-- Back to Table of ContentsObjectives. To review the recent literature on possible causes of the increase in frequency of diagnosed autism reported from three countries, and to compare the medical diagnoses and drug therapy from a new series of autistic boys and their mothers with that of comparable nonautistic boys and their mothers.
Design. Case-control evaluation.
Participants. Members of over 250 general practices in the United Kingdom.
Measurements and Main Results. Frequency of exposure to drugs and presence of preexisting clinical illnesses in autistic children and their mothers were compared with nonautistic children and their mothers over time. According to published studies, the incidence of boys diagnosed with autism rose dramatically in the 1990s. Numerous published studies have concluded that the measles-mumps-rubella vaccine is not responsible for the large rise in diagnosed autism. In our study, boys diagnosed with autism had medical and drug histories, such as vaccines, before diagnosis, that were closely similar to those of nonautistic boys, except that developmental and sensory disorders were far more common in autistic boys. No material differences during pregnancy were found between the mothers of autistic boys and those of nonautistic boys in relation to illness or drug therapy. In the early 1990s, boys with diagnosed developmental disorders were infrequently diagnosed with autism. In the later 1990s, such boys more often were diagnosed with autism.
Conclusion. A major cause of the recent large increase in the number of boys diagnosed with autism probably is due to changing diagnostic practices.
Key Words: MMR vaccine, epidemiology, autism.
(Pharmacotherapy 2003;23(12):1524-1530)
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Study Objective. To compare the pharmacodynamic profiles of linezolid, levofloxacin, and vancomycin against clinical strains of Streptococcus pneumoniae, including vancomycin-tolerant and fluoroquinolone-resistant isolates.
Design. In vitro pharmacodynamic model.
Setting. Biosafety level 2, university research laboratory.
Bacterial Strains. Ciprofloxacin-susceptible (79), ciprofloxacin-resistant (R921), and vancomycin-tolerant (P9802-020) clinical strains of S. pneumoniae.
Intervention. An in vitro pharmacodynamic model was used to simulate standard dosing regimens of linezolid, levofloxacin, and vancomycin against the isolates 79, R921, and P9802-020.
Measurements and Main Results. Bacterial density was profiled over 48 hours. Minimum inhibitory concentrations (MICs) for linezolid, levofloxacin, and vancomycin, respectively, were 1, 1, 0.5 µg/ml for isolate 79; 1, 4, 0.5 µg/ml for R921; and 0.5, 0.5, 0.5 µg/ml for P9802-020. Vancomycin minimum bactericidal concentration (MBC) values varied across large ranges for the tested strains. Linezolid achieved 99.9% kill against 79 and R921 by 24 and 28 hours, respectively. Levofloxacin achieved 99.9% kill against 79 and P9802-020 by 28 and 4 hours, respectively. Vancomycin achieved 99.9% kill against 79 and R921 by 8 and 24 hours, respectively. Levofloxacin did not demonstrate activity against R921 at the 48-hour end point. Minimal kill (< 2 log) at 48 hours was noted for vancomycin and linezolid against P9802-020.
Conclusion. Vancomycin tolerance appeared to be more reliably characterized by persistent viability in time-kill analyses than by MBC:MIC ratios. Vancomycin exhibited bactericidal activity against the non-vancomycin-tolerant strains of S. pneumoniae. Linezolid exhibited both bactericidal and bacteriostatic activity against all three strains tested, whereas levofloxacin demonstrated bactericidal activity against the fluoroquinolone-susceptible isolates. Further investigation of treatment alternatives for infections due to vancomycin-tolerant S. pneumoniae are needed.
Key Words: Streptococcus pneumoniae, vancomycin-tolerant Streptococcus pneumoniae, linezolid, tolerance, pharmacodynamic, in vitro model
(Pharmacotherapy 2003;23(12):1531-1537)
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Study Objective. To compare in vitro aerosol deposition from a beclomethasone dipropionate metered-dose inhaler (MDI) containing hydrofluoroalkane propellant with that of the MDI in combination with two common valved holding chambers (VHCs) to evaluate how these VHCs affect the respirable dose of beclomethasone dipropionate.
Design. In vitro aerosol deposition study.
Setting. University research center.
Devices. Beclomethasone dipropionate hydrofluoroalkane MDI alone, the MDI with OptiChamber VHC, and the MDI with AeroChamber-Plus VHC.
Intervention. The respirable dose (1-5-µm aerosol particles) of beclomethasone dipropionate was determined by sampling 10 80-µg actuations from five runs with each configuration (MDI alone, MDI with OptiChamber, and MDI with AeroChamber-Plus), using a well-established in vitro cascade impactor method.
Measurements and Main Results. Beclomethasone dipropionate aerosol was washed from the impactor with 50% methanol and quantified by means of high-performance liquid chromatography. Differences among outcomes were determined by using analysis of variance. Mean beclomethasone dipropionate respirable dose from AeroChamber-Plus (27.2 ± 10.0 µg/actuation) was not significantly different (p>0.05) from that of the MDI alone (29.0 ± 7.0 µg/actuation). OptiChamber respirable dose (12.8 ± 6.0 µg/actuation) was less than half that produced by either the AeroChamber-Plus or the MDI alone (p=0.013).
Conclusions. The OptiChamber and AeroChamber-Plus VHCs do not demonstrate equivalent in vitro performance when used with a beclomethasone dipropionate MDI that contains hydrofluoroalkane propellant. The respirable dose of beclomethasone dipropionate aerosol from the hydrofluoroalkane MDI was decreased by only 6% when the MDI was mated to an AeroChamber-Plus VHC and by 56% when used with an OptiChamber VHC.
Key Words: asthma, beclomethasone, holding chamber, metered-dose inhaler
(Pharmacotherapy 2003;23(12):1538-1544)
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Study Objective. To compare the two-stage method, a widely used analytical method in pharmacokinetic studies, with nonparametric population modeling by using the same data set for determining the oral bioavailability of ribavirin.
Design. Pharmacokinetic analysis.
Setting. Clinical research center.
Material. Oral bioavailability data of ribavirin determined previously in six healthy adults.
Intervention. After 13C3-ribavirin 150 mg intravenously and unlabeled ribavirin 400 mg orally had been given 1 hour apart, serial serum and urine samples were obtained for up to 169 hours. Concentrations of 13C3-ribavirin and unlabeled ribavirin in serum and urine were determined by a high-performance liquid chromatography tandem mass spectrometric method.
Measurements and Main Results. Serum and urine concentration-time profiles were comodeled with a three-compartment model. The analysis was performed again by using the nonparametric population analysis technique. Serum ribavirin concentrations underwent Monte Carlo simulation for 1000 subjects receiving a single 600-mg oral dose. Both methods were similar in determining the mean ± SD bioavailability (51.8 ± 21.8% by the two-stage method vs 54.8 ± 16.4% by nonparametric modeling, p=0.79). However, the estimates of dispersion of model parameters and simulated drug exposures were substantially reduced by the population-modeling technique, as it takes into account covariance among model parameters and intersubject variability.
Conclusion. Although the study sample was small, our parallel analyses of the same data set clearly demonstrated that more precise parameter estimates are likely to result with the population-modeling technique. Having accurate and precise estimation of population pharmacokinetic parameters and their true variances is crucial, as, at any dose, there will be a lower probability of encountering a concentration-driven toxicity because of fewer outliers as the variance associated with the parameters decreases.
Key Words: population pharmacokinetic modeling, ribavirin, bioavailability
(Pharmacotherapy 2003;23(12):1545-1549)
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Study Objective. To compare the relationship between serum and salivary concentrations of lamotrigine in pediatric and adult epilepsy populations.
Design. Paired-sample pharmacokinetic study.
Setting. University neurology clinic.
Patients. Thirty-seven patients with epilepsy, aged 2-60 years, who were taking lamotrigine and whose physicians had ordered a lamotrigine serum concentration.
Measurements and Main Results. Patients spit a minimum of 0.25 ml into a cup to provide saliva samples. Blood samples were obtained by phlebotomy. Serum and salivary lamotrigine concentrations were determined by high-performance liquid chromatography. Linear regression analysis was used to evaluate correlations. Six patients’ results were omitted due to the lack of a serum or saliva specimen or clearly erroneous results, leaving 31 patients for analysis. There was a strong correlation between the serum results reported by two reference laboratories (coefficient of correlation [r] = 0.988). The correlations between salivary and serum lamotrigine concentrations were similar for reference laboratory A (r = 0.81) and reference laboratory B (r = 0.84). Saliva:serum concentration ratios ranged from 0.41-1.26 (mean ± SD 0.62 ± 0.19) for reference laboratory A and from 0.40-1.19 ((mean ± SD 0.64 ± 0.18) for reference laboratory B.
Conclusion. There is a good correlation between salivary and serum concentrations for lamotrigine. However, there is wide interpatient variability in the saliva:serum ratio. The data suggest that salivary monitoring may play a role in the monitoring of lamotrigine for adult and pediatric patients.
Key Words: lamotrigine, salivary concentration, therapeutic drug monitoring, pharmacokinetics
(Pharmacotherapy 2003;23(12):1550-1557)
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Study Objective. To assess the influence of various clinical factors on antibody production induced by hepatitis B vaccine in patients receiving hemodialysis up to 24 months after vaccination.
Design. Retrospective cohort study.
Setting. Outpatient dialysis center.
Patients. Adult patients undergoing hemodialysis who received a three-dose series of intramuscular hepatitis B vaccine 40 µg at time 0, 1, and 6 months, according to protocol.
Measurements and Main Results. Antibody to hepatitis B surface antigen (anti-HBs) titers were monitored quarterly, and booster doses were given according to protocol. Patients with anti-HBs of at least 10 mIU/ml were considered seropositive. Clinical variables -- age, diabetes mellitus status, serum albumin level, and equilibrated Kt/V (eKt/V; Kt/V is a measure of urea clearance during dialysis, used to quantify the delivered dose of hemodialysis) -- were compared between seropositive and seronegative patients 12 months (cohort 1) and 24 months (cohort 2) after vaccination. In cohort 1 (66 patients), 24 (36.4%) were seropositive at 12 months. In cohort 2 (40 patients), 15 (37.5%) were seropositive at 24 months. Comparison of seropositive and seronegative patients revealed no statistically significant differences in mean age, sex, serum albumin level, or eKt/V. However, at 24 months, patients with diabetes were 2.5 times more likely to demonstrate seropositivity than those without diabetes (60% vs 24%, respectively, p=0.02).
Conclusion. Long-term seroprevalence induced by hepatitis B vaccine was low in our patients 12 and 24 months after vaccination. These results were comparable to previously reported long-term results. Larger, prospective studies would be needed to confirm the finding that patients with diabetes had superior hepatitis B vaccine-induced antibody production at 24 months.
Key Words: renal dialysis, hepatitis B, hepatitis B vaccine, diabetes mellitus
(Pharmacotherapy 2003;23(12):1558-1563)
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Study Objective. As the results of the Heart Outcomes Prevention Evaluation trial suggested that patients with both coronary artery disease (CAD) and diabetes mellitus would benefit from angiotensin-converting enzyme (ACE) inhibitor therapy, our objective was to increase the percentage of patients with both of these conditions receiving the goal dosage (20 mg/day) or highest tolerated dosage of the ACE inhibitor lisinopril through intervention of a clinical pharmacy service.
Study Design. Prospective study with historic comparison (control group).
Setting. Clinical Pharmacy Cardiac Risk Service.
Patients. Hospitalized patients with CAD and type 2 diabetes mellitus.
Measurements and Main Results. At hospital discharge, lisinopril 5 mg/day was started in eligible patients; the drug was titrated to a goal dosage of 20 mg/day or the highest tolerated dosage. Potassium level, serum creatinine level, and blood pressure were monitored at baseline, at each dosage titration, and 2 weeks after the goal or highest tolerated dosage was reached. The group receiving usual care (control group) consisted of 95 patients; the treatment group had 101 patients. At baseline, 19 patients (20%) in the control group were receiving the goal dosage of lisinopril, 34 (36%) were taking a suboptimal dosage, 16 (17%) were excluded from treatment, and 26 (27%) were eligible but were not receiving lisinopril therapy. After 9 months, ACE inhibitor dosages had changed minimally in the control group. In the treatment group, at baseline, 37 patients (36%) were at their goal dosage and therefore titration was not necessary; 15 (15%) were receiving a suboptimal dosage, 35 (35%) were excluded from treatment, and 14 (14%) were eligible but not receiving therapy. After the titration period, 55 (54%) treatment group patients were at the goal dosage, 11 (11%) were taking a suboptimal dosage, and 35 (35%) were not candidates for ACE inhibitor therapy. The most common reasons for exclusion were renal insufficiency, cough, and baseline hypotension. Changes in potassium level, serum creatinine level, and blood pressure were not significant during the study.
Conclusion. The clinical pharmacy service more than doubled the number of patients with CAD and diabetes who achieved the goal dosage of an ACE inhibitor, a drug class that has been shown to decrease morbidity and mortality in this patient population.
Key Words: lisinopril, coronary artery disease, diabetes mellitus, pharmacist
(Pharmacotherapy 2003;23(12):1564-1572)
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Over 16 million women in the United States take oral hormonal contraceptives, yet approximately 5% experience an unintended pregnancy during the first year of use. Compliance with the regimen is important in maintaining cycle control and preventing pregnancy. New hormonal contraceptive agents, norelgestromin-ethinyl estradiol patch, etonogestrel- ethinyl estradiol vaginal ring, and medroxyprogesterone-estradiol cypionate injection, were designed to increase compliance and decrease adverse effects while maintaining efficacy. Each one has potential advantages for women seeking alternatives to traditional oral contraceptives or for those who have trouble remembering to take a daily pill. Each agent also may have its own disadvantages, including application site reactions, need for monthly injections, and device-related events; however, all have similar efficacy and adverse-effect profiles compared with current oral hormonal contraceptives.
Key Words: transdermal contraceptive patch, injectable hormonal contraceptive, contraceptive vaginal ring, ethinyl estradiol, etonogestrel, norelgestromin, estradiol cypionate, medroxyprogesterone, hormonal contraception.
(Pharmacotherapy 2003;23(12):1573-1591)
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Invasive aspergillosis is an increasingly common and often fatal opportunistic fungal infection in patients with hematologic malignancies. Prolonged and profound neutropenia remains a key risk factor for the development of invasive aspergillosis. However, qualitative deficiencies in host immune responses resulting from prolonged corticosteroid therapy, graft-versus-host disease, and cytomegalovirus infection are important risk factors for the recurrence and progression of Aspergillus infections after bone marrow recovery. Early diagnosis of invasive aspergillosis remains a challenge, and few tools are available for monitoring its course once the diagnosis is established. Even with the recent introduction of new antifungal therapies, mortality in patients with invasive aspergillosis remains high, and uniformly effective prophylaxis or preemptive therapeutic strategies are lacking. Strategies such as combination antifungal therapy and immunotherapy often are used as first-line treatment approaches in patients with documented invasive aspergillosis despite a paucity of clinical trial data. Recent advances in our understanding of the epidemiology, pathogenesis, and treatment of invasive aspergillosis in patients with hematologic malignancies are reviewed. The problems and controversies associated with defining optimal treatment strategies for invasive aspergillosis in this heavily immunocompromised population are highlighted.
Key Words: aspergillosis, antifungal therapy, hematologic malignancies
(Pharmacotherapy 2003;23(12):1592-1610)
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Study Objective. To quantify the relative risk of cardiovascular events associated with microalbuminuria in patients with both diabetes mellitus and hypertension.
Design. A structured literature search from January 1990-December 2002 using MEDLINE, IPA, and CINAHL.
Measurements and Main Results. We identified original studies that reported the presence or absence of microalbuminuria and estimates of risk associated with cardiovascular events in patients with both diabetes and hypertension. Abstracted information consisted of study design, patient demographics and risk factors, treatment regimens, and outcome variables. Point estimates and confidence intervals for relative risk were calculated from available data. Of 651 citations identified and reviewed based on title and abstract, 72 were selected for full review. Seven met the inclusion criteria. Because of lack of homogeneity among studies, the results were not conducive to pooling. Cardiovascular end points associated with the presence of microalbuminuria in these studies were all-cause mortality, cardiovascular mortality, and composite cardiovascular morbidity. The relative risk of cardiovascular end points associated with the presence of microalbuminuria ranged from 1.6 (95% confidence interval [CI] 1.2-2.2) to 7.9 (95% CI 2.5-25.3.
Conclusion. From the limited information available, the risk of cardiovascular events and mortality is estimated to be 2-8 times higher when microalbuminuria is present in patients with diabetes and hypertension. Point estimates in relative risk of cardiovascular morbidity and mortality in patients with diabetes and hypertension were generally higher compared with studies estimating risk in those with only diabetes. Studies that examine the relationship between microalbuminuria (scaled as a continuous or ordinal variable) and cardiovascular events are necessary to clarify potential benefits of pharmacotherapies that reduce levels of urinary albumin.
Key Words: microalbuminuria, hypertension, diabetes mellitus, cardiovascular events
(Pharmacotherapy 2003;23(12):1611-1616)
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Radiographic contrast material-induced nephropathy (RCIN) is the third most common cause of hospital-acquired renal insufficiency and has been associated with an increase in patient mortality. Many strategies to prevent RCIN have been explored unsuccessfully. The standard of care remains hydration with 0.45% sodium chloride before and after administration of contrast material. Recently, N-acetylcysteine and fenoldopam have been studied to determine their efficacy in preventing RCIN. Of seven prospective studies using various dosing regimens of N-acetylcysteine, four revealed beneficial results. Although some discrepancies exist, the data strongly suggest that N-acetylcysteine has a role in patients at risk for the development of RCIN. The data for fenoldopam are more limited, with only one retrospective study showing benefit. Additional prospective data are required to determine if fenoldopam has a role in the prevention of RCIN.
Key Words: fenoldopam, N-acetylcysteine, nephropathy, radiographic contrast.
(Pharmacotherapy 2003;23(12):1617-1626)
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To minimize antibiotic resistance, pharmacists increasingly are becoming involved in antibiotic surveillance, formulation of antibiotic use policies, and day-to-day control of problematic antibiotic use. Population-based antibiotic surveillance has become common with the proliferation of electronic databases. The most widely applied measure of antibiotic consumption is the defined daily dose/1000 patient days. Most studies correlating antibiotic consumption with resistance have focused on antibiogram-related end points; antibiogram data generally reflect institutional nosocomial infection patterns. Most study designs have been derived from traditional epidemiology such as case-control with regression modeling or simple linear regression; however, these methods have limitations. Several experimental designs show promise. Many historical-control studies, including a multicentered study, suggest that population-based antibiotic surveillance and policy intervention can decrease antibiotic resistance in hospitals. Further research on the relationships among antibiotic surveillance, structured antibiotic policy interventions, and other microbiologic, patient-oriented, and economic end points is needed.
Key Words: antibiotics, resistance, surveillance.
(Pharmacotherapy 2003;23(12):1627-1633)
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Efforts to improve the outcomes of patients with mental illness often have involved incorporating the skills of a variety of health care professionals into collaborative care models. For over 30 years, clinical pharmacists have contributed to these care models in capacities ranging from educator to consultant to provider. This systematic review evaluates the quantity and quality of medical literature examining the impact of pharmacists in mental health from 1972-2003. Although we identified approximately 35 publications describing the roles of clinical pharmacists in this regard, only 16 were of sufficient scientific rigor to permit evaluation and comparison. The 16 studies were divided equally between inpatient and outpatient settings and were conducted in a variety of health care organizations (e.g., Veterans Administration, health maintenance organizations, community mental health clinics, and nursing homes). Nine of the studies examined the role of pharmacists in providing treatment recommendations and patient education, five featured pharmacists as providers (with prescriptive authority), and the remaining two described the impact pharmacists have in delivering education to the psychiatric staff. Six of the 16 studies were prospective, but only three of these incorporated a randomization procedure for patients or facilities. Collectively, the results of the 16 studies were positive, demonstrating improvements in outcomes, prescribing practices, patient satisfaction, and resource use. Unfortunately, most of the investigations were small, and significant limitations in study design limited further comparison. Given the long history and anecdotal success of pharmacists in mental health care settings, additional multicenter cost-effectiveness trials are warranted to further support the role of the psychiatric pharmacist.
Key Words: pharmacists, behavioral health, mental health, collaborative care, psychiatry, disease management.
(Pharmacotherapy 2003;23(12):1634-1644)
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A 45-year-old woman was hospitalized to rule out acute myocardial infarction after coming to the emergency department with a complaint of substernal chest pressure. Her initial electrocardiogram indicated normal sinus rhythm with T-wave inversion and nonspecific ST changes suggestive of possible ischemia. She had no medical problems and took no prescription drugs. Further evaluation revealed that for approximately 4 years she had been taking Metabolife 356 preparations -- a source of ephedrine alkaloids -- for weight loss, and that she was at low risk for atherosclerotic coronary artery disease. Due to elevated cardiac markers, cardiac catheterization was performed, which revealed no atherosclerosis in the coronary arteries. The patient’s acute myocardial infarction was attributed to coronary artery vasospasm induced by ephedrine alkaloids. Clinicians should be aware of the growing evidence that supports life-threatening cardiovascular toxicities associated with these substances.
Key Words: myocardial infarction, ephedrine alkaloids, ephedra.
(Pharmacotherapy 2003;23(12):1645-1651)
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A 42-year-old man was brought to the emergency department with ethylene glycol intoxication. He was hemodynamically stable and had normal renal function. His serum ethylene glycol concentration was 284 mg/dl approximately 1 hour after ethylene glycol consumption. The patient was treated with fomepizole and forced diuresis. Elimination of ethylene glycol in this patient followed first-order pharmacokinetics. Elimination pharmacokinetics in this patient were compared with that in a patient who received fomepizole and hemodialysis. Fomepizole monotherapy can be given in patients without renal failure or metabolic acidosis even with serum ethylene glycol concentrations greater than 50 mg/dl. However, cost estimates based on this case suggest that if the patient is treated adequately with a single hemodialysis session and 24-hour hospitalization, then fomepizole monotherapy may be more expensive than the combination regimen of fomepizole and hemodialysis.
Key Words: ethylene glycol, renal dialysis, poisoning, case report, antidotes.
(Pharmacotherapy 2003;23(12):1652-1658)
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A 15-year-old Caucasian boy experienced severe fever, fatigue, and a 40-lb weight loss after 2 years of minocycline therapy. A workup for infectious causes was negative. One week after minocycline discontinuation, the patient reported that his fever had resolved. Two months later, he reported full resolution of symptoms, weight gain, and a return to normal activity. An objective causality assessment indicated that his illness probably was caused by minocycline, which is considered a safe drug; however, it has been associated with rare serious adverse effects. This patient’s presentation of fever was noteworthy not only because minocycline is a rare cause of drug fever, but also because of the delayed onset. Clinicians should be aware that minocycline may cause severe fever and illness even after an extended period of drug exposure.
Key Words: minocycline, drug fever.
(Pharmacotherapy 2003;23(12):1659-1662)
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Clinical guidelines for cholesterol testing and management have been updated recently. With the evolving recognition of benefits and intensified recommendations for cholesterol management, many more patients will require cholesterol-lowering drugs. All the statins share similar adverse-effect profiles, with a low overall frequency of undesirable effects. Emerging data associate statins with a decreased risk of Alzheimer’s disease; however, we report two women who experienced significant cognitive impairment temporally related to statin therapy. One woman took atorvastatin, and the other first took atorvastatin, then was rechallenged with simvastatin. Clinicians should be aware of cognitive impairment and dementia as potential adverse effects associated with statin therapy.
Key Words: atorvastatin, simvastatin, statins, cognitive impairment.
(Pharmacotherapy 2003;23(12):1663-1667)
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A 30-g venlafaxine overdose resulted in death for a 39-year-old woman whose 43-day clinical course was highlighted by refractory hypotension and the resulting complications of bowel ischemia and perforation. Her venlafaxine and O-desmethylvenlafaxine levels, analyzed by high-performance liquid chromatography one day after ingestion, were 21.82 mg/L (therapeutic range 0.1-0.5 mg/L) and 3.33 mg/L (0.2-0.4 mg/L), respectively. These levels remained elevated for over 7 days. Postulated explanations for these extended elevated levels were saturation of drug metabolism, decreased drug metabolism, and existence of a genetic polymorphism. Our patient’s venlafaxine overdose produced a wide variety of clinical challenges, to include seizures, tachycardia, decreased level of consciousness, refractory hypotension, and bowel dysmotility. In addition, this case augments the growing body of literature that suggests that venlafaxine may be fatal in overdose situations.
Key Words: venlafaxine, overdose, pharmacokinetics, metabolism.
(Pharmacotherapy 2003;23(12):1668-1672)
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