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Background: Fluid overload (FO) in the intensive care unit (ICU) is common, serious, and may be preventable. Intravenous medications (including administered volume) are a primary cause for FO but are challenging to evaluate as a FO predictor given the high frequency and time-dependency of their use and other factors affecting FO. We sought to employ unsupervised machine learning methods to uncover medication administration patterns correlating with FO., Methods: This retrospective cohort study included 927 adults admitted to an ICU for ≥72 h. FO was defined as a positive fluid balance ≥7% of admission body weight. After reviewing medication administration record data in 3-h periods, medication exposure was categorized into clusters using principal component analysis (PCA) and Restricted Boltzmann Machine (RBM). Medication regimens of patients with and without FO were compared within clusters to assess their temporal association with FO., Results: FO occurred in 127 (13.7%) of 927 included patients. Patients received a median (interquartile range) of 31(13-65) discrete intravenous medication administrations over the 72-h period. Across all 47,803 intravenous medication administrations, 10 unique medication clusters, containing 121 to 130 medications per cluster, were identified. The mean number of Cluster 7 medications administered was significantly greater in the FO cohort compared with patients without FO (25.6 vs.10.9, p < 0.0001). A total of 51 (40.2%) of 127 unique Cluster 7 medications were administered in more than five different 3-h periods during the 72-h study window. The most common Cluster 7 medications included continuous infusions, antibiotics, and sedatives/analgesics. Addition of Cluster 7 medications to an FO prediction model including the Acute Physiologic and Chronic Health Evaluation (APACHE) II score and receipt of diuretics improved model predictiveness from an Area Under the Receiver Operation Characteristic (AUROC) curve of 0.719 to 0.741 (p = 0.027)., Conclusions: Using machine learning approaches, a unique medication cluster was strongly associated with FO. Incorporation of this cluster improved the ability to predict FO compared to traditional prediction models. Integration of this approach into real-time clinical applications may improve early detection of FO to facilitate timely intervention., (© 2025 Pharmacotherapy Publications, Inc.)

The avian influenza is a serious infection caused by influenza virus that is native to birds. Avian influenza remains a global challenge due to high transmission and mortality rates. The highly pathogenic strain of H5N1 resulted in significant outbreaks and deaths globally since the late 1800s. The most recent outbreaks in wild birds, domestic birds, and cows with some genetic variations and mutations among H5N1 strains has raised major concerns about potential transmission and public health risks. Symptoms range from asymptomatic to mild flu-like illness to severe illness that requires hospitalization. There are multiple vaccines in development for humans to protect against avian influenza, specifically the H5N1 virus. This includes a cell-based vaccine approved by the FDA for people aged 6 months and older who are at higher risk of exposure to the H5N1 virus called Audenz. Chemoprophylaxis against avian influenza following a suspected exposure should be started as soon as possible or no later than 48 h, and it is recommended to be continued for 7 days. The majority of avian influenza viruses are susceptible to neuraminidase inhibitors and cap-dependent endonuclease inhibitor. Neuraminidase inhibitors are the mainstay of the avian influenza treatment and includes oseltamivir, peramivir, and zanamivir. Baloxavir marboxil is a cap-dependent endonuclease inhibitor. This clinical review aims to highlight the background, epidemiology, clinical presentation, complications and current treatment and prevention strategies for avian influenza H5N1., (© 2024 Pharmacotherapy Publications, Inc.)

Cannabinoids have emerged as a potential treatment for obstructive sleep apnea (OSA). This systematic review aimed to summarize the efficacy and safety of cannabinoids to treat OSA. Databases including Ovid MEDLINE, EMBASE, Scopus, PsycINFO, and International Pharmaceutical Abstracts were searched; experimental and observational studies were eligible for inclusion. One-hundred seventy unique records were screened, and nine studies included: five full-text studies and four published abstracts. The five full-text studies were judged for quality appraisal: two studies deemed at low risk for bias, one study deemed to have some concerns for bias, and two studies deemed to have high risk for bias. Seven of nine total studies were experimental designs and evaluated dronabinol, and the other two studies were observational designs evaluating cannabis. The range of cannabinoid therapy duration spanned from 1 to 6 weeks, and the median duration was 3 weeks. Eight of nine total studies reported statistically significant, positive OSA outcomes due to cannabinoid therapy including reductions in the apnea hypopnea index and improvements in patient-reported daytime sleepiness scales. Between 70% and 80% of study participants reported neuropsychiatric and gastrointestinal adverse events attributable to cannabinoids. The American Academy of Sleep Medicine does not recommend using cannabinoids to treat OSA due to a lack of long-term safety and efficacy data. This systematic review found similar limitations, with the median cannabinoid treatment duration being only 3 weeks. Adequately powered experimental trials over longer time frames are necessary to more completely assess the long-term efficacy and safety of cannabinoids in the treatment of OSA and its effects on common comorbid conditions, such as obesity and cardiovascular disease., (© 2024 Pharmacotherapy Publications, Inc.)

Treatment options are currently limited for persons with HIV-1 (PWH) who are heavily treatment-experienced and/or have multidrug-resistant HIV-1. Three agents have been approved by the U.S. Food and Drug Administration (FDA) since 2018, representing a significant advancement for this population: ibalizumab, fostemsavir, and lenacapavir. However, there is a paucity of recommendations endorsed by national and international guidelines describing the optimal use (e.g., selection and monitoring after initiation) of these novel antiretrovirals in this population. To address this gap, a modified Delphi technique was used to develop these consensus recommendations that establish a framework for initiating and managing ibalizumab, fostemsavir, or lenacapavir in PWH who are heavily treatment-experienced and/or have multidrug-resistant HIV-1. In addition, future areas of research are also identified and discussed in the main document., (© 2024 The Authors. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy published by Wiley Periodicals LLC on behalf of Pharmacotherapy Publications, Inc.)

Treatment options are currently limited for persons with HIV-1 (PWH) who are heavily treatment-experienced and/or have multidrug-resistant HIV-1. Three agents have been approved by the U.S. Food and Drug Administration (FDA) since 2018, representing a significant advancement for this population: ibalizumab, fostemsavir, and lenacapavir. However, there is a paucity of recommendations endorsed by national and international guidelines describing the optimal use (e.g., selection and monitoring after initiation) of these novel antiretrovirals in this population. To address this gap, a modified Delphi technique was used to develop these consensus recommendations that establish a framework for initiating and managing ibalizumab, fostemsavir, or lenacapavir in PWH who are heavily treatment-experienced and/or have multidrug-resistant HIV-1. In addition, future areas of research are also identified and discussed., (© 2024 The Authors. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy published by Wiley Periodicals LLC on behalf of Pharmacotherapy Publications, Inc.)

Maternal mortality continues to be an issue globally despite advances in technology and pharmacotherapy. Pregnancy can lead to complications that necessitate immediate action to prevent severe morbidity and mortality. Patients may need escalation to the ICU setting for close monitoring and administration of advanced therapies not available elsewhere. Obstetric emergencies are rare but high-stakes events that require clinicians to have prompt identification and management. The purpose of this review is to describe complications of pregnancy and provide a focused resource of pharmacotherapy considerations that clinicians may encounter. For each disease state, the epidemiology, pathophysiology, and management are summarized. Brief descriptions of non-pharmacological (e.g., cesarean or vaginal delivery of the baby) interventions are provided. Mainstays of pharmacotherapy highlighted include oxytocin for obstetric hemorrhage, methotrexate for ectopic pregnancy, magnesium and antihypertensive agents for preeclampsia and eclampsia, eculizumab for atypical hemolytic uremic syndrome, corticosteroids, and immunosuppressive agents for thrombotic thrombocytopenic purpura, diuretics, metoprolol, and anticoagulation for peripartum cardiomyopathy, and pulmonary vasodilators for amniotic fluid embolism., (© 2023 Pharmacotherapy Publications, Inc.)

Safe and thoughtful medication management of pregnant patients requiring intensive care unit (ICU) level of care is key to optimizing outcomes for both mother and fetus. Pregnancy induces physiologic alterations that closely mirror the changes expected in a critically ill patient. These changes can be predictable depending on the gestational age and trimester and will directly impact the pharmacokinetic profile of medications commonly used in the ICU; examples include decreased gastric emptying, increased blood and plasma volume, increased glomerular filtration, and increased cardiac output. When pregnant patients require ICU care, the resulting impact on drug absorption, distribution, metabolism, and elimination can be difficult to predict. In addition, there are many nuances of medication metabolism and interface with the placental barrier that should be considered when selecting pharmacotherapy for the pregnant patient. Critical care clinicians need to be aware of medication interactions with the placenta and weigh the risk versus benefit profile of medication use in this patient population. Obstetric critical care admissions have increased over the years, especially during the coronavirus waves. Therefore, understanding the interplay between pregnancy and critical illness to optimize pharmacotherapy selection is crucial to improving health outcomes of mother and fetus. This review highlights pharmacotherapy considerations in the pregnant ICU patient for the following topics: physiologic alterations, categorizing medication risk, supportive care, sepsis, cardiogenic shock, acute respiratory distress syndrome, and venous thromboembolism., (© 2023 Pharmacotherapy Publications, Inc.)

The HIV epidemic continues to pose a significant burden on the healthcare system. Although the incidence of annual new infections is decreasing, health disparities persist and most new infections remain concentrated into different racial, ethnic, and minority groups. Pre-exposure prophylaxis (PrEP), which involves those at high risk of acquiring HIV to take chronic medications to prevent acquisition of the virus, is key to preventing new HIV infections. The purpose of this article is to review medication therapies for PrEP and examine their role in personalizing PrEP in different patient populations. Additionally, new medications currently under development for PrEP are reviewed, as well as treatment as prevention (TasP) and post-exposure prophylaxis (PEP). There are currently four medications available for PrEP: the oral options of co-formulated emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or emtricitabine/tenofovir alafenamide (FTC/TAF); injectable long-acting cabotegravir (CAB-LA); and the vaginal ring dapivirine (DPV-VR). FTC/TAF is not currently indicated for persons at risk for HIV through vaginal sex due to lack of studies, but trials are currently ongoing. DPV-VR is available in Zimbabwe and South Africa and has been endorsed by the World Health Organization but is not currently available in the United States. Several agents are also in development for use in PrEP: the novel long-acting injectable lenacapavir, a first-in-class capsid inhibitor, which has no cross-resistance to any existing HIV drug class; the subdermal implant islatravir, a first-in-class translocation inhibitor; and VRC01, a broadly neutralizing antibody (bnAb) which has been evaluated in proof-of-concept studies that may lead to the development of more potent bnAbs. Overall, PrEP is highly effective at preventing HIV infection in high-risk populations. Identifying optimal PrEP regimens in different patient populations is complex and must consider patient-specific factors and medication cost and access considerations. Lastly, providers should consider individual patient preferences with regard to prevention to improve access, retention in care, and adherence., (© 2023 The Authors. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy published by Wiley Periodicals LLC on behalf of Pharmacotherapy Publications, Inc.)

Study Objective: The purpose of this study was to evaluate the utility of routine anti-Xa peak monitoring for trauma patients initiated on weight-based enoxaparin for venous thromboembolism (VTE) prophylaxis and identify patient populations where monitoring is necessary., Design: Retrospective study., Setting: Augusta University (AU) Medical Center in Augusta, Georgia, a level 1 trauma center., Patients: Adult patients admitted to the trauma surgery service requiring chemical VTE prophylaxis., Intervention: At least three consecutive doses of enoxaparin 0.5 mg/kg subcutaneously every 12 hour for VTE prophylaxis prior to an anti-Xa peak as the initial chemical VTE prophylaxis strategy., Measurements: The primary end point was the percentage of patients who achieved goal anti-Xa peak of 0.2-0.6 unit/ml. The incidence of newly diagnosed VTE and clinically significant bleeding were assessed as secondary end points., Main Results: From January 1, 2018, through February 28, 2019, 300 patients met inclusion criteria. Anti-Xa peaks were within goal in 91% of all patients, 7.7% were below goal, and 1.3% were above goal. For patients who did not meet the goal, dose adjustments were made in 70.4% of patients. New levels were obtained in 73.7% of those patients, and all repeat levels was within goal. Clinically significant bleeding occurred in 5.3% of patients. Newly diagnosed VTE occurred in 1.7% of patients., Conclusions: The use of initial weight-based enoxaparin dosing in trauma patients routinely achieved the prespecified target anti-Xa goal. In conclusion, anti-Xa levels are not necessary for routine monitoring of weight-based enoxaparin for VTE prophylaxis in trauma patients. Incidence of clinically significant bleeding and newly diagnosed VTE were similar to previous studies., (© 2021 Pharmacotherapy Publications, Inc.)

Therapeutic drug management is regularly performed for aminoglycosides in an effort to maximize their effectiveness and safety. The ratio of maximum plasma drug concentration to minimum inhibitory concentration (Cmax/MIC) has long been regarded as the primary pharmacokinetic/pharmacodynamic (PK/PD) index of clinical efficacy for aminoglycosides due to their concentration-dependent killing. In this review, however, we discuss why the area under the plasma concentration-time curve (AUC)/MIC ratio may be a more reliable indicator of bacterial killing and clinical efficacy for these agents. The definitive AUC/MIC efficacy targets for aminoglycosides are less clear, unlike those that exist for fluoroquinolones. Evaluation of available literature suggests that an AUC/MIC ratio of 30-50 for aminoglycoside therapy may provide optimal outcomes when targeting non-critically ill immunocompetent patients with low-bacterial burden gram-negative infections such as urinary tract infections or in patients receiving additional gram-negative therapy with good source control. However, an AUC/MIC target of 80-100 may be more prudent when treating patients with aminoglycoside monotherapy or in critically ill patients with high-bacterial burden infections, such as nosocomial pneumonia. Reappraisal of current antimicrobial susceptibility breakpoints for aminoglycosides against gram-negative bacteria may also be necessary to achieve these AUC/MIC targets and ensure that current empiric doses are not grossly suboptimal in critically ill patients. Although it has been historically difficult to calculate AUCs in clinical practice, equation-based and Bayesian approaches now can be used to estimate the AUC in clinical practice, with limited PK sampling. Additional research is needed to better define optimal AUC/MIC targets for efficacy, especially when drugs are used in combination, as well as PK/PD targets associated with suppression of resistance. It is also important to determine if AUC can predict nephrotoxicity of these agents or whether trough concentrations should be used instead., (© 2018 Pharmacotherapy Publications, Inc.)

Antiretroviral (ART) therapy for the treatment of human immunodeficiency virus (HIV) infection has undergone significant changes over the past 30 years. Many single-tablet regimens (STRs), including newer fixed-dose combination (FDC) tablets, are available, offering patients several options for choosing a treatment regimen that works best for them. Given these changes, patients are more likely to adhere to treatment, achieve better clinical outcomes, and experience both fewer side effects and drug-drug interactions. Newer STRs include dolutegravir (DTG)/lamivudine (3TC)/abacavir (ABC) (Triumeq; Viiv Healthcare, Research Triangle Park, NC), rilpivirine (RPV)/emtricitabine (FTC)/tenofovir alafenamide (TAF) (Odefsey; Gilead, Foster City, CA), RPV/FTC/tenofovir disoproxil fumarate (TDF) (Complera; Gilead), elvitegravir (EVG)/cobicistat (COBI)/FTC/TDF (Stribild; Gilead), and EVG/COBI/FTC/TAF (Genvoya; Gilead). Recently approved FDCs, such as atazanavir (ATV)/COBI (Evotaz; Bristol-Myers Squibb, Princeton, NJ), darunavir (DRV)/COBI (Prezcobix; Janssen Products, Titusville NJ), and FTC/TAF (Descovy; Gilead), are also now available. The Department of Health and Human Services treatment guidelines for HIV recommend many of these integrase strand transfer inhibitor (INSTI) STRs as a preferred choice for initiation of treatment in both ART-naive and -experienced patients because they offer comparably faster rates of virologic suppression, reduced rates of resistance development (especially with DTG), and overall better adherence than protease inhibitors or NNRTIs. Numerous phase 3 clinical trials support these recommendations including several switch or simplification clinical trials. Notably, the novel pharmacokinetic booster COBI, with its water soluble properties, has enabled the development and coformulation of a few of these STRs and FDCs. Also, a newer tenofovir salt formulation, TAF, has an advantageous pharmacokinetic profile, contributing to better overall renal and bone tolerability compared with TDF. Further simplification regimens comprising dual ART therapies are currently being explored. This review provides an overview of the clinical efficacy and safety data for these coformulated agents, highlighting the relative impact on comparative adverse events, assessing the potential for experiencing fewer drug-drug interactions, and discussing the clinical implications regarding adherence to treatment., (© 2017 Pharmacotherapy Publications, Inc.)

Pregnant women with opioid use disorder can be treated with methadone, buprenorphine, or naltrexone to reduce opioid use and improve retention to treatment. In this review, we compare the pregnancy outcomes of methadone, buprenorphine, and naltrexone in clinical trials and discuss the potential behavioral and developmental effects of these agents seen in offspring in animal studies. Important clinical considerations in the management of opioid use disorder in pregnant women and their infants are also discussed. Outside of pregnancy, buprenorphine is used in combination with naloxone to reduce opioid abuse and diversion. During pregnancy, however, the use of buprenorphine as a single agent is preferred to prevent prenatal naloxone exposure. Both methadone and buprenorphine are widely used to treat opioid use disorder; however, compared with methadone, buprenorphine is associated with shorter treatment duration, less medication needed to treat neonatal abstinence syndrome (NAS) symptoms, and shorter hospitalizations for neonates. Despite being the standard of care, medication-assisted treatment with methadone or buprenorphine is still underused, making it apparent that more options are necessary. Naltrexone is not a first-line treatment primarily because both detoxification and an opioid-free period are required. More research is needed to determine naltrexone safety and benefits in pregnant women. Animal studies suggest that changes in pain sensitivity, developmental processes, and behavioral responses may occur in children born to mothers receiving methadone, buprenorphine, or naltrexone and is an area that warrants future studies., (© 2017 Pharmacotherapy Publications, Inc.)

The prevention and treatment of chemotherapy-induced nausea and vomiting (CINV) continues to pose a challenge for clinicians. The development of 5-hydroxytryptamine (serotonin) antagonists and neurokinin-1 receptor antagonists (NK1 -RAs) have demonstrated significant improvements in acute and delayed CINV for highly and moderately emetogenic chemotherapy. Delayed and breakthrough CINV, however, continue to be difficult to manage despite available treatment agents. Randomized clinical trial data suggest that olanzapine, a second-generation thienobenzodiazepine, traditionally used in the treatment of manifestations of psychotic disorders, is an effective agent in these clinical settings. The short-term use of olanzapine has a favorable adverse event profile and was not associated with grade 3 or 4 toxicity in a phase III study. Olanzapine is recommended as an option within first-line prophylaxis for CINV in the National Comprehensive Cancer Network (NCCN) guidelines and is an option for treatment of refractory CINV in the Multinational Association of Supportive Care in Cancer/European Society for Medical Oncology and NCCN guidelines., (© 2016 Pharmacotherapy Publications, Inc.)

During pregnancy, untreated sexually transmitted or urinary tract infections are associated with significant morbidity, including low birth weight, preterm birth, and spontaneous abortion. Approximately one in four women will be prescribed an antibiotic during pregnancy, accounting for nearly 80% of prescription medications in pregnant women. Antibiotic exposures during pregnancy have been associated with both short-term (e.g., congenital abnormalities) and long-term effects (e.g., changes in gut microbiome, asthma, atopic dermatitis) in the newborn. However, it is estimated that only 10% of medications have sufficient data related to safe and effective use in pregnancy. Antibiotics such as beta-lactams, vancomycin, nitrofurantoin, metronidazole, clindamycin, and fosfomycin are generally considered safe and effective in pregnancy. Fluoroquinolones and tetracyclines are generally avoided in pregnancy. Physiologic changes in pregnancy lead to an increase in glomerular filtration rate, increase in total body volume, and enhanced cardiac output. These changes may lead to pharmacokinetic alterations in antibiotics that require dose adjustment or careful monitoring and assessment., (© 2015 Pharmacotherapy Publications, Inc.)

Study Objective: To determine whether granulocyte colony-stimulating factor (G-CSF) prophylaxis after consolidation with high- or intermediate-dose cytarabine (H/IDAC) for treatment of acute myeloid leukemia (AML) reduces the frequency of neutropenia-associated complications., Design: Retrospective medical record review., Setting: Academic medical center., Patients: Seventy-eight patients aged 18 years or older in whom H/IDAC consolidation chemotherapy was initiated for consolidation of AML between November 2004 and November 2010., Measurements and Main Results: Patient demographic data, information on the hospitalization for consolidation, data on G-CSF use after H/IDAC chemotherapy, and details on any readmissions were collected. Patients were deemed to have received G-CSF prophylaxis if there was documentation of the intent for use of either filgrastim or pegfilgrastim. Outcome data also were collected, including dates of relapse or second induction treatment course, and death or last follow-up visit. We compared data based on patient receipt of G-CSF (G-CSF vs no G-CSF) after each chemotherapy cycle. We assessed differences in the duration of hospitalization, fever, intravenous antibiotic use, and neutropenia, as well as rate of documented infections, time to disease recurrence, and overall survival. Compared with no G-CSF, use of G-CSF after cycle 1 of H/IDAC significantly reduced the rate of hospitalization for febrile neutropenia (p=0.039); however, no significant differences were noted for subsequent cycles. No significant differences were seen in duration of hospitalization, rate of documented infections, or time to treatment failure between groups. Overall survival was longer for patients who received G-CSF during their first cycle (p=0.018) and for those who received G-CSF during any of their cycles (p=0.04)., Conclusion: Use of G-CSF prophylaxis after cycle 1 of H/IDAC consolidation for AML appears to reduce the frequency of hospitalization for febrile neutropenia and to increase overall survival compared with no G-CSF use. Prospective, controlled studies are needed to support our findings., (© 2012 Pharmacotherapy Publications, Inc.)

Approximately 50% of patients hospitalized for stroke develop fever. In fact, experimental evidence suggests that high body temperature is significantly correlated to initial stroke severity, lesion size, mortality, and neurologic outcome. Fever occurring after stroke is associated with poor outcomes. We investigated the etiology of fever after stroke and present evidence evaluating the efficacy and safety of interventions used to treat stroke-associated fever. Oral antipyretics are only marginally effective in lowering elevated body temperature in this population and may have unintended adverse consequences. Nonpharmacologic approaches to cooling have been more effective in achieving normothermia, but whether stroke outcomes can be improved remains unclear. We recommend using body temperature as a biomarker and a catalyst for aggressive investigation for an infectious etiology. Care must be taken not to exceed the new standard of a maximum acetaminophen dose of 3 g/day to avoid patient harm.

Negative symptoms of schizophrenia are characterized by affective flattening, alogia, avolition, and anhedonia and are often nonresponsive to antipsychotic therapy. Because negative symptoms are predictive of poor occupational and social functioning, as well as poor global outcomes, numerous studies evaluating adjunct therapy to antipsychotics have been conducted. This review focuses on the use of the antidepressant mirtazapine as adjunct therapy to antipsychotics for the treatment of negative symptoms of schizophrenia. A literature search of the MEDLINE database (from inception-March 2011) identified eight relevant articles: six were randomized, double-blind, placebo-controlled trials, and two were open-label trials. Of the six randomized trials reviewed, four studies assessed add-on mirtazapine to second-generation antipsychotics, whereas two studies examined add-on mirtazapine to first-generation antipsychotics. Five of the six randomized trials supported the use of mirtazapine for negative symptoms of schizophrenia. Of the two open-label trials, one naturalistic study demonstrated that mirtazapine add-on therapy to clozapine was not associated with improvements in negative symptoms; however, this study focused primarily on improvements in cognition, not negative symptoms. An open-label extension phase to a randomized controlled trial showed that mirtazapine continued to produce significant improvement in negative symptoms over a longer duration of time, when added to first-generation antipsychotic therapy. Overall, mirtazapine appears to be well tolerated and associated with few drug interactions. Although adjunct mirtazapine to antipsychotics has been shown to be effective at doses of 30 mg/day in most of the trials, limitations of these studies include short study duration and small sample sizes. To improve generalizability, larger multicenter studies with broader inclusion criteria should be conducted. In addition, studies of longer duration that use different mirtazapine dosages are needed to further assess the benefits of mirtazapine for negative symptoms of schizophrenia.

A literature search was conducted to examine the safety and effectiveness of low-dosage methotrexate for treatment and maintenance of remission in patients with inflammatory bowel disease. Nine published articles indicated that for patients with Crohn's disease, oral or intramuscular methotrexate 20-25 mg/week is safe and effective to induce remission, followed by a lower dosage to maintain remission. In addition, methotrexate allows for corticosteroid dosage reduction. Therapy may be continued until the disease flares or adverse events occur. Evidence is insufficient to support methotrexate as treatment for ulcerative colitis.

Endothelin (ET)-1 is an endothelium-derived peptide with potent vasoconstrictor and proliferative properties. The ET system is activated in several cardiovascular disease states associated with functional and structural vascular changes, including hypertension and heart failure. The two ET receptor subtypes are known as ET(A)R and ET(B)R. The former is located mainly on vascular smooth muscle cells and is responsible for mediating vasoconstriction and proliferation. The latter is present predominantly on endothelial cells and mediates vasorelaxation as well as ET-1 clearance. Activation of smooth muscle ET(B)R causes vasoconstriction. Selective ET(A)R antagonists as well as nonselective ET(A)R-ET(B)R antagonists have been developed. Studies with animal models and early-phase clinical trials provided strong evidence that these agents are effective in the treatment of heart failure, essential hypertension, pulmonary hypertension, and atherosclerosis. However, the complexity of biologic effects mediated by two different receptor subtypes complicates therapy with selective versus nonselective ET receptor antagonists. In addition to subtype selectivity and potency, changes in receptor subtype distribution under different pathologic conditions and different patient populations will play a crucial role in the evaluation of these potentially therapeutic drugs.

Study Objective: To document the health-related quality of life (HRQOL) of depressed patients receiving antidepressant drugs., Design: Cross-sectional study., Setting: Community pharmacy-based setting., Patients: Fifty-seven depressed patients., Intervention: Independent pharmacist members of the Community Pharmacists Research Network in Georgia administered the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) to subjects., Measurements and Main Results: Sixty-one percent of patients were treated with a selective serotonin reuptake inhibitor (SSRI) and 38.6% were treated with a non-SSRI. Those receiving SSRIs scored higher on the mean physical (PCS) and mental (MCS) health summary scores of the SF-36 than those not receiving the drugs. No significant differences were seen in PCS or MCS scores of men and women., Conclusion: Community pharmacists documented better HRQOL in patients receiving SSRIs than in those given other antidepressants.

An area of unidirectional conduction block is one requirement for reentrant arrhythmias to occur. Functional block caused by dispersion of repolarization and refractoriness is the most probable mechanism of drug-induced unidirectional conduction block. We assessed the effects of lidocaine on spatial dispersion of myocardial repolarization and refractoriness in the intact porcine heart. Monophasic action potential duration at 90% repolarization, effective refractory period (ERP), and ventricular fibrillation cycle length (VFCL) were measured at two endocardial and one epicardial sites at baseline and during a treatment phase with D5W (n=11) or lidocaine 10 mg/kg/hour (n=12). Dispersion was calculated as the difference between the maximum and minimum values of the three recording sites. Lidocaine produced significant changes in ERP, VFCL, paced QRS duration, and intraventricular conduction time. It did not change basal levels of dispersion in repolarization and refractoriness. Lidocaine produced changes in myocardial electrophysiology that are uniform across the myocardium and thus did not change myocardial electrical heterogeneity. This may be a mechanism of the agent's lower proarrhythmic effects compared with other sodium channel blockers that increase myocardial electrical heterogeneity.

Distinct cytokine profiles are clearly associated with and relate to the severity of several types of infections. Cytokine networks are apparent with selected human infectious diseases, such as mycobacterial infections (leprosy, tuberculosis), the parasitic infection leishmaniasis, human immunodeficiency virus (HIV) infection, and gram-negative sepsis. Cytokine profiles are determined to some extent by two functional subsets of T lymphocytes, Th1 and Th2. The Th1 cytokines (interferon gamma, interleukin-2 [IL-2], IL-12) enhance cell-mediated immunity, inhibit humoral immunity, and result in protective effect for pathogens that are removed primarily through cell-mediated immunity (Mycobacterium tuberculosis, Mycobacterium leprae, Leishmania). The Th2 cytokines (IL-4, IL-5, IL-10, IL-13) enhance humoral immunity and inhibit cell-mediated immunity, and result in protective effect for pathogens removed primarily through humoral mechanisms. Progression of HIV infection is associated with a switch from a Th1 to a Th2 profile. For sepsis, uncontrolled activation of proinflammatory cytokines (IL-1, tumor necrosis factor-alpha, interferon-gamma) may be a fundamental defect that promotes the detrimental aspects of inflammation, whereas Th2 cytokines may be beneficial in controlling inflammation. Knowledge of basic cytokine immunopharmacology, networks, and relationships with infectious processes will aid clinicians in determining treatment approaches that are likely to be effective.

Intraabdominal infections are a wide range of diseases that include penetrating abdominal trauma, appendicitis, peritonitis, and abscess. Most are polymicrobic, involving aerobic and anaerobic bacteria. The primary treatment is surgery, but important issues regarding administration of antimicrobials may affect patient outcome. Evaluation of an antimicrobial regimen must include consideration of outcomes--survival, organ failure, adverse drug effects, and superinfection. Single-agent regimens have demonstrated benefit in patients with acute intraabdominal contamination and established infections. Guidelines for selecting antimicrobial agents are available from the Surgical Infection Society. Regimens are effective when active against most bacteria isolated from the focus of abdominal infection. The patient's clinical response, not culture results independent of clinical findings, is the primary guide for directing changes in therapy.

For the treatment of intraabdominal infection, single-agent antimicrobial regimens such as beta-lactams with good antianaerobic activity are frequent alternatives to combination regimens such as aminoglycosides or aztreonam plus an antianaerobic agent such as clindamycin or metronidazole. The major issues in selecting a regimen are relative efficacy, potential for adverse drug effects, and cost. Single agents are clearly equivalent to combinations in preventing infectious complications after penetrating abdominal trauma and in treating established intraabdominal infections of mild to moderate severity or in relatively low-risk patients. A few trials demonstrated their equivalency in patients at high risk of mortality, although experience is limited. Single-agent regimens may reduce the risks of adverse drug effects compared with combination regimens, but they are not always less expensive.