bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacodynamics of High-Dose Methotrexate in Pediatric Patients
Authors: Aquerreta Irene , Aldaz Azucena , Giráldez Joaquín , Sierrasesúmaga Luis
Published: June 2003

OBJECTIVE:

To establish a relationship between the pharmacokinetics of high-dose methotrexate (MTX) and toxicity in children of a pediatric oncology department and to reassess MTX concentrations at which the patients would be at high risk for toxic effects.

METHODS:

This study included 37 patients (227 treatment courses) who received a median dose of 4.87 g/m2 of MTX in a 4-hour infusion. The population pharmacokinetic parameters of MTX were estimated by parametric (IT2B) and nonparametric methods (NPEM). Gastrointestinal, renal, and hematologic toxicity were evaluated. The relationship between pharmacokinetic parameters and toxicity was analyzed by logistic regression and multiple linear regression.

RESULTS:

Equations to predict hematologic and nonhematologic toxicity were obtained. An increase of 100 μmol/L in the MTX peak concentration meant a 12% (p = 0.03) higher risk of vomiting; a significant delay in MTX elimination implied a 5.76-fold higher risk of mucositis (p < 0.001). An increase of 1 μmol/L in the MTX concentration 24 hours after the end of the infusion (Cp24h) led to a 43% increase in the risk of renal toxicity (p < 0.001). Hematologic toxicity was significantly conditioned by the baseline leukocyte count and Cp24h (p < 0.001).

CONCLUSIONS:

The analysis of high-dose MTX pharmacokinetic/pharmacodynamic relationship to toxicity has led to equations able to predict toxicity that are easily applicable to daily practice. Cp24h >3.5 μmol/L was confirmed as an indicator of high risk of toxicity.
Interactions between Recreational Drugs and Antiretroviral Agents
Authors: Antoniou Tony , Tseng Alice Lin-In
Published: June 2003

OBJECTIVE:

To summarize existing data regarding potential interactions between recreational drugs and drugs commonly used in the management of HIV-positive patients.

DATA SOURCES:

Information was obtained via a MEDLINE search (1966–August 2002) using the MeSH headings human immunodeficiency virus, drug interactions, cytochrome P450, medication names commonly prescribed for the management of HIV and related opportunistic infections, and names of commonly used recreational drugs. Abstracts of national and international conferences, review articles, textbooks, and references of all articles were also reviewed.

STUDY SELECTION AND DATA EXTRACTION:

Literature on pharmacokinetic interactions was considered for inclusion. Pertinent information was selected and summarized for discussion. In the absence of specific data, prediction of potential clinically significant interactions was based on pharmacokinetic and pharmacodynamic properties.

RESULTS:

All protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors are substrates and potent inhibitors or inducers of the cytochrome P450 system. Many classes of recreational drugs, including benzodiazepines, amphetamines, and opioids, are also metabolized by the liver and can potentially interact with antiretrovirals. Controlled interaction studies are often not available, but clinically significant interactions have been observed in a number of case reports. Overdoses secondary to interactions between the “rave” drugs methylenedioxymethamphetamine (MDMA) or γ-hydroxybutyrate (GHB) and PIs have been reported. PIs, particularly ritonavir, may also inhibit metabolism of amphetamines, ketamine, lysergic acid diethylmide (LSD), and phencyclidine (PCP). Case series and pharmacokinetic studies suggest that nevirapine and efavirenz induce methadone metabolism, which may lead to symptoms of opiate withdrawal. A similar interaction may exist between methadone and the PIs ritonavir and nelfinavir, although the data are less consistent. Opiate metabolism can be inhibited or induced by concomitant PIs, and patients should be monitored for signs of toxicity and/or loss of analgesia. PIs should not be coadministered with midazolam and triazolam, since prolonged sedation may occur.

CONCLUSIONS:

Interactions between agents commonly prescribed for patients with HIV and recreational drugs can occur, and may be associated with serious clinical consequences. Clinicians should encourage open dialog with their patients on this topic, to avoid compromising antiretroviral efficacy and increasing the risk of drug toxicity.
Medicaid Prescriber Compliance with Joint National Committee VI Hypertension Treatment Guidelines
Authors: Clause Steven L , Hamilton Robert A
Published: June 2003

BACKGROUND:

Since the early 1970s, the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) has been tasked with the formulation of national guidelines for the management of hypertension. These were significantly changed in 1993 with publication of JNC-5. JNC-6 kept many basic treatment recommendations (i.e., initiation of therapy with a thiazide diuretic or β-blocker), partly in response to the low adoption rate of the treatment recommendations of JNC-5.

OBJECTIVE:

To describe single-drug outpatient therapy of hypertension and temporally correlate these therapies with the publication of JNC-5 and JNC-6.

METHODS:

The electronic records of randomly selected New York State Medicaid recipients without hospitalization who had a diagnosis of hypertension and who were receiving only 1 antihypertensive medication were analyzed for 1994, 1997, and 1999. This analysis identified the medications selected for monotherapy of hypertension and compared these therapies with JNC recommendations. The analysis was correlated to patient comorbidities to further account for provider selection of a non—first-line agent.

RESULTS:

In 1994, angiotensin-converting enzyme (ACE) inhibitors and calcium-channel blockers accounted for 69% of therapies, with 67.5% of these patients having no JNC-recognized individualizing consideration for their use. In 1999, the combined use of ACE inhibitors and calcium-channel blockers accounted for over 65% of all single-drug therapy; 60% of these patients had no individualizing considerations. Also, in 1999, 47.7% of all patients appeared to be receiving antihypertensive therapies that are not compliant with JNC recommendations.

CONCLUSIONS:

Single-drug therapy of hypertension in a nonhospitalized New York state Medicaid population from 1994 through 1999 did not closely follow JNC recommendations for the single-agent treatment of hypertension.
Constipation, Polyuria, Polydipsia, and Edema Associated with Orlistat
Authors: Packard Kathleen A , Wurdeman Richard L , Reyes Antonio P
Published: June 2003

OBJECTIVE:

To report the occurrence of a novel group of adverse effects associated with initiation and rechallenge of orlistat.

CASE SUMMARY:

A 42-year-old white woman developed symptoms of constipation, polyuria, polydipsia, and increased lower-leg edema after 2 weeks of treatment with orlistat 120 mg 3 × daily. The drug was discontinued for 4 days and the symptoms resolved. On reinstitution of the orlistat treatment, the symptoms reappeared within 2 days. Thereafter, the medication was permanently discontinued.

DISCUSSION:

Common gastrointestinal adverse reactions associated with orlistat use include fecal urgency and abdominal pain and discomfort. Pedal edema has also been reported to occur, although less frequently. No reports were discovered documenting the occurrence of constipation, polydipsia, and polyuria associated with the use of orlistat. Despite careful consideration of other possible causes of these symptoms, the temporal association between initiation, discontinuation, and rechallenge of orlistat and the patient's symptoms suggest a medication-related adverse event. Based on the Naranjo probability scale, the likelihood that orlistat was the cause of this cluster of adverse effects is possible.

CONCLUSIONS:

It is important for the healthcare provider to be aware of these adverse effects to promptly evaluate and differentiate between possible causes of similar reactions.
Use of Alternative Medications in Patients with Neurologic Disorders
Authors: Ryan Melody , Johnson Mitzi S
Published: June 2003

OBJECTIVE:

To determine alternative medication use in a neurology clinic population and to predict patients likely to use alternative medications.

DESIGN:

Survey of 216 adults presenting to a university-affiliated neurology clinic.

METHODS:

Subjects were queried regarding diagnosis, medications, satisfaction with medications, alternative medications, and demographics. Alternative medications were defined as herbal therapies, holistic therapies, minerals, or vitamins other than multiple vitamins. Frequencies were tabulated for categorical data; means and standard deviations were calculated for continuous data. Logistic regression was performed to predict use of alternative therapies.

RESULTS:

The most frequent conditions seen in all subjects were headache, epilepsy, and stroke. Mean ratings of patients' satisfaction with their conventional medications and health were 6.8 ± 2.64 and 6.4 ± 2.23 on a 10-point scale, respectively. Forty subjects were taking alternative therapies. Regression analysis suggests that patients with higher levels of education are more likely to use alternative therapies.

CONCLUSIONS:

Forty of 216 subjects (18.5%) seen in the neurology clinic took alternative therapies. Increased educational level was associated with use of alternative therapies.
Divalproex Sodium Therapy in Elderly with Dementia-Related Agitation
Authors: Pratt Crystal E , Davis Steven M
Published: June 2003

OBJECTIVE:

To review available literature regarding the use of divalproex sodium in the treatment of agitation in elderly patients with dementia.

DATA SOURCES:

Clinical trials and review articles were identified by MEDLINE search (1966 — March 2002).

DATA SYNTHESIS:

The literature provides information regarding the potential benefits and tolerability of divalproex sodium in the treatment of dementia-related agitation. This article analyzes 7 studies to better understand the role of divalproex sodium in the treatment of dementia.

CONCLUSIONS:

Divalproex sodium may offer a slight benefit to elderly patients suffering from dementia-related agitation. Until better-controlled trials demonstrate statistical significance and comparisons with established treatments are performed, practitioners should use divalproex sodium cautiously.
A Critical Evaluation of the Therapeutic Range of Indinavir
Authors: Rayner Craig R , Galbraith Kirsten J , Marriott Jennifer L , Duncan Gregory J
Published: June 2003

OBJECTIVE:

To provide a summary of the patient population, study characteristics, and important findings of the key studies in the literature evaluating concentration—effect relationships and the therapeutic range for indinavir.

DATA SOURCES:

Literature search strategy involved using MEDLINE (1966–July 2001) and AIDSLINE (MEDSCAPE) databases (up to July 2001). Reference lists from primary literature and review articles were also examined, and conference abstracts were obtained.

STUDY SELECTION:

English-language articles were considered suitable for review if the clinical trials in HIV patients reported on concentration—effect relationships and/or pharmacokinetic breakpoints or threshold concentrations. A search of the literature identified 20 peer-reviewed references from 18 separate studies including journal articles and conference abstracts.

DATA EXTRACTION:

The targeted pharmacokinetic parameters and breakpoint values, the rationale for their selection or method of identification, and other study details and limitations were summarized.

DISCUSSION:

This article highlights the heterogeneity of studies evaluating the therapeutic range of indinavir and provides a summary of important findings of the key studies in the literature evaluating concentration-effect relationships and therapeutic range. Tables are provided to enable clinicians to make use of currently available information on the therapeutic range of indinavir.

CONCLUSIONS:

There is insufficient evidence to recommend a general therapeutic range for indinavir. Future investigations should incorporate both pharmacokinetics and pharmacodynamics in order to define a broadly applicable therapeutic range.
CNS Relapses of Acute Promyelocytic Leukemia after All-Trans Retinoic Acid
Authors: Burry Lisa D , Seki Jack T
Published: June 2003

OBJECTIVE:

To review the role of all- trans retinoic acid (ATRA) and arsenic trioxide in central nervous system (CNS) relapses of acute promyelocytic leukemia (APL).

CASE SUMMARY:

A 69-year-old white man diagnosed with APL presented with bleeding diathesis. His molecular and cytogenetic studies were positive for promyelocytic leukemia—retinoic acid receptorα (PML-RARα) and t(15;17) transformation. Complete molecular and cytogenetic remission was achieved with ATRA, daunorubicin, and cytarabine. Within 6 months, the patient was readmitted for investigation of severe global headaches and an ataxic gait. His peripheral blood and cerebral spinal fluid were positive for PML-RARα fusion protein. Intrathecal chemotherapy and radiation, as well as ATRA, were the main treatment modalities provided. Molecular and cytogenetic remission was again obtained. Three months later, a second relapse occurred in the CNS and the peripheral blood.

DISCUSSION:

APL is typically treated with anthacycline-based chemotherapy and ATRA. Approximately 85–95% of patients achieve complete remission (CR); however, the relapse rate has been reported to be about 30–40%. A thorough literature search (MEDLINE, EMBASE, CANCERLIT, 1966–January 2002) revealed only 54 cases of extramedullary disease, of which 35 involved the CNS.

CONCLUSIONS:

The introduction of ATRA has improved patient survival dramatically. APL relapse, in general, has been in part attributable to repetitive or prolonged exposure to ATRA and the possibility of additional chromosomal changes, making the disease more refractory to treat. Given the evidence, one could argue that, with repeated ATRA treatment, CR duration may be shortened. However, limited data are available to guide the appropriate management of APL relapsed to the CNS with either ATRA, chemotherapy, or arsenic trioxide. In our opinion, treatment using arsenic trioxide is an unconventional option worthy of exploring.
Nightmares and Panic Disorder Associated with Carvedilol Overdose
Authors: Maebara Chiharu , Ohtani Hisakazu , Sugahara Hideyo , Mine Kazunori , Kubo Chiharu , Sawada Yasufumi
Published: June 2003

OBJECTIVE:

To report a case of nightmares and sleep disorder associated with improper use of carvedilol, an α/β-blocker, and to model the time course of receptor occupancy in this patient.

CASE SUMMARY:

A 41-year-old man with panic disorder had been treated with alprazolam 1.2 mg/d (3 × daily), carvedilol 10 mg/d (once in the morning), and etizolam 0.5 mg (for anxiety attack). Although the physical and psychological symptoms gradually improved, he reported nightmares and panic attacks. An interview revealed that he had been taking carvedilol 5 mg twice a day after lunch and dinner on his own initiative, in addition to the prescribed dosage. The patient was asked to take carvedilol 10 mg only after breakfast, as had been advised. Consequently, the sleep disorder and nightmares disappeared.

METHODS:

We calculated the time courses of β2-adrenoceptor binding occupancy in the central nervous system after oral administration of carvedilol with the ordinary and improper regimens by using pharmacokinetic/pharmacodynamic parameters obtained from the literature.

RESULTS:

Compared with the ordinary dose of carvedilol 10 mg once a day, the improper regimen (10 mg after breakfast followed by 5 mg after lunch and dinner) increases the β2-adrenoceptor binding occupancy at night (2300) to as high as the mean β2-adrenoceptor binding occupancy after an ordinary dose of propranolol.

CONCLUSIONS:

The sleep disorder and nightmares experienced by this patient had been induced by elevation of central β2-adrenoceptor binding occupancy at night as the result of improper use of carvedilol.
Treatment of Itching Associated with Intrahepatic Cholestasis of Pregnancy
Authors: Jenkins J Kimble , Boothby Lisa A
Published: June 2003

OBJECTIVE:

To review the drug therapy for the treatment of itching associated with intrahepatic cholestasis of pregnancy (ICP).

DATA SOURCES:

A comprehensive literature search was conducted in MEDLINE (1966–July 2002) using the following MeSH terms: pregnancy, itching, intrahepatic cholestasis, cholestyramine, ursodeoxycholic acid, and phenobarbital. Current Contents (1966–July 2002), International Pharmaceutical Abstracts (1970–June 2002), and Cochrane Database were also searched using those terms. Web of Science search was used to search references found in articles.

DATA SYNTHESIS:

Eight clinical trials and several observational studies were identified evaluating the safety and efficacy of ursodeoxycholic acid (UDCA) in the treatment of ICP. Although these studies were small and inconsistent, improvement in maternal and fetal morbidity was demonstrated. Observational studies suggest that cholestyramine may be associated with improved maternal morbidity without a documented improvement in fetal outcome. Two observational studies evaluated the efficacy of phenobarbital for ICP treatment. Phenobarbital use was not associated with improved maternal or fetal morbidity/mortality.

CONCLUSIONS:

Data from large, well-designed, randomized, controlled trials of treatment of ICP are lacking. Data that are available support the use of UDCA as a first-line agent and cholestyramine as a second-line agent for treatment of ICP. There is little evidence to recommend phenobarbital in the treatment of itching associated with that condition.
Possible Gatifloxacin-Induced Hypoglycemia
Authors: Baker Stacey E , Hangii Matthew C
Published: June 2003

OBJECTIVE:

To report a case of hypoglycemia in a patient receiving gatifloxacin for presumed exacerbation of chronic obstructive pulmonary disease (COPD).

CASE SUMMARY:

A 73-year-old white man with an extensive past medical history significant for type 2 diabetes mellitus and COPD was prescribed gatifloxacin 400 mg/d for a COPD exacerbation. After 2 days of therapy, the patient presented to the emergency department (ED) reporting worsening symptoms; he had a blood glucose concentration of 22 mg/dL. Because he had not eaten well for several days, the patient discontinued his oral antidiabetic medications prior to presenting to the ED, but continued to take gatifloxacin. The patient had never before experienced a symptomatic hypoglycemic episode during the years of taking his antidiabetic medications. In the ED, he received 1 last dose of gatifloxacin and was treated aggressively with intravenous dextrose. By the end of his hospitalization, antidiabetic medication was restarted to control hyperglycemia.

DISCUSSION:

Although gatifloxacin has been shown to alter glucose homeostasis, the mechanism of action has not been elucidated. Other recognized risk factors that contribute to the development of hypoglycemia are discussed. Our patient experienced hypoglycemia after receiving gatifloxacin and recovered 24 hours after discontinuation. The Naranjo probability scale suggests a possible drug-related event.

CONCLUSIONS:

The temporal relationship of gatifloxacin administration and the hypoglycemic episode suggests that gatifloxacin likely precipitated the event. Clinicians should be aware of this adverse effect in patients taking gatifloxacin presenting with hypoglycemia.
Rhabdomyolysis with Concurrent Atorvastatin and Diltiazem
Authors: Lewin John J , Nappi Jean M , Taylor Marian H
Published: June 2003

OBJECTIVE:

To report a case of rhabdomyolysis and acute hepatitis associated with the coadministration of atorvastatin and diltiazem.

CASE SUMMARY:

A 60-year-old African American man with a significant past medical history presented to the emergency department with acute renal failure secondary to rhabdomyolysis. In addition, liver enzymes were elevated to greater than 3 × normal. The only change in medication was the initiation of diltiazem 3 weeks earlier for atrial fibrillation to a complicated medication regimen that included atorvastatin.

DISCUSSION:

Rhabdomyolysis has been reported in patients receiving hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors when coadministered with agents that may inhibit their metabolism. Atorvastatin is the most potent of this class of agents currently available and is commonly used in the treatment of hyperlipidemia. Rhabdomyolysis resulting from the drug interaction between diltiazem and other HMG-CoA reductase inhibitors has been described in the literature. However, no report has specifically associated this adverse event with atorvastatin and diltiazem. We describe a patient with a complex medication regimen who was admitted for rhabdomyolysis and accompanying acute renal failure, along with acute hepatitis, thought to be secondary to a drug interaction between atorvastatin and diltiazem.

CONCLUSIONS:

While optimizing the patient's lipid profile should be the primary factor in choosing one statin over another, the potential for drug interactions requires close attention. All patients beginning HMG-CoA reductase inhibitor therapy should be counseled regarding the signs and symptoms of muscle injury; particular attention should be paid to those patients who are taking medications that may interact.
Role of N-Acetylcysteine in the Prevention of Radiocontrast-Induced Nephropathy
Authors: Brophy Donald F
Published: June 2003

OBJECTIVE:

To examine the role of N-acetylcysteine (NAC) in the prevention of radiocontrast—induced nephropathy (RIN).

DATA SOURCES:

A literature search of MEDLINE (1966–December 2001) was performed using the following search terms: N-acetylcysteine, nephropathy, acute renal failure, and radiocontrast.

STUDY SELECTION:

Pertinent English-language animal and human studies were reviewed.

DATA SYNTHESIS:

Few small animal trials have demonstrated that NAC significantly prevents the development or reduces the severity of acute renal failure. Two human studies demonstrated NAC significantly reduces the occurrence of RIN.

CONCLUSIONS:

NAC may reduce the occurrence of RIN in high-risk patients. Further large-scale studies are needed to corroborate findings from earlier trials.
Drug—Drug Interactions in the Elderly
Authors: Björkman Ingeborg K , Fastbom Johan , Schmidt Ingrid K , Bernsten Cecilia B ,   Pharmaceutical Care of the Elderly in Europe Research (PEER) Group, Bernsten Cecilia B , Björkman Ingeborg K , Caramona Margarida , Crealey Grainne , Frøkjær Bente , Grünberger Erika , Gustafsson Tove , Henman Martin , Herborg Hanne , Hughes Carmel , McElnay James C , Magner Maeve , van Mil Foppe , Schaeffer Marion , Silva Sonia , Søndergaard Birthe , Sturgess Ian , Tromp Dick , Vivero Lisa , Winterstein Almut
Published: June 2003

OBJECTIVE:

To detect the frequency of potential drug—drug interactions (DDIs) in an outpatient group of elderly people in 6 European countries, as well as to describe differences among countries.

DATA SOURCES AND METHODS:

Drug use data were collected from 1601 elderly persons living in 6 European countries. The study population participated in a controlled intervention study over 18 months investigating the impact of pharmaceutical care. Potential DDIs were studied using a computerized detection program.

RESULTS:

The elderly population used on average 7.0 drugs per person; 46% had at least 1 drug combination possibly leading to a DDI. On average, there were 0.83 potential DDIs per person. Almost 10% of the potential DDIs were classified to be avoided according to the Swedish interaction classification system, but nearly one-third of them were to be avoided only for predisposed patients. The risk of subtherapeutic effect as a result of a potential DDI was as common as the risk of adverse reactions. Furthermore, we found differences in the frequency and type of potential DDIs among the countries.

CONCLUSIONS:

Potential DDIs are common in elderly people using many drugs and are part of a normal drug regimen. Some combinations are likely to have negative effects; more attention must be focused on detecting and monitoring patients using such combinations. As differences in potential DDIs among countries were found, the reasons for this variability need to be explored in further studies.
Hemorrhagic Gastritis from Topical Isopropanol Exposure
Authors: Dyer Sara , Mycyk Mark B , Ahrens William R , Zell-Kanter Michele
Published: June 2003

OBJECTIVE:

To report the occurrence of hemorrhagic gastritis after topical isopropanol application in an infant.

CASE SUMMARY:

A 2-year-old Hispanic boy developed coffee-ground emesis during emergency department evaluation for lethargy and fever. After an initial inconclusive workup for sepsis, further history revealed an isopropanol rubdown for fever reduction. Isopropanol concentrations and acetone metabolites were elevated, the patient recovered with supportive therapy, and other causes for hemorrhagic gastritis were excluded.

DISCUSSION:

Isopropanol sponge bathing is commonly used as a home remedy for infants with fever. Topical absorption of isopropanol has previously been reported to cause mental status changes, ketosis, and metabolic acidosis. We report a case of hemorrhagic gastritis as a complication of topical isopropanol absorption in a febrile infant. An objective causality assessment revealed that the adverse event was probably caused by the isopropanol. Previous reports of pediatric isopropanol poisoning and its management are discussed.

CONCLUSIONS:

Severe morbidity from topical isopropanol exposure may occur in young children.
Impact of NSAIDs Prior Authorization Policy on Patients' QoL
Authors: Momani Aiman A , Madhavan S Suresh , Nau David P
Published: June 2003

BACKGROUND:

In 1996, the West Virginia Medicaid program targeted nonsteroidal antiinflammatory drugs (NSAIDs) for prior authorization (PA) to ensure cost-effective and appropriate utilization. PA guidelines required that patients must have tried and failed treatment with 2 different classes of generic NSAIDs before a brand-name NSAID could be approved.

OBJECTIVE:

To evaluate the impact of the requirement of PA for branded NSAIDs on the health-related quality of life (HRQoL) of patients who are chronic users of NSAIDs.

DESIGN:

Pre- and postintervention quasiexperimental design was used for this study. The sample consisted of continuously eligible Medicaid recipients who were <65 years old and who were diagnosed with rheumatoid arthritis, osteoarthritis, spondylitis, or chronic pain syndromes. Data were collected through a mail survey using the abbreviated version of the Arthritis Impact Measurement Scales.

RESULTS:

A total of 181 (37.1%) completed surveys were received, 110 (39.2%) from the branded-NSAID user group and 71 (32.7%) from the generic-NSAID user group. Patients who were restricted to generic NSAIDs did not report deterioration in any of the HRQoL domains measured, including mobility, walking and bending, hand and finger function, self care, household activities, social activities, and tension.

CONCLUSIONS:

The requirement of PA for the use of branded NSAIDs did not compromise patients' HRQoL at 8 weeks follow-up.
Phenytoin/Isradipine Interaction Causing Severe Neurologic Toxicity
Authors: Cachat Francois , Tufro Alda
Published: June 2003

OBJECTIVE:

To report a young man on phenytoin who developed acute neurologic symptoms after isradipine was introduced to his treatment regimen and discuss the possible causes of this drug interaction.

CASE SUMMARY:

A 21-year-old white man, with propionic acidemia and seizures treated with phenytoin and carbamazepine, was started on isradipine for essential hypertension. Soon thereafter, he developed acute and severe lethargy, ataxia, dysarthria, and weakness that resolved once isradipine was withheld. Phenytoin concentrations were within normal limits or elevated, despite sequential reductions of phenytoin dosage, during concomitant isradipine administration.

DISCUSSION:

Isradipine is a known inhibitor of the CYP450 isoenzyme family. Although the daily dose of phenytoin was decreased significantly, phenytoin blood concentrations remained high, suggesting a pharmacokinetic interaction. Previously, the patient had never had neurologic symptoms associated with increased phenytoin concentrations. This also indicates a likely pharmacodynamic interaction between phenytoin and the calcium-channel blocker. Both phenytoin and isradipine have been shown to bind to calcium channels and to inhibit calcium entry into the cells. Binding of isradipine to the brain has been described in humans and animals, and calcium-channel blockers have been shown to cause potentiation of anticonvulsant action of phenytoin.

CONCLUSIONS:

Acute pharmacokinetic and pharmacodynamic interactions between phenytoin and isradipine were probably responsible for the lethargy, dysarthria, ataxia, and weakness our patient developed. The combination of phenytoin and calcium-channel blockers should be used with caution.
Aspirin Resistance
Authors: Howard Patricia A
Published: June 2003

OBJECTIVE:

To review the literature addressing the problem of aspirin resistance in patients with vascular disease.

DATA SOURCES:

A MEDLINE search (1966–February 2002) was performed. Key search terms included aspirin, resistance, resistant, failure, tolerance, and nonresponder. English-language studies were identified as well as pertinent references from these articles.

DATA SYNTHESIS:

Aspirin resistance has been reported in patients with cardiovascular, cerebrovascular, and peripheral vascular disease. Because of differences in the definition of resistance, variations in detection methods, and a lack of controlled trials, the true significance of the problem remains unknown. Multiple mechanisms for resistance have been proposed, including increased reactivity to platelet aggregating factors, genetic polymorphism, and alternate pathways for thromboxane synthesis. The studies to date have failed to demonstrate consistent relationships between aspirin's platelet-inhibiting effects, the impact of dosage escalation, and clinical outcomes.

CONCLUSIONS:

For many patients, aspirin is an effective antithrombotic agent. However, patients taking aspirin may demonstrate highly variable responses to in vitro tests for platelet aggregation and may experience breakthrough thromboembolic events. Although this phenomenon has been termed aspirin resistance, the lack of a uniform definition or agreement on diagnostic criteria precludes definitive recommendations at this time. In addition, strategies are needed to identify patients at risk for aspirin resistance who might benefit from alternative or combined antiplatelet therapy.
Current and Emerging Therapy for Primary Pulmonary Hypertension
Authors: Pass Steven E , Dusing Michelle L
Published: June 2003

OBJECTIVE:

To review the epidemiology, pathophysiology, clinical symptoms, and diagnostic workup of primary pulmonary hypertension (PPH) and to discuss the available data on the current and emerging therapies being used to treat this disorder.

DATA SOURCES:

Primary and review articles were identified with a MEDLINE search (1966–December 2001) and through secondary sources.

STUDY SELECTION AND DATA EXTRACTION:

All articles identified from the data sources were evaluated and all information deemed relevant was included in this review.

DATA SYNTHESIS:

In the absence of a definable cause, PPH is a disorder classified by a progressive increase in pulmonary vascular resistance and mean pulmonary artery pressure. A relatively rare condition, PPH has an annual incidence of 1–2 cases per million people, slightly higher in women than men. The prognosis is poor, with a mean survival time of 2.8 years after diagnosis if untreated. Vasoconstriction, vascular remodeling, and thrombosis are hallmarks of the disease process. Anticoagulation and vasodilators are the most commonly employed treatment options, showing benefits in clinical outcomes, hemodynamic parameters, and mortality. Several new vasodilators are being evaluated for the treatment of PPH. Bosentan was recently approved as the first oral agent for the treatment of PPH. Iloprost, treprostinil, and beraprost are investigational agents in Phase III studies.

CONCLUSIONS:

Until additional studies and experience with these agents become available, calcium-channel blockers (CCBs) remain the first option for therapy. For patients not responding to CCBs, therapeutic options will now include epoprostenol and bosentan. Since there are no comparison trials between these 2 agents, therapeutic decisions should be based on patient-specific concerns. Clinical data and experience support the use of epoprostenol; however, in patients at risk or considered unsuitable candidates, bosentan may become a preferred option. Additional studies are warranted to address the potential therapeutic benefits of combination therapy and long-term benefits of agents to treat PPH.
Sialorrhea — Therapeutic Drug Options
Authors: Tscheng Dorothy Z
Published: June 2003

OBJECTIVE:

To review the efficacy and safety of various drug treatments for sialorrhea. Pharmacotherapy for drug-induced sialorrhea is not addressed.

DATA SOURCES:

Clinical studies were identified using PubMed (1966–October 2001). Key search terms included sialorrhea and drug therapy.

DATA SYNTHESIS:

Sialorrhea is a social and physical detriment to patients. Drug treatment, although not necessarily the treatment of choice for all patients, can offer some symptom relief.

CONCLUSIONS:

Literature has documented that benztropine, glycopyrrolate, and scopolamine can reduce the incidence of sialorrhea. Although the literature evaluating the therapeutic options has limitations (e.g., small sample size, inconsistent outcome measurements), glycopyrrolate may have an advantage over the other agents due to fewer adverse effects.
Patient-Specific Factors Predictive of Warfarin Dosage Requirements
Authors: Absher Randall K , Moore M Elisabeth , Parker Mary H
Published: June 2003

OBJECTIVE:

To identify patient-specific factors predictive of maintenance warfarin dosage requirements >5 mg/d.

METHODS:

One hundred forty-six adults taking warfarin were identified from a community hospital and an outpatient anticoagulation clinic. Patient demographics and data on warfarin doses, laboratory results, and medication use were obtained by abstracting patient records. Estimates of vitamin K intake were obtained using a questionnaire and structured interview. Multiple logistic regression was used to identify patient characteristics independently predictive of warfarin maintenance requirements >5 mg/d. An assessment tool for estimating an individual patient's likelihood of requiring warfarin maintenance doses >5 mg/d was derived from the logistic regression model and was assessed in both the study cohort and a separate historical validation cohort of 125 patients.

RESULTS:

Five factors were independently associated with warfarin requirements >5 mg/d: age <55 years, male gender, African American ethnicity, vitamin K intake >400 μg/d, and body weight ≥91 kg. The assessment tool derived from these factors correctly classified semiquantitative warfarin requirements as non—high-dose in 84 of 93 study cohort patients and 71 of 78 validation cohort patients, and correctly classified requirements as high-dose in 10 of 13 study cohort patients and 11 of 15 validation cohort patients.

CONCLUSIONS:

African American ethnicity is a newly identified predictor of warfarin requirements >5 mg/d and is independent of dietary vitamin K intake. An assessment tool incorporating this and other predictors can estimate a patient's likelihood of requiring such dosages.
Eplerenone — A Novel Selective Aldosterone Blocker
Authors: Zillich Alan J , Carter Barry L
Published: June 2003

OBJECTIVE:

To review the pharmacology, pharmacokinetics, clinical efficacy, and safety of eplerenone, a new selective aldosterone blocker.

DATA SOURCES:

Primary literature and review articles were obtained via MEDLINE search (1966–April 2002). Additional studies and abstracts were identified from the bibliographies of reviewed literature.

STUDY SELECTION AND DATA EXTRACTION:

Studies and review articles related to eplerenone, aldosterone, aldosterone antagonist, and spironolactone were reviewed. Data pertinent to this article were included.

DATA SYNTHESIS:

Eplerenone is a selective aldosterone blocker. Recent data have demonstrated the deleterious effects of aldosterone in several chronic disease states including hypertension and heart failure. Animal studies using eplerenone have shown a positive role for aldosterone antagonism in the treatment of hypertension, heart failure, myocardial infarction, renal disease, and atherosclerosis. In humans, eplerenone appears to be effective for the treatment of hypertension. An ongoing study will examine the effect of eplerenone for heart failure. To date, the incidence of adverse effects with eplerenone has been slightly lower than with spironolactone.

CONCLUSIONS:

Eplerenone appears to be a promising drug in a new class of agents called selective aldosterone blockers. The drug may be approved for treatment of hypertension in 2002. Additional studies are ongoing that may provide information on other clinical uses for this medication.
Rhabdomyolysis Associated with Gemfibrozil—Colchicine Therapy
Authors: Atmaca Hulusi , Sayarlıoğlu Hayriye , Külah Eyüp , Demircan Nejat , Akpolat Tekin
Published: June 2003

OBJECTIVE:

To report a case of rhabdomyolysis possibly due to combination therapy with colchicine and gemfibrozil.

CASE SUMMARY:

A 40-year-old man with amyloidosis and hepatitis B virus—related chronic liver disease was admitted to the university hospital because of fatigue, lack of appetite, dark brownish urine, and myalgia for 2 weeks. The patient was receiving colchicine and gemfibrozil. Elevations of serum creatine kinase, lactate dehydrogenase, and aspartate aminotransferase concentrations with myalgia were compatible with the diagnosis of rhabdomyolysis.

DISCUSSION:

To our knowledge, myopathy and rhabdomyolysis due to a combination of colchicine and gemfibrozil therapy have not been previously reported. Preexisting mild renal failure, hepatitis B—related chronic liver disease, and amyloidosis may be contributing risk factors for the development of rhabdomyolysis in this patient. An objective causality assessment revealed that the adverse drug event was possible.

CONCLUSIONS:

Patients receiving combination therapy with colchicine and gemfibrozil, especially those with renal and hepatic dysfunction, should be monitored for rhabdomyolysis, and concomitant colchicine and gemfibrozil therapy should be considered in the differential diagnosis of rhabdomyolysis.
Fluvastatin-Induced Rhabdomyolysis
Authors: Modi Jitu R , Cratty Michael S
Published: June 2003

OBJECTIVE:

To demonstrate a case of rhabdomyolysis with acute renal failure in a patient receiving fluvastatin and to present evidence that this was an adverse drug reaction to fluvastatin.

CASE SUMMARY:

A 51-year-old white man with a past medical history significant for hyperlipidemia treated with fluvastatin presented with malaise, myalgias, nausea, and lumbar back pain. The patient had azotemia with elevated creatine kinase (CK), lactate dehydrogenase, and transaminases. He developed hematuria and proteinuria. Laboratory results demonstrated a normal antinuclear antibody, rheumatoid factor, angiotensin-converting enzyme, antineutrophil cytoplasmic antibody, and thyroid-stimulating hormone. Cytomegalovirus and Epstein-Barr virus titers were negative for recent infection. There were no signs of systemic infection; the white blood cell count was normal and blood and urine cultures were negative. Renal ultrasound showed hyperechoic renal cortices with no obstruction. The discontinuation of fluvastatin and hemodialysis led to a rapid decrease in CK and improvement in symptoms.

DISCUSSION:

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have the potential to cause rhabdomyolysis. However, fluvastatin is rarely associated with rhabdomyolysis when compared to other statins. Differences in biochemical and pharmacokinetic properties between fluvastatin and other HMG-CoA reductase inhibitors may be important in the development of rhabdomyolysis.

CONCLUSIONS:

Fluvastatin was the precipitating factor causing rhabdomyolysis in this case report. This patient had no other findings to suggest infection or other disorder inducing rhabdomyolysis. An objective causality assessment revealed that the adverse drug reaction was probable as determined by the Naranjo probability scale. Fluvastatin has the potential to cause serious adverse effects. Therefore, a heightened awareness by the patient and physician for potential signs of myopathy is recommended.
Single-Patient Drug Trial Methodology for Allergic Rhinitis
Authors: Reitberg Donald P , Rio Eve Del , Weiss Sidney L , Rebell Gerbert , Zaias Nardo
Published: June 2003

BACKGROUND:

Historically, single-patient trials (SPTs) have been specifically designed for each patient, requiring significant time and effort for execution. There has been no previous attempt to standardize an SPT for routine commercial availability.

OBJECTIVE:

To validate the use of an SPT method to discriminate effectiveness and adverse events while comparing drugs/doses in patients with allergic rhinitis.

DESIGN:

Double-blind, randomized, 4 paired—period, multiple-crossover SPT.

SETTING:

Academic and commercial investigative sites.

PATIENTS:

Thirty-six patients with allergic rhinitis were evaluated for the most appropriate treatment; 6 of these participated in 2 different SPTs.

INTERVENTIONS:

Treatment of symptoms of allergic rhinitis by comparing either loratadine with chlorpheniramine maleate or loratadine with placebo in a series of SPTs.

MEASUREMENTS:

Effectiveness endpoints were selected from a modern, Food and Drug Administration (FDA)-approved new drug application. Expected adverse events were directly solicited; unsolicited events were also recorded. Total signs and symptoms cumulatively included sneezing, runny nose, itchy nose, teary eyes, and itchy eyes. Quality of life was measured by the most bothersome symptom and the patient's global evaluation.

RESULTS:

Of 42 initiated SPTs, 40 (95%) provided complete data and 1 (2%) provided partial data, resulting in 41 (98%) evaluable tests. Thirty-one evaluable SPTs compared loratadine 10 mg/d with chlorpheniramine maleate 12 mg twice daily, and 10 SPTs compared loratadine 10 mg/d with placebo. Four of 31 SPTs (13%) showed significant superiority for loratadine over chlorpheniramine maleate and 5 of 31 (16%) for chlorpheniramine maleate over loratadine. Twenty-two of 31 (71%) showed parity performance between loratadine and chlorpheniramine maleate. Loratadine was significantly superior to placebo in 3 of 10 trials (30%), consistent with rates found in 3 pivotal group trials used for FDA approval (24%, 17%, and 0%). Sleepiness could be discriminated for loratadine versus placebo and for chlorpheniramine maleate versus loratadine.

CONCLUSIONS:

The allergic rhinitis SPT proved to be acceptable to patients, feasible to administer, and reproducible. It can statistically discriminate effectiveness and adverse events, serving as a useful, prognostic tool in community practice.
Management of Botulism
Authors: Robinson Renee F , Nahata Milap C
Published: June 2003

OBJECTIVE

To provide a concise review of the presentation and treatment of botulism.

DATA SOURCES

Searches of MEDLINE (1966–November 2001), tertiary references, and public and government Internet sites were conducted.

STUDY SELECTION

All articles and additional references from those articles were thoroughly evaluated.

DATA SYNTHESIS

Clostridium botulinum toxin blocks acetylcholine release in a dose-dependent fashion, resulting in acute symmetric diplopia, dysarthria, dysphonia, dysphagia, and possible neurologic sequelae despite the route of exposure (i.e., food-borne, wound, intestinal, inhalation). Disease secondary to genetically engineered C. botulinum may differ from that of inadvertent exposure. Present treatment is primarily supportive care, respiratory support, rapid decontamination, and antitoxin administration (i.e., trivalent, pentavalent, heptavalent antitoxin). Early initiation of antitoxin limits the extent of paralysis, but does not reverse it.

CONCLUSIONS

Supportive care and the use of antitoxin have been effective in the treatment of botulism from food-borne, intestinal, and wound exposure. However, the effectiveness of antitoxin in the treatment of inhaled C. botulinum has not been proven.
Fatal Aspiration Pneumonia during Transition from Donepezil to Rivastigmine
Authors: Taylor Amy M , Hoehns James D , Anderson Doris M , Tobert Daren G
Published: June 2003

OBJECTIVE:

To report a case of fatal aspiration pneumonia in a patient shortly after initiation of rivastigmine and discontinuation of donepezil, with no washout period between therapies.

CASE SUMMARY:

An 83-year-old white man presented to the emergency department in respiratory distress (O2 saturation 70%; RR 44 breaths/min) secondary to aspiration. He had started rivastigmine 1.5 mg twice daily that same day. The patient had been previously treated with donepezil 10 mg/d, and there was no washout period. He was intubated due to worsening respiratory status and was transferred to the cardiac care unit. He then became hypotensive and required dopamine and fluid support. Brief bronchoscopy revealed food particles in the lower airways and bile-stained secretions. Intubation was notable for the large amount of secretions. The patient died approximately 27 hours after presentation to the emergency department. Blood and sputum cultures were subsequently positive for Haemophilus influenzae.

DISCUSSION:

Cholinesterase (ChE) inhibitors approved for treatment of Alzheimer disease are associated with nausea and vomiting in a sizable percentage of patients, ranging from 5% to 31% in clinical trials. Most of these adverse events occur during the initiation/titration phase of therapy. An additive risk of adverse events may be expected with coadministration of ChE inhibitors or cholinergic agents or, potentially, with an inadequate washout period between such agents. Review of MEDLINE (1966–July 2002) and International Pharmaceutical Abstracts (1970–July 2002) failed to identify any previous reports of aspiration with rivastigmine or donepezil.

CONCLUSIONS:

A washout period should be considered when switching between ChE inhibitors to minimize the risk of vomiting and aspiration.