bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neurologic, Psychological, and Aggressive Disturbances with Sildenafil
Authors: Milman Harry A , Arnold Suzanne B 
Published: June 2003

BACKGROUND: Anecdotal reports and case studies have described psychological disturbances and aggressive behavior in some men taking sildenafil. In the course of assisting the defense in a trial in which a man was alleged to have committed rape and in which sildenafil was implicated, a mechanistic hypothesis was formulated by the first author for central nervous system (CNS) adverse effects associated with the use of sildenafil. OBJECTIVE: To examine whether there was any scientific information available to suggest a possible mechanism for or an association between exposure to sildenafil and aggressive behavior. METHODS: The scientific literature on sildenafil, nitric oxide (NO), and the NO—cyclic-guanosine monophosphate (cyclic-GMP) signaling pathway was reviewed. Adverse event reports that referenced sildenafil and were filed with the Food and Drug Administration Adverse Event Reporting System between January 4, 1998, and February 21, 2001, also were examined. RESULTS: Published studies reported that sildenafil crosses the blood—brain barrier, that it exerts various biochemical and physiologic effects in the brain, and that it affects information processing. Other published reports indicated that phosphodiesterase type 5 (PDE-5), NO synthase, and guanylyl cyclase are present at highest activities in areas of the brain responsible for behavior, sexual drive, and emotion, and that NO modulates aggression and sexual behavior in male mice. In addition, 274 adverse event reports designated sildenafil as the primary suspect of various neurologic disturbances, amnesia, and aggressive behavior. DISCUSSION: Evidence has been presented for an association between sildenafil and various CNS adverse effects, including aggressive behavior. Whether sildenafil causes these effects by inhibiting PDE-5 in the brain, accumulating cyclic-GMP, decreasing NO, and affecting cell—cell signaling and modulation of aggressive behavior requires further investigation. CONCLUSIONS: It is recommended that, before prescribing sildenafil for erectile dysfunction, clinicians should caution their patients and their partners on the possibility of neurologic, emotional, or psychological disturbances; amnesia or loss of consciousness; or aggressive behavior.
Comparison of Plasma Concentrations for Two Amiodarone Products
Authors: Sauro Shari C , DeCarolis Douglas D , Pierpont Gordon L , Gornick Charles C 
Published: June 2003

BACKGROUND: A generic formulation of amiodarone was recently approved by the Food and Drug Administration based on single-dose equivalence data. Because amiodarone has complex pharmacokinetic properties, a narrow therapeutic range, and a significant adverse effect profile, concern about equivalency persists. OBJECTIVE: To compare steady-state plasma concentrations of the brand-name reference product Cordarone with the AB-rated generic formulation, Pacerone, in patients exposed to both products. METHODS: A retrospective analysis was performed at the Minneapolis Veterans Affairs Medical Center on 138 patients who were taking a stable dose of amiodarone before and after an amiodarone generic product substitution. RESULTS: Seventy-seven patients had steady-state plasma concentrations documented for each product at the same dose. The mean steady-state plasma concentrations of amiodarone were not significantly different for Cordarone compared with Pacerone (1.07 ± 0.48 vs. 1.19 ± 0.66 μg/mL, respectively); similarly, the concentrations of the active metabolite (desethylamiodarone) did not differ (0.95 ± 0.30 vs. 0.96 ± 0.49 μg/mL, respectively). However, the variability in plasma drug concentrations between products was increased as compared to variability within each product. CONCLUSIONS: This study indicates that comparable steady-state concentrations can be achieved with a change in formulation from Cordarone to Pacerone. However, individual responses vary, suggesting that monitoring of plasma concentrations is prudent 1–3 months after any change from one product to another.
Ticlopidine-Induced Cholestatic Hepatitis
Authors: Skurnik Yair D , Tcherniak Alexandra , Edlan Karl , Sthoeger Zev 
Published: June 2003

OBJECTIVE: To report 2 cases of ticlopidine-induced cholestatic hepatitis, investigate its mechanism, and compare the observed main characteristics with those of the published cases. CASE SUMMARIES: Two patients developed prolonged cholestatic hepatitis after receiving ticlopidine following percutaneous coronary angioplasty, with complete remission during the follow-up period. T-cell stimulation by therapeutic concentration of ticlopidine was demonstrated in vitro in the patients, but not in healthy controls. DISCUSSION: Cholestatic hepatitis is a rare complication of the antiplatelet agent ticlopidine; several cases have been reported but few in the English literature. Our patients developed jaundice following treatment with ticlopidine and showed the clinical and laboratory characteristics of cholestatic hepatitis, which resolved after discontinuation of the drug. Hepatitis may develop weeks after discontinuation of the drug and may run a prolonged course, but complete remission was observed in all reported cases. An objective causality assessment revealed that the adverse drug event was probably related to the use of ticlopidine. The mechanisms of this ticlopidine-induced cholestasis are unclear. Immune mechanisms may be involved in the drug's hepatotoxicity, as suggested by the T-cell stimulation study reported here. CONCLUSIONS: Cholestatic hepatitis is a rare adverse effect of ticlopidine that may be immune mediated. Patients receiving the drug should be monitored with liver function tests along with complete blood cell counts. This complication will be observed even less often in the future as ticlopidine is being replaced by the newer antiplatelet agent clopidogrel.
Electrocardiographic and Hemodynamic Effects of Panax Ginseng
Authors: Caron Michael F , Hotsko Audrea L , Robertson Stacy , Mandybur Lilia , Kluger Jeffrey , White C Michael 
Published: June 2003

OBJECTIVE: To determine whether Panax ginseng ingestion can acutely or chronically alter electrocardiographic parameters: PR, QRS, QT, QTc, and RR intervals, and QT and QTc interval dispersion. Effects of P. ginseng on blood pressure and heart rate also were evaluated. METHODS: This is a prospective, randomized, double-blind, placebo-controlled study of healthy adults at the University of Connecticut. Thirty subjects were randomly allocated to receive 28 days of therapy with either P. ginseng extract 200 mg or placebo. Baseline 12-lead electrocardiograms (ECGs) were obtained. Subsequent ECGs were performed following study drug ingestion at 50 minutes, 2 hours, and 5 hours on days 1 and 28. Blood pressure readings were taken with each ECG. RESULTS: P. ginseng ingestion increased the QTc interval by 0.015 seconds on day 1 at 2 hours compared with the placebo group (p = 0.03). It also reduced diastolic blood pressure from 75 ± 5 mm Hg at baseline to 70 ± 6 mm Hg at the same time point (p = 0.02). The observed effects are not believed to be clinically significant. No other statistically significant changes were found in electrocardiographic or hemodynamic variables on days 1 or 28. CONCLUSIONS: P. ginseng, at doses of 200 mg of the extract daily, increases the QTc interval and decreases diastolic blood pressure 2 hours after ingestion in healthy adults on the first day of therapy.
Possible Gatifloxacin-Induced Fulminant Hepatic Failure
Authors: Coleman Craig I , Spencer Jeffrey V , Chung Jenny O , Reddy Prabashni 
Published: June 2003

OBJECTIVE: To report a case of fulminant hepatic failure associated with the use of gatifloxacin. CASE SUMMARY: A 76-year-old white man was found to have an approximate 1-week history of worsening jaundice on the last day of a 10-day course of gatifloxacin for treatment of impetigo while at his skilled nursing facility. Liver function tests including aspartate aminotransferase (AST), alanine aminotransferase (ALT), international normalized ratio, activated partial thromboplastin time, and ammonia concentrations were found to be markedly elevated, consistent with hepatocellular necrosis commonly seen with fluoroquinolones. Screening for other causes of hepatotoxicity, including alcoholic or viral hepatitis, obstruction, or autoimmune-mediated processes, were negative. Other potential medication causes were less likely. The patient's liver function steadily declined, eventually resulting in multiple organ failure. The patient died 25 days after completing the course of gatifloxacin. DISCUSSION: This case of hepatotoxicity was associated with gatifloxacin. Other fluoroquinolones, most notably trovafloxacin, have been observed to cause variable degrees of hepatotoxicity, ranging from asymptomatic elevations of liver enzymes to fulminant hepatic failure. Fluoroquinolones are thought to cause hepatocellular necrosis, which results in elevated ALT and AST concentrations with a normal alkaline phosphatase concentration. A variable degree of hyperbilirubinemia is often seen, with the presence and degree of jaundice often correlating to a poorer prognosis. Hepatic encephalopathy and coagulopathy are also commonly present. CONCLUSIONS: Fluoroquinolones, including trovafloxacin, ciprofloxacin, ofloxacin, enoxacin, norfloxacin, and, in this case report, gatifloxacin, have been associated with hepatotoxicity. It is important that these medications be considered a possible cause when the patient being treated has liver disease.
Sudden Late Onset of Clozapine-Induced Agranulocytosis
Authors: Patel Nick C , Dorson Peter G , Bettinger Tawny L 
Published: June 2003

OBJECTIVE: To report a patient who suddenly developed agranulocytosis after long-term clozapine therapy. CASE SUMMARY: A 41-year-old white man suddenly developed agranulocytosis after 89 months of nearly continuous clozapine therapy. During this time, which included the addition of risperidone to the treatment regimen, his white blood cell (WBC) and granulocyte counts remained stable. One week after having stable hematologic counts, the patient suddenly developed agranulocytosis. WBC and granulocyte counts returned to baseline shortly after discontinuation of all medications and administration of sargramostim. DISCUSSION: The main factor limiting the use of clozapine as a first-line agent in mentally ill patients is the risk of agranulocytosis. Although the greatest risk of developing this adverse reaction is during the initial 6-month exposure, clozapine-induced agranulocytosis continues to pose a risk after years of exposure. Current product labeling requires weekly WBC and granulocyte monitoring for the first 6 months of treatment with clozapine, which may be decreased to biweekly monitoring after 6 months. Based on the sudden and late onset of agranulocytosis in our patient, clinicians may consider opting for weekly monitoring of hematologic function for patients on long-term clozapine therapy. The likelihood that clozapine was the cause of the agranulocytosis was rated possible according to the Naranjo probability scale. CONCLUSIONS: Clinicians must remain vigilant to trends in WBC and granulocyte counts and may wish to consider weekly hematologic monitoring regardless of duration of clozapine therapy. Patient and treatment system compliance with the registries' protocol regarding WBC monitoring is instrumental in reducing morbidity and mortality rates associated with clozapine use.
Tolterodine-Associated Acute Mixed Liver Injury
Authors: Schlienger Raymond G , Keller Martin J , Krähenbühl Stephan 
Published: June 2003

OBJECTIVE: To report a patient with an acute mixed liver injury associated with tolterodine therapy. CASE SUMMARY: An 81-year-old white woman with urge incontinence experienced malaise, fever, and gastrointestinal disturbances 18 days after starting tolterodine 2 mg twice daily. The patient's concurrent medications included flunitrazepam, diclofenac, and dorzolamide/timolol eye drops. Laboratory examination was consistent with the presentation of an acute mixed liver injury with increased transaminase enzymes, alkaline phosphatase, λ-glutamyltransferase, and bilirubin. Additionally, she had mild leukocytosis with eosinophilia. After tolterodine was discontinued, the abnormal liver and hematologic parameters returned to normal within 4 weeks. DISCUSSION: Tolterodine, a muscarinic receptor antagonist, has predominantly anticholinergic effects. To our knowledge, this is the first case published describing tolterodine-associated acute mixed liver injury. However, some of the patient's additional symptoms can also be considered part of a drug-induced hypersensitivity syndrome. This is usually defined by the triad of fever, cutaneous reaction, and involvement of internal organs, mainly affecting the liver. The close temporal relationship between the start of tolterodine therapy and the first symptoms and the reversibility after dechallenge led us to conclude that the adverse reaction was possibly related to tolterodine exposure. CONCLUSIONS: Our case illustrates that tolterodine may rarely be associated with liver injury. This may have been an organ manifestation of tolterodine-induced hypersensitivity syndrome.
SIADH and Hyponatremia with Theophylline
Authors: Liberopoulos Evagelos N , Alexandridis George H , Christidis Dimitris S , Elisaf Moses S 
Published: June 2003

OBJECTIVE: To report a case of possible theophylline-induced hyponatremia due to the syndrome of inappropriate antidiuretic hormone (SIADH). CASE SUMMARY: An 88-year-old man developed severe symptomatic hyponatremia (serum sodium 112 mEq/L) associated with inappropriate natriuresis (urinary sodium 58 mEq/L) temporally related to the initiation of theophylline. The patient fulfilled the criteria for the diagnosis of SIADH after all other causes of hyponatremia were excluded. Furthermore, no other drugs or conditions that could have evoked SIADH were found. DISCUSSION: Theophylline has rarely been associated with hyponatremia. A thiazide-like action of the drug on the stimulation of SIADH could be the underlying mechanism for SIADH. CONCLUSIONS: Theophylline should be considered as a possible cause of hyponatremia.
Valacyclovir versus Acyclovir for HSV Prophylaxis in Neutropenic Patients
Authors: Warkentin Dawn I , Epstein Joel B , Campbell Lara M , Yip Judy G , Cox Victoria C , Ransier Allison , Barnett Michael J , Marra Fawziah 
Published: June 2003

BACKGROUND: It is common practice to administer acyclovir as prophylaxis to patients with hematologic malignancies during neutropenia; however, effective therapy requires frequent dosing, which is difficult in this setting. Valacyclovir has greater oral bioavailability and requires less frequent dosing. OBJECTIVE: To evaluate the efficacy and safety of valacyclovir compared with acyclovir. METHODS: Patients who had been treated with chemotherapy or stem-cell transplantation were randomized to receive acyclovir 400 mg orally 3 × daily (n = 51), valacyclovir 500 mg orally twice daily (n = 48), or valacyclovir 250 mg orally twice daily (n = 52) during neutropenia. RESULTS: Clinical success, defined as the absence of an active herpes simplex virus (HSV) lesion or asymptomatic viral shedding, was similar between the 3 groups (acyclovir 96%, valacyclovir 500 mg 95%, valacyclovir 250 mg 100%). The overall rates of adverse events were similar in the 3 groups. CONCLUSIONS: Prophylactic treatment with valacyclovir is an effective and safe alternative to acyclovir for the prevention of HSV reactivation in patients with hematologic malignancies.
Tolerance of Simulated Amniotic Fluid in Premature Neonates
Authors: Sullivan Sandra E , Calhoun Darlene A , Maheshwari Akhil , Ashmeade Terri L , Auerbach David A , Hudak Mark L , Beltz Susan E , Christensen Robert D 
Published: June 2003

OBJECTIVE: To assess the tolerance of simulated amniotic fluid enterally administered in premature neonates. DESIGN: A multicentered, Phase I, dose-escalation trial was accomplished among 30 preterm neonates. Groups of 10 patients received 5, 10, or 20 mL/kg/d enterally of the amniotic fluid solution, divided into every-3-hour dosing, for 3 days. MAIN OUTCOME MEASURES: Amount and character of emesis, stools, and gastric residuals; changes in abdominal girth; presence of a skin rash; blood pressure instability; the diagnosis of necrotizing enterocolitis (NEC) or intestinal perforation. RESULTS: Thirty patients were studied: 10 received 5 mL/kg/d, 10 received 10 mL/kg/d, and 10 received 20 mL/kg/d of amniotic solution. Gestational ages ranged from 25 to 31 weeks. The Data Safety and Monitoring Board met after each group of 10 patients completed the study, reviewed the outcome measurements, and recommended continuance of the study. Dosing was discontinued for 3 patients prior to receiving all 24 doses because of gastric residuals (n = 1; 5 mL/kg), stage I NEC (n = 1; 10 mL/kg), or symptomatic patent ductus arteriosus (n = 1; 20 mL/kg). The remaining patients completed the doses with no evidence of intolerance: specifically, no increased gastric residuals, increased abdominal girth, diarrhea, blood pressure change, rash, NEC, or intestinal perforation. CONCLUSIONS: Enteral administration of an amniotic fluid—like solution to preterm neonates is well tolerated in doses ≤20 mL/kg/d.
Metoclopramide-Induced Supersensitivity Psychosis
Authors: Lu Mong-Liang , Pan Jan-Jhy , Teng Hui-Wen , Su Kuan-Pin , Shen Winston W 
Published: June 2003

OBJECTIVE: To report 2 cases of metoclopramide-induced supersensitivity psychosis. CASE SUMMARIES: A 74-year-old Taiwanese man was treated with metoclopramide 5 mg 4 × daily for 6 months. A second patient, a 65-year-old Taiwanese man, was treated with metoclopramide 5 mg 4 × daily for 3 months. After discontinuation of metoclopramide, both patients developed hallucinatory experiences and delusions. DISCUSSION: This is the first report of metoclopramide-induced supersensitivity psychosis. Chronic administration of a dopamine antagonist (e.g., metoclopramide) might induce dopamine receptor supersensitivity. It is hypothesized that exacerbation or occurrence of psychotic symptoms following neuroleptic withdrawal results from mesolimbic dopamine supersensitivity. CONCLUSIONS: The complications of long-term metoclopramide therapy should be seriously considered when the treatment regimens are being planned. Clinicians should attempt to treat patients with the lowest effective dosage of medication for the briefest therapeutic period to minimize the risks of adverse reactions.
Recombinant Human Activated Protein C for Use in Severe Sepsis
Authors: Bearden David T , Garvin Cory G 
Published: June 2003

OBJECTIVE: To review the efficacy and safety of drotrecogin alfa (recombinant human activated protein C) in the treatment of sepsis. DATA SOURCES: Literature was identified through a MEDLINE search (1966–January 2002), the product manufacturer, and the Food and Drug Administration. STUDY SELECTION/DATA EXTRACTION: All relevant information identified from the data sources was evaluated. DATA SYNTHESIS: Drotrecogin alfa reduces coagulation and inflammation in septic patients. A large placebo-controlled clinical trial (n = 1690) of drotrecogin alfa in severely septic patients demonstrated a reduction in mortality (24.7% vs. 30.8%; p = 0.005), with increased bleeding risks (24.9% vs. 17.7%; p <0.001). Patients with more severe sepsis appeared to gain the most benefit. The complete clinical and economic impact of this agent requires further analysis. CONCLUSIONS: Drotrecogin alfa offers a significant advance in the treatment of severe sepsis. Judicious use in appropriate patients is necessary to control cost and maximize clinical benefits.
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.