-French pigtail catheter for controlling malignant pleural effusions.DESIGN:A prospective study in which patients were followed until their death.SETTING:A university-affiliated tertiary-care teaching hospital.PATIENTS:Medical oncology patients admitted with symptomatic malignant pleural effusions were considered for iodized talc pleurodesis.MAIN OUTCOME MEASURES:The control of pleural effusion. Treatment failure was defined as any reaccumulation of fluid in the pleural space.RESULTS:Fifteen patients were treated for a total of 17 instillations. The median follow-up on all patients until death was 6 months (range 1–20). The most frequent adverse effect in the study group was pleuritic chest pain (60%). The probability of control of effusion, as determined by the method of Kaplan–Meier, was 81% (SEM 9.7%). The cost of preparing 5 g of iodized talc was $4.32 (US).CONCLUSIONS:Iodize...

Possible Increased Anticoagulation Effect of Warfarin Induced by Azithromycin

Abstract: 65. 3. Kaplan JA, Krieff DM. Quinolones for the treatment and prophylaxis of tuberculosis. Ann Pharmacother 1996;30:1020-2. 4. Peloquin CA. Quinolones and tuberculosis (editorial). Ann Pharmacother 1996;30:1034-5. 5. Kennedy N, Berger L, Curram J, Fox R, Gutmann J, Kisyombe GM, et al. Randomized controlled trial of a drug regimen that includes ciprofloxacin for the treatment of pulmonary tuberculosis. Clin Infect Dis 1996;22:827-33. 6. Mor N, Vanderkolk J, Heifets L. Inhibitory and bactericidal activities of levofloxacin against Mycobacterium tuberculosis in vitro and in human macrophages. Antimicrob Agents Chemother 1994;38:1161-4. 7. Drlica K, Xu C, Wang JY, Burger RM, Malik M. Fluoroquinolone action in mycobacteria: similarity with effects in Escherichia coli and detection by cell lysate viscosity. Antimicrob Agents Chemother 1996;40: 1594-9. 8. Kocagöz T, Hackbarth CJ, Ünsal I, Rosenberg EY, Nikaido H, Chambers HF. Gyrase mutations in laboratory-selected, fluoroquinolone-resistant mutants of Mycobacterium tuberculosis H37Ra. Antimicrob Agents Chemother 1996;40:1768-74. 9. Ebert SC, Craig WA. Pharmacodymanic properties of antibiotics: application to drug monitoring and dosage regimen design. Infect Control Hosp Epidemiol 1990;11:319-26. 10. Peloquin CA. Using therapeutic drug monitoring to dose the antimycobacterial drugs. Clin Chest Med 1997;18:79-87. 11. Davis R, Bryson HM. Levofloxacin. A review of its antibacterial activity, pharmacokinetics, and therapeutic efficacy. Drugs 1994;47:677-700.

Providing Pharmaceutical Care in a Physician Office

Abstract: Objective To develop a physician office–based pharmaceutical care practice and evaluate the impact on the participating physicians, their staff, and patients. Setting Internal medicine physician office. Practice Description Two physicians and two nurses practice in a medical office complex in a rural setting in eastern Washington. Practice Innovation Development of an experimental pharmaceutical care program in which a registered pharmacist works in a physician office to evaluate the medication needs of patients and to provide pharmaceutical care and medication information to health professionals and patients. Main Outcome Measures Functions and interventions performed by the pharmacist; types of disease states in patients that were confronted by the pharmacist; summary of time spent with patients; and attitudes of physicians and patients concerning the pharmacist interventions. Results 660 pharmacist interventions or functions occurred during the seven months of the project. Of 107 recommendations to the physicians concerning changes in therapy, 89 were accepted. Patients suffered from 53 different disease states that were evaluated by the pharmacist. The pharmacist spent from less than 5 minutes to more than an hour with individual patients, 5 to 15minutes with the majority of patients. Both patients and physicians were impressed with the service and strongly desired to have it continued. Conclusion There is a career opportunity for pharmacists to provide pharmaceutical care in the setting of a physician office practice. Many of the barriers to providing pharmaceutical care can be eliminated or diminished in this setting.

Cost of managing anemia with and without prophylactic epoetin alfa therapy in breast cancer patients receiving combination chemotherapy.

Abstract: The cost of managing anemia with prophylactic epoetin alfa therapy versus blood transfusions in breast cancer patients receiving combination chemotherapy was studied. A retrospective study of anemia in breast cancer patients treated with four cycles of cyclophosphamide and doxorubicin with fluorouracil (CAF) or without fluorouracil (CA) was conducted. For each cycle of chemotherapy, patients were assessed for fatigue, subsequent blood transfusions administered, and potential response to and adverse effects of blood transfusions. Transfusions were given at the prescriber's discretion rather than in accordance with standard guidelines. The lowest hemoglobin concentration and hematocrit of each patient per cycle were reported. Data on these patients, along with data from published studies of prophylactic use of epoetin alfa, were used in a decision analysis of the costs associated with using epoetin alfa versus red blood cell transfusions to manage anemia. The charts of 50 patients were reviewed. In the study group, the percentage of patients with anemia and the frequency of fatigue rose with each chemotherapy cycle. In general, blood transfusions were not used. The cost of using epoetin alfa prophylactically for all four cycles was estimated at $6483 per patient for the literature-based group versus $169 for the study group. The cost of managing anemia in breast cancer patients was substantially lower when blood transfusions were used than when epoetin alfa was given prophylactically throughout four cycles of therapy with CAF or CA; the absence of standard guidelines for transfusion might have exaggerated the difference in costs.

Treatment of Extravasation from Parenteral Nutrition Solution

Abstract: OBJECTIVETo report two cases of parenteral nutrition extravasation and their treatment in adult patients.CASE SUMMARIES:Case 1: A 23-year-old white woman was admitted to our hospital diagnosed with a gastrointestinal infection by Salmonella paratyphi sv. B. The treatment included peripheral parenteral nutrition (osmolarity 652 mOsm/L). After 4 days an extravasation of parenteral nutrition was detected in the left antecubital fossa. The affected area soon became inflamed. Chondroitinsulfatase 150 turbidity-reducing units (TRUs), diluted in 3 mL of NaCl 0.9% and administered in six subcutaneous applications around the area, was prescribed. The treatment was successful. The patient was discharged several days later with no sequelae of the extravasation.Case 2A 33-year-old white woman was admitted to the intensive care unit after surgery for a necrohemorrhagic pancreatitis. The treatment included parenteral nutrition via a central catheter (osmolarity 2130 mOsm/L). Two days later the patient presented a paren...

Effect of pharmacist interventions on medication use and cost in hospitalized patients with or without HIV infection

Abstract: Pharmacotherapeutic interventions and drug acquisition costs in HIV-positive and HIV-negative patients on a hospital medical service were studied. In November and December 1995, HIV-positive and HIV-negative patients were randomly selected and matched on the basis of admission date. Pharmacotherapeutic interventions were recorded by a pharmacist until the time of discharge. Drug acquisition costs were obtained through records of medications ordered. The two patient groups were compared with respect to length of stay (LOS), number and cost of medications, and number of interventions. HIV-positive patients had significantly more medication orders and required more interventions than HIV-negative patients. Mean LOS was not significantly different. HIV status and number of medications were significantly associated with requiring five or more interventions. Drug acquisition costs were significantly higher in the HIV-positive group. The mean pharmacist-attributed cost saving per patient was $134 for HIV-positive patients and $27 for HIV-negative patients. HIV-positive patients required more interventions and consumed more medication resources than HIV-negative patients. Pharmacist interventions produced drug acquisition cost savings for both groups, with more savings being realized for positive patients.

Otitis media: focus on antimicrobial resistance and new treatment options.

Abstract: Antimicrobial resistance among organisms that cause acute otitis media (AOM) and new approaches in the prevention and treatment of AOM are discussed. Organisms commonly responsible for causing AOM include Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. The evolution of pneumococcal resistance to penicillins, erythromycin, trimethoprim-sulfamethoxazole, and oral cephalosporins may require treatment with agents such as vancomycin or rifampin in certain patients. H. influenzae and M. catarrhalis are becoming increasingly resistant to penicillins, trimethoprim-sulfamethoxazole, oral cephalosporins, and macrolides. Mechanisms of resistance include changes in penicillin-binding proteins, production of beta-lactamase, alterations in target enzymes, and inhibition of drug access to the site of action. Because of changing resistance patterns and the limited spectra of activity of many currently available antimicrobials, new antimicrobials have been developed in the hope of improving therapy. While amoxicillin and trimethoprim-sulfamethoxazole are appropriate first-line agents, children at risk for resistant infections may be treated initially with cefuroxime axetil, cefpodoxime proxetil, cefprozil, or amoxicillin-clavulanate. After local resistance patterns, patient adherence to therapy, in vitro data, and cost factors have been weighed, other agents to consider include loracarbef, clarithromycin, azithromycin, and ceftriaxone. Along with the efforts to improve treatment, research is focusing on the prevention of otitis media with bacterial and viral vaccines. The emergence of resistant strains of organisms causing AOM has complicated its treatment.

Ticlopidine-Induced Phenytoin Toxicity

Abstract: OBJECTIVE:To report a probable case of ticlopidine-induced phenytoin toxicity.CASE SUMMARY:A 72-year-old man suddenly developed combative behavior, refused to leave his room, stopped eating, and began falling to the floor 6 weeks after being given ticlopidine. The total phenytoin concentration was measured at 43.6 μg/mL; the dosage of phenytoin was decreased and the symptoms later resolved. After ticlopidine was discontinued, the patient was rechallenged with the same dose of phenytoin without symptoms of toxicity.DISCUSSION:Possible mechanisms of the drug interaction are discussed with emphasis on cytochrome P450 metabolism.CONCLUSIONS:Clinicians should be aware of this potentially serious drug interaction and either avoid the phenytoin–ticlopidine combination, or monitor closely for phenytoin toxicity.

Levofloxacin for Drug-Resistant Mycobacterium Tuberculosis

Abstract: moxifen. Vitamin B12 and folate concentrations were measured to rule out nutritional deficiencies as a cause of peripheral neuropathy. Vitamin B12 concentration of 374 pg/mL (normal range 200–1100) and folate of 8.2 ng/mL (2–20) were within normal limits at this visit, with no history of megaloblastic anemia, diabetes mellitus, toxic exposures, or clinical evidence of malabsorption. Based on her symptoms and abnormalities in the physical examination, including decreased sensation in a stocking-glove distribution bilaterally causing her to drop objects from her hands, decreased sensation to touch and pin prick, intact reflexes (2+ bilaterally in all extremities), and no weakness, the patient was diagnosed with peripheral neuropathy suspected to be secondary to metronidazole therapy. It was believed that the patient was dropping objects due to poor touch sensation, not to carpal tunnel syndrome. The patient’s metronidazole therapy was discontinued and no further treatment for peripheral neuropathy was instituted. The patient reported improvement 4 months after metronidazole discontinuation; the peripheral neuropathy was completely resolved as evaluated by physical examination of sense to touch and pin prick at her follow-up 5 months after discontinuation. Discussion. This case is unique because of the presence of peripheral neuropathy in a patient receiving metronidazole 2 g/d for 5 days every other month. Reported cases of metronidazole-induced peripheral neuropathy occurred among patients receiving 1.5 g or more daily for more than 30 days.3 Three cases of peripheral neuropathy associated with amitriptyline have been reported in the literature,6-8 and paresthesias have been reported rarely with both lisinopril and omeprazole. However, it is unlikely these agents contributed to our patient’s peripheral neuropathy as amitriptyline, lisinopril, and omeprazole were continued after metronidazole discontinuation and the patient experienced resolution of the peripheral neuropathy. This case presents new concerns about the predictability of metronidazole-induced peripheral neuropathy. With the increasing use of metronidazole for the treatment of Helicobacter pylori–associated peptic ulcer disease, practitioners should be cognizant of the potential for peripheral neuropathy with repeated short courses of metronidazole.

Successful Desensitization to Dapsone for Pneumocystis Carinii Prophylaxis in an HIV-Positive Patient

Abstract: OBJECTIVE:To report a case of successful desensitization to dapsone for Pneumocystis carinii pneumonia (PCP) prophylaxis in a patient unable to tolerate trimethoprim/sulfamethoxazole (TMP/SMX) desensitization or dapsone at standard doses.CASE SUMMARY:A 37-year-old HIV-positive African-American man was treated for pneumonia with TMP/SMX and then continued on the drug for PCP prophylaxis. After experiencing a pruritic maculopapular rash with TMP/SMX, both at standard doses and after attempting a desensitization regimen to the drug, he was started on dapsone for PCP prophylaxis. He experienced a rash and fever after taking dapsone at standard PCP prophylactic doses. At this time, an 18-day oral dapsone rechallenge by dose escalation was attempted, and it was well tolerated.CONCLUSIONS:This case suggests that utilization of a dapsone desensitization regimen may permit a viable treatment option in patients previously thought to be intolerant to the agent. More regimens of this type should be attempted and the ...

Pharmacokinetics of Anticancer Drugs in Cerebrospinal Fluid

Abstract: OBJECTIVE:To examine the pharmacokinetics of anticancer drugs in the cerebrospinal fluid (CSF) during chemotherapy by the lumbar– ventricular (LV) and ventricular–lumbar (VL) routes.CASE SUMMARY:A 69-year-old Japanese woman with disseminated glioblastoma received two LV and four VL courses of CSF perfusion chemotherapy with methotrexate, nimustine, and cytarabine hydrochloride. Samples of CSF from the ventricles and lumbar spinal canal were obtained via Ommaya reservoirs during one LV and one VL course. Drug concentrations in the CSF were measured by fluorescence polarization immunoassay or HPLC.RESULTS:During LV CSF perfusion, the highest CSF drug concentrations in both the ventricles and the lumbar spinal canal were observed at the end of perfusion. During treatment, the concentrations of all three drugs in the lumbar spinal canal were higher than those in the ventricles. The CSF AUC of methotrexate in the ventricles was 16.1% of that in the lumbar spinal canal. During VL CSF perfusion, the highest drug...

Significance of a Tetracycline and Pepto-Bismol Interaction in the Management of Helicobacter Pylori–Induced Peptic Ulcer Disease:

Abstract: TO THE EDITOR: Triple therapy is considered to be one of the most effective regimens in the management of Helicobacter pylori–induced peptic ulcer disease. There are many efficacious triple-therapy regimens, involving numerous combinations of antibacterials. Widespread application of any particular regimen depends on efficacy, adverse effects, cost, and the simplicity of regimen design. A commonly prescribed tripletherapy treatment regimen consists of a bismuth salt, metronidazole, and tetracycline or amoxicillin. In compliant patients, triple therapy with tetracycline, bismuth, and metronidazole has been studied extensively and produces eradication rates of approximately 90%.1-4 The primary reason for eradication failure has been attributed to noncompliance with these rather complicated treatment regimens. The commonly prescribed four times daily dosing frequency is further complicated by the pharmacist-driven recommendation to space the administration of tetracycline with divalent cations (e.g., bismuth and calcium salts comprising the Pepto-Bismol formulations). The implication of this potential drug interaction is that patients may administer drug(s) up to eight times per day. Simplification of regimen design for triple therapy would, therefore, be highly desirable. It is well established that the bioavailability of tetracycline can be decreased through the concomitant administration of calcium and bismuth salts.5,6 Whether gastrointestinal chelation significantly alters the antiHelicobacter activity of these luminally acting agents is not as well understood. The literature on H. pylori eradication provides little evidence of exactly how tetracycline is coadministered with the bismuth salts. The actual number of dosing times in any given day is poorly documented in these clinical trials. Graham, a pioneer of H. pylori therapy, reports that patients in his trials were counseled to take tetracycline and bismuth salts simultaneously (personal communication, David Y Graham MD, Professor of Medicine and Molecular Virology, Baylor College of Medicine and Veterans Affairs Medical Center, Houston, TX, June 1996). His eradication rates for triple-therapy regimens have been greater than 90%.7 If tetracycline was inactivated by the bismuth salt, we would anticipate that a bismuth/metronidazole regimen alone would have activity equivalent to that of triple therapy. The evidence suggests otherwise. Bismuth/metronidazole regimens have yielded inconsistent and inferior eradication rates, ranging from 72% to 90%.8-10 Considering the above, chelation may be occurring; however, it appears clinically insignificant in the treatment of this disorder. Based on the higher eradication rates with triple therapy, we believe that concerns about a tetracycline/bismuth salt interaction are unfounded, as the combination does not appear to diminish its luminal anti-Helicobacter activity. Nevertheless, there have been no clinical trials directly comparing bismuth/metronidazole with triple therapy. Based on existing clinical knowledge and experience, there is little information to suggest that coadministration of tetracycline and bismuth salts compromises the efficacy of this drug regimen. Bismuth salts may decrease the oral bioavailability of administered tetracycline; however, the drug interaction has little effect on the eradication of this luminal infection. The ability to disregard this drug interaction allows for greater simplicity with some triple-therapy regimens. Simplified anti–H. pylori regimens will greatly enhance drug compliance and support greater eradication rates in the management of this form of peptic ulcer disease. CAROL L TKACH BScPharm Pharmacist Department of Pharmacy St. Boniface General Hospital Winnipeg

Comparison of Phenytoin Serum Concentrations in Premature Neonates following Intravenous and Oral Administration

Abstract: OBJECTIVE:To compare the serum concentrations attained following intravenous and oral administration of phenytoin in premature neonates.DESIGN:A prospective, uncontrolled study was conducted over 6 years. Phenhydan concentrate for infusion (Desitin, Hamburg, Germany) was used for intravenous infusion, and Epanutin suspension (Parke-Davis, Freiburg, Germany) was used for oral therapy. Blood samples were analyzed by using a fluorescence polarization immunoassay analyzer TDx model by Abbott Laboratories.SETTING:A university-affiliated district hospital.PARTICIPANTS:Twenty premature neonates who were administered intravenous and/or oral phenytoin between February 1991 and February 1997.MAIN OUTCOME MEASURES:Serum phenytoin concentrations on intravenous and oral phenytoin.RESULTS:Nine patients received intravenous (group A) and 15 patients received oral (group B) therapy. Mean ± SD postnatal age (41 ± 8.7 vs. 48 ± 17 d; p = 0.03) and actual body weight (1.56 ± 0.38 vs. 1.88 ± 0.75 kg; p = 0.02) were slightly h...

Comment: Unexpectedly Low Phenytoin Concentration in a Patient Receiving Ciprofloxacin

Abstract: from the once-daily aminoglycoside dosing technique has not been thoroughly evaluated in a wide spectrum of critically ill patients. Many of these patients have aminoglycoside volumes of distribution above 0.3 L/kg and hence may not achieve the desired peak concentration with standard dosing.2 Because our clinical experience with once-daily aminoglycoside therapy in surgical intensive care unit (ICU) patients suggested lower-thananticipated serum concentrations, we conducted a prospective evaluation to validate our impression. Methods. All general surgical ICU patients with a calculated Clcr greater than 70 mL/min who were prescribed either gentamicin or tobramycin dosed once-daily were studied for 6 months. The drug was administered over 1 hour via a gravity-controlled mini-bag system followed by flushing of the intravenous line. Serum was obtained for aminoglycoside concentrations (measured by flourescence immunoassay) at 1 hour and 8–12 hours after the end of the infusion. Pharmacokinetic parameters were calculated using standard one-compartment equations.3 The Cmax was calculated by extrapolating the concentration–time curve to the end of the infusion, while the minimum concentration was extrapolated to 24 hours using patient-specific elimination rate constant. Discussion. Seventeen patients were studied, with an average age of 48 ± 16 years, calculated Clcr of 125 ± 35 mL/min, and APACHE II score of 12 ± 5. Eight patients had experienced trauma, while the remaining 9 had a variety of acute surgical conditions. Nine patients received gentamicin and 8 received tobramycin, for an average dose of 547 ± 82 mg (6.6 ± 1.0 mg/kg). Aminoglycoside pharmacokinetics are shown in Table 1. The variability in pharmacokinetic parameters is highlighted by a more than threefold range in Cmax and nearly sixfold range in elimination half-life in patients with normal renal function. The average Cmax of 16 μg/mL was considerably lower than the Hartford nomogram target concentration of 20 μg/mL.4 Eight patients exhibited Cmax values below 15 μg/mL. In fact, once-daily dosing was abandoned in 5 of 17 patients (29%) due to lower-than-expected drug concentrations. The time spent below a serum aminoglycoside concentration of 1 μg/mL averaged 11 ± 6 hours. In 11 patients, time below this value was more than 10 hours. In addition to lower drug preparation and administration costs, one of the purported pharmacoeconomic advantages of once-daily aminoglycoside dosing is the lack of need to monitor drug concentrations.5 Our findings of variable pharmacokinetics and a large volume of distribution in critically ill surgical patients suggest frequent aminoglycoside concentration monitoring is needed when once-daily dosing is used, to assure achievement of therapeutic drug concentrations. For example, one aminoglycoside concentration is required to assess Cmax, with a second concentration needed at 8–12 hours to ensure concentrations remain above the minimum inhibitory concentration of the organism for a sufficient period of time. If the dosage regimen fails to achieve the desired concentrations, standard dosing based on patient-specific pharmacokinetic parameters can be employed followed by reevaluation of the serum concentrations at steady-state. This necessary additional serum concentration monitoring adds to the total cost of care. The cost of a tobramycin concentration at Ohio State University (OSU) Medical Center is estimated at $9.75 (personal communication, Tony Wigton, OSU Medical Center, Financial Services, May 27, 1998). Thus, the additional cost of obtaining 2–4 aminoglycoside concentrations during once-daily aminoglycoside therapy in surgical ICU patients ranges from $19 to $39, excluding the cost of pharmacist monitoring. Although clinical and microbiologic outcome data are needed, we conclude that some patients admitted to a general surgery ICU with normal renal function are not appropriate candidates for once-daily aminoglycoside dosing.

Increase in Serum Carbamazepine Concentrations after Acute Viral Hepatitis

Abstract: TO THE EDITOR: Carbamazepine is a useful antiepileptic agent for the treatment of both generalized and partial seizures. The drug is not bound extensively to plasma proteins and the unbound percentage in plasma is about 25%. Carbamazepine elimination depends almost entirely on hepatic biotransformation by epoxidation and hydroxylation.1 In the same way, carbamazepine is restrictively cleared by the liver and is considered to have a low hepatic extraction ratio (<0.3).2 For drugs primarily eliminated by the liver, hepatic dysfunction may result in drug intoxication if reductions in drug dosage are not made. Conditions such as cirrhosis and acute or chronic viral hepatitis can induce pathophysiologic changes in hepatic blood flow, enzyme activity, or hepatocyte function that can affect pharmacokinetics.3 Little is known about the effects of liver disease on carbamazepine pharmacokinetics. A rise in unbound drug concentrations was observed in one study.4 We describe a case of increased serum carbamazepine concentrations with symptoms of toxicity after acute viral hepatitis. Case Report. An 18-year-old white woman came to the emergency department because of dizziness, nausea, and vomiting for the prior 10 days, and epigastralgia and biliuria for the last 2 days. She smoked 20 cigarettes a week and had no drinking habits or known risk factors for HIV infection. She received outpatient care at our neurology department during the last 7 years because she had a history of absence-like seizures since childhood, due to a neonatal pathology; generalized seizures had developed within the last year. Her usual treatment had been carbamazepine 300–200–300 mg/d and lamotrigine 100 mg twice daily for the prior 9 months. Carbamazepine serum concentrations had been maintained at 6–7 μg/mL during the last 2 years. The dose of carbamazepine was adjusted depending on the frequency of the seizures, but no change had been needed in the past 9 months. Talking with the physician and the pharmacist in the emergency department, the patient affirmed that she was compliant and denied having taken an extra dose of carbamazepine before the admission. On physical examination, her BP was 80/40 mm Hg and T was 36.4 ̊C. She was icteric and unable to stand because of vertigo with mild ataxic gait. Her abdomen was soft with no tenderness; there was no evidence of hepatosplenomegaly or adenopathy. An ultrasonographic examination of the abdomen was normal. Initial laboratory data showed alanine aminotransferase (ALT) 2407 U/L (normal 0–31) and a carbamazepine concentration of 14.62 μg/mL (4–11), which was obtained 12 hours after the last dose of carbamazepine. The prothrombin time was 19.4 seconds (control 13.4), with a Quick’s ratio of 56%. The patient was admitted with the initial diagnosis of carbamazepine-induced hepatotoxicity; the drug was therefore withdrawn. She continued taking lamotrigine at the same dose, and supportive measures were taken. Two days later the most remarkable laboratory values were glucose 68 mg/dL (76–110), total bilirubin 8.95 mg/dL (0–1), indirect bilirubin 1.32 mg/dL (0–0.75), direct bilirubin 7.63 mg/dL (0–0.25), aspartate aminotransferase (AST) 1170 U/L (0–31), ALT 1764 U/L (0–31), γ-glutamyl transferase (GGT) 210 U/L (7–32), and alkaline phosphatase 396 U/L (98–279). Quick’s ratio was 58%. Serologic studies for viral hepatitis performed 3 days after admission were positive for hepatitis B surface antigen, negative for hepatitis B core, and negative for hepatitis C virus. Carbamazepine concentrations decreased to 4.8 μg/mL 3 days after stopping the treatment, and the patient had a quick recovery. Seven days after admission biochemical values were AST 377 U/L, ALT 421 U/L, GGT 249 U/L, and alkaline phosphatase 294 U/L. The patient was discharged the next day. Carbamazepine 200 mg tid was reintroduced and 40 days later the serum carbamazepine concentration was 4.4 μg/mL, with serum hepatic enzymes within the normal range. Five months later, her treatment was changed to carbamazepine 300–200–300 mg and lamotrigine 100 mg twice daily. The carbamazepine concentration was 6.8 μg/mL and GGT was 46 U/L. This was probably a case of carbamazepine intoxication precipitated by acute viral hepatitis type B. This woman was taking chronic antiepileptic therapy and serum carbamazepine drug concentrations had remained within the therapeutic range for more than 2 years. The patient showed signs and symptoms of carbamazepine toxicity only after hepatic dysfunction produced by viral hepatitis appeared. In fact, once hepatic function was restored to normal, carbamazepine concentrations were normal and stable with the same doses as the patient had taken previously. Although it can be argued that all the symptoms were related to acute hepatitis, vertigo and ataxia were present and neither of these is a prominent feature of viral hepatitis. Also, the patient recovered from these symptoms the day after the withdrawal of carbamazepine. Another possible hypothesis is that an interaction between carbamazepine and lamotrigine may have caused the carbamazepine toxicity. The effect of this combination is not clear; some authors5 maintain that patients taking both drugs have a higher incidence of central nervous system adverse events (e.g., dizziness, headache, diplopia); others6 found that the plasma concentration of carbamazepine was reduced when lamotrigine treatment was introduced. We consider this possibility highly unlikely in our patient since she had received the same treatment for a long time. In acute viral hepatitis, a decrease in hepatocellular metabolic activity is expected while hepatic blood flow can increase or remain unchanged.7 In drugs with low hepatic extraction, the elimination depends mainly on uptake and metabolism, and is independent of hepatic blood flow. Thus, hepatic clearance is sensitive to the unbound fraction of drug in the blood and to the intrinsic ability of the liver to clear the drug. An increase in carbamazepine clearance could be expected when the unbound fraction increases. However, when the plasma binding is low, the concentration of drug at the enzyme site will not be changed significantly. Therefore, slight increases of the unbound carbamazepine fraction, observed in hepatic disease,4 would not produce significant changes.8 A decrease in intrinsic clearance due to a dysfunction in hepatocellular activity would increase the elimination half-life of a drug with a risk of accumulation and toxicity. It is probable that the decrease in enzyme activity affects more than the changes in unbound drug fraction. In our patient, this could be why carbamazepine toxicity occurred, since the hepatocyte function is assumed to be reduced during an acute inflammatory liver disease such as viral hepatitis. In fact, even though the effect of acute hepatitis on drug disposition is difficult to predict, a similar behavior has been observed in some drugs with pharmacokinetics similar to those of carbamazepine.7 Because the liver is the major site for carbamazepine metabolism, special care should be taken in patients with hepatic disease who are receiving this antiepileptic agent. Careful monitoring of serum carbamazepine concentrations and appropriate drug dosage adjustments are advisable in patients with symptoms of viral hepatitis.