HIV Pharmacist's Impact on Inpatient Antiretroviral Errors.

OBJECTIVES: Transitions in care between out-patient and in-patient settings provide ample opportunity for medication errors to occur in HIV-infected patients. The purpose of this study was to examine the effectiveness of an HIV pharmacist monitoring service in decreasing antiretroviral medication errors in a large south central teaching hospital in the USA. METHODS: A retrospective, observational study was conducted to examine the frequency of antiretroviral medication errors in HIV-seropositive patients with hospital admissions between 1 September 2011 and 30 September 2013 at a single tertiary care centre in Oklahoma. Patient assignment to the 12-month pre-intervention and intervention study periods was determined by admission date. Demographic, laboratory, and in-patient medication data were collected. Bivariate analyses were conducted using χ2 analysis with the Yates correction factor for continuity to examine frequencies in specific antiretroviral classes and error categories. A multivariable Poisson regression was employed to examine the frequency of medication errors before and after initiation of the pharmacist service. RESULTS: Medication errors were examined in a total of 330 patient admissions during the 2-year study period. A multivariable-adjusted decrease of 73.9% in the number of errors was observed between the pre-intervention and intervention periods (P < 0.001). Patients on protease inhibitor regimens or with impaired renal function had 2.6-fold and 2.8-fold higher numbers of errors, respectively (P < 0.001). CONCLUSIONS: HIV pharmacist monitoring can decrease medication errors in HIV-infected patients as they transition between out-patient and in-patient care. Patients receiving protease inhibitor-based therapy or with renal insufficiency are at higher risk for medication errors upon admission.

Current HIV treatment guidelines--an overview.

Use of highly active antiretroviral therapy has resulted in significant reductions in HIV-related morbidity and mortality. Current therapeutic approaches target cellular entry, viral transcription, and maturation of newly formed virus. Combination therapy is necessary to provide durable suppression of viral replication and immune reconstitution. A variety of consensus treatment guidelines addressing prophylaxis and treatment of HIV infection and opportunistic infections have been developed to serve as resources for clinicians. A summary of U.S. Department of Health and Human Services Guidelines for Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and International AIDS Society-USA Panel recommendations for Treatment of Adult HIV infection are presented. Considerations for selection of antiretroviral therapy in special populations (e.g., pregnancy, coinfection with tuberculosis, hepatitis B and C virus) are highlighted. U.S. Public Health Service guidelines for management of occupational exposure to HIV and initiation of postexposure prophylaxis are discussed as well as World Health Organization recommendations for use of antiretroviral therapy in resource-limited settings. The pathophysiology of HIV infection, viral load testing methods, viral dynamics, and classification of antiretrovirals are also briefly reviewed.

Management protocol for abacavir-related hypersensitivity reaction.

OBJECTIVE: To develop an abacavir hypersensitivity reaction management protocol for the University of Oklahoma Health Sciences Center. DATA SYNTHESIS: Conference abstracts, published literature, and manufacturer-provided materials were reviewed to define the syndrome and manifestations and to recommend steps to take when a patient develops abacavir-related reactions. RESULTS: Initial education, formalized contact and response mechanism, and intervention levels were incorporated into a protocol for clinicians. CONCLUSIONS: Abacavir, a newly approved agent for the treatment of HIV, has been associated with a fatal hypersensitivity reaction. Our protocol provides a mechanism to minimize progression of abacavir hypersensitivity reaction by providing a formalized management procedure.

Hyperkalemia associated with high-dose trimethoprim-sulfamethoxazole in a patient with the acquired immunodeficiency syndrome.

When given in standard dosages to treat bacterial respiratory and urinary tract infections, trimethoprim-sulfamethoxazole (TMP-SMX) is not commonly associated with hyperkalemia. However, the emergence of the acquired immunodeficiency syndrome has led to increased numbers of patients with Pneumocystis carinii pneumonia (PCP) who require high-dose TMP-SMX therapy. A 25-year-old man with human immunodeficiency virus infection developed hyperkalemia while receiving high-dose TMP-SMX for PCP. His baseline serum potassium of 3.0 mEq/L, which increased to 4.2 mEq/L after potassium replacement therapy, rose to 6.9 mEq/L after 8 days of TMP-SMX. No other etiology was found for the hyperkalemia, and the disorder resolved when TMP-SMX was stopped. It recurred when the patient was rechallenged with high doses of TMP-SMX during a second treatment course for PCP. This case and a review of previous reports highlight the importance of monitoring serum potassium concentrations in patients receiving high-dose TMP-SMX.

Hantavirus pulmonary syndrome: the Four Corners disease.

OBJECTIVE: To review the epidemiology, pathogenesis, clinical features, diagnosis, and treatment of hantavirus infections, focusing on the recent outbreak of hantavirus pulmonary syndrome in the US. DATA SOURCES: A MEDLINE search (1966 to present) of English language literature pertaining to hantaviruses was performed. Additional literature was obtained from reference lists of pertinent articles identified through the search. STUDY SELECTION AND DATA EXTRACTION: All articles were considered for possible inclusion in the review. Pertinent information, as judged by the authors, was selected for discussion. DATA SYNTHESIS: Hemorrhagic fever with renal syndrome (HFRS) has long been recognized in Eurasia and is the predominant disease manifestation of hantavirus infection worldwide. Hantavirus pulmonary syndrome (HPS) recently has been described in the US and exhibits greater pulmonary involvement and mortality than HFRS. Historically, 4 hantavirus serotypes (Hantaan, Seoul, Puumala, Prospect Hill) are recognized; however, additional serotypes have been proposed as distinct serogroups, including the serotype responsible for HPS in the Four Corners area: the Four Corners virus (FCV). Phylogenetic analysis shows that FCV is most closely related to Prospect Hill virus, another hantavirus previously isolated in the US that has not yet been identified with human disease. Additional hantavirus serotypes isolated in the US may provide insight into the prevalence of hantavirus infection and disease in this country. Inhalation of aerosolized virus is the predominant mechanism of hantavirus infection. Diagnosis is based primarily on clinical findings and serologic evidence of hantavirus antibody or direct evidence in clinical tissue specimens. Limited clinical studies evaluating ribavirin as a therapeutic modality demonstrated that the agent improves clinical outcome in HFRS. However, the role of ribavirin in the treatment of HPS remains to be determined. CONCLUSIONS: Hantavirus infections are becoming increasingly recognized as a cause of disease worldwide. Recognition of hantavirus disease in the US suggests enzoonosis of pathogenic hantaviruses. In the absence of a well-established cure, early diagnosis is imperative so that aggressive supportive care can be initiated.

Surrogate markers for assessing treatment response in HIV disease.

OBJECTIVE: To provide an awareness of the issues surrounding the selection and utility of surrogate markers to evaluate treatment response for new antiretroviral therapies for HIV infection. DATA SOURCES: A MEDLINE search of applicable articles published between 1987 to the present, including clinical trials, commentaries, and editorials, was performed. DATA SYNTHESIS: Surrogate markers are proximal indicators that are predictive of rare or distant outcomes and can be used in clinical trials to decrease sample size and study duration. Characteristics of potential surrogate endpoints include relevance to disease state, face validity, ability to be detected in the majority of patients, and correlation between treatment-induced changes and terminal endpoints. Potential surrogate markers for assessing treatment response in HIV infection can be categorized as either virologic (p24 antigen, plasma viremia, proviral DNA) or immunologic (CD4+ lymphocytes, neopterin, beta 2-microglobulin, soluble interleukin-2 receptors, immunoglobulin A [IgA]). The CD4+ lymphocyte count and the p24 antigen have been evaluated in most of the clinical trials examining antiretroviral agents and have the greatest documentation supporting their use. Neopterin and beta 2-microglobulin are nonspecific markers, but may improve the predictive value of the CD4+ count when used in combination. Other markers (i.e., soluble interleukin-2 receptors, IgA) remain relatively unstudied at this point. CONCLUSIONS: There is no current consensus regarding the selection of surrogate markers for HIV disease. On the basis of the present literature, the CD4+ lymphocyte count has the greatest endorsement: however, combination with several surrogate markers may prove to be useful in clinical trials. Studies are needed to verify the reliability of surrogate markers used alone and in combination to predict therapeutic response from antiretroviral therapy.

Didanosine therapy in patients intolerant of or failing zidovudine therapy.

OBJECTIVE: To examine the effect of didanosine (2',3'-dideoxyinosine, ddI) on surrogate markers of HIV infection (CD4+ lymphocyte count, p24 antigen) and to evaluate the incidence of adverse effects from ddI. DESIGN: This study was performed as a retrospective chart review of patients who were enrolled in Bristol-Myers Squibb's expanded-access program for ddI. SETTING: Patient records were obtained from primary care physicians' offices. PATIENTS: Twenty-five HIV-infected patients diagnosed with AIDS or AIDS-related complex (ARC) who were intolerant of zidovudine (ZDV) therapy or deteriorating clinically despite ZDV therapy and were eligible for inclusion in the ddI expanded-access program. INTERVENTION: ddI was administered orally in a citrate-phosphate buffer every 12 hours. Patients were followed by their private physician on a monthly basis. MAIN OUTCOME MEASURES: Laboratory analysis at each month included CD4+ lymphocyte count, hemoglobin, hematocrit, serum amylase, uric acid, serum triglycerides, and p24 antigen. Mean CD4+ cell count, serum amylase, hemoglobin, and uric acid at each month during ddI therapy were compared with baseline concentrations for nine months. RESULTS: Patients had received prior ZDV therapy for an average of 15.5 months before starting ddI. Mean CD4+ cell counts increased from 53.9/mm3 at baseline to 72.4/mm3 after 4 months of therapy (p = 0.04) but returned to concentrations comparable with those at baseline after 5 months. One case of documented pancreatitis, two cases of suspected pancreatitis, and nine cases of peripheral neuropathy occurred during ddI therapy. The estimated mean cumulative dose for the development of neuropathy was 1.16 g/kg, which is lower than previously reported. CONCLUSIONS: Patients who have received prolonged therapy with ZDV or who have low initial CD4+ counts may not have sustained increases in CD4+ counts from ddI therapy. Also, development of peripheral neuropathy may occur at lower cumulative doses in these patient populations.

Current and investigational therapies for AIDS-associated Mycobacterium avium complex disease.

The epidemiology, pathogenesis, clinical manifestations, and treatment of Mycobacterium avium complex (MAC) infection are reviewed. MAC infection is one of the most common infections in AIDS patients. Its pathogenesis is poorly understood, but it is believed to develop by gastrointestinal colonization followed by systemic invasion. The relatively poor response to treatment may be partly accounted for by the tremendous mycobacterial load present by the time patients develop systemic symptoms. Clinically, MAC infection is difficult to differentiate from the signs and symptoms of AIDS or from other opportunistic infections. Signs and symptoms include fever, malaise, anorexia, night sweats, and weight loss; diarrhea and abdominal pain may also be present. There is no established therapy for MAC infection, although combinations of three to five antimicrobial agents are typically used. There has been consistently poor correlation between in vitro results and in vivo outcomes in the treatment of MAC infection. Currently, the role of treatment is mainly to suppress the progression of infection and to relieve symptoms. Recent in vitro studies and animal studies have revealed possible alternative agents and combinations of agents (e.g., macrolide antibiotics, quinolones, amikacin, cytokines) that may influence therapy of MAC infection. No known therapy for MAC has been shown to prolong survival in AIDS patients, possibly because of the high organism load that exists once patients become symptomatic. Research is needed to find improved methods for earlier detection of MAC infection, determine optimal dosage regimens of current antimycobacterial agents, develop better antimycobacterial drug-delivery systems (e.g., liposomes), and discover new antimicrobials with better activity against MAC and methods of immune modulation that will overcome immune system defects.

Pharmacology of LY201409, a potent benzamide anticonvulsant.

LY201116 [4-amino-N-(2,6-dimethylphenyl)benzamide], an effective anticonvulsant in several animal models, is rapidly metabolized by N-acetylation in rats, mice and monkeys. In an attempt to preclude metabolic N-acetylation sterically, we investigated LY201409, an analogue possessing two methyl groups ortho to the 4-amino substituent. This structural modification successfully altered the metabolic pathway, and LY201409 displayed potent anticonvulsant activity. LY201409 antagonized maximal electroshock (MES)-induced seizures with ED50 values of 16.2 and 4.2 mg/kg after oral administration to mice and rats, respectively. The compound did not effectively antagonize seizures induced by a variety of chemical convulsants in rats, but did block pentylenetetrazol-induced seizures in mice. Thus, among the classic anticonvulsants, the profile of phenytoin most closely resembles that of LY201409. Studies conducted with the rotorod and horizontal screen assays in mice and behavioral studies in rats suggested that doses of LY201409 that produced CNS side-effects such as sedation or ataxia were well separated from the anti-MES doses. LY201409 was a potent, dose-dependent potentiator of hexobarbital-induced sleeping time in mice. Oral administration of 6.0 mg/kg led to a 372% increase in sleep time relative to control values. Although LY201409 is a potent and effective anticonvulsant, it is also one of the most potent potentiators of hexobarbital-induced sleep time yet described.

Anticonvulsant effects of phencyclidine-like drugs: relation to N-methyl-D-aspartic acid antagonism.

Various compounds that have been identified in the literature as binding to the [3H]phencyclidine receptor site and as producing behavioral effects similar to phencyclidine (phencyclidine-like) protected mice from maximal electric shock-induced tonic-extensor seizures. These anticonvulsant effects appear to be due to blockade of the N-methyl-D-aspartic acid receptor, as recently reported for phencyclidine-like compounds. Phencyclidine-like compounds produced their anticonvulsant effects at doses that were also neurologically impairing.

Pharmacological effects of enantiomers of 4-amino-N-(alpha-methylbenzyl)benzamide, a chemically novel anticonvulsant.

LY 188544,S,R-4-amino-N-(alpha-methylbenzyl) benzamide, and its two stereoisomers are structurally novel anticonvulsants. The anticonvulsant profile of LY 188544 after intraperitoneal administration to mice was determined in standard anticonvulsant tests: maximal electric shock (MES), strychnine tonic-extensor, and threshold tests using pentylenetetrazol, picrotoxin, and bicuculline. In this series of tests, LY 188544 had good activity in the MES test and some activity in the three threshold tests. Thus, its profile of activity was most similar to that of phenobarbital, and less similar to that of phenytoin and carbamazepine. After oral administration to mice and rats, LY188544 was effective in the MES test, but did not provide complete protection in the threshold pentylenetetrazol test. When the individual stereoisomers, LY188545 (S isomer) and LY188546 (R isomer), were evaluated after oral administration, LY188545 was 2.2 times more potent than LY188546 against MES-induced seizures. However, when evaluated after intravenous administration, the potency difference was only 1.1. LY188546 was the least toxic in terms of neurological impairment. All compounds had good protective indexes (ratio between doses for neurological impairment and doses for anticonvulsant efficacy in the MES test). LY188545 and LY188546 potentiated hexobarbital sleeping time after acute administration but not after chronic (4-day) administration. Tolerance did not develop to the effects of LY188546 on MES or neurological impairment after 4 days of administration. These results suggest that LY188546 is a chemically novel anticonvulsant with a promising pharmacological profile.

Structure-activity relationships of (arylalkyl)imidazole anticonvulsants: comparison of the (fluorenylalkyl)imidazoles with nafimidone and denzimol.

A recently discovered and structurally distinct class of antiepileptic drugs is the (arylalkyl)imidazoles. Two independently discovered representatives of this class, denzimol (alpha-[4-(2-phenylethyl)phenyl]-1H-imidazole-1-ethanol) and nafimidone (2-(1H-imidazol-1-yl)-1-(2-naphthalenyl)ethanone), are undergoing clinical evaluation. Our structure-activity relationship (SAR) studies revealed that in addition to the naphthalenyl and phenethylphenyl aryl moieties of nafimidone and denzimol, respectively, fluorenyl, benzo[b]thienyl, and benzofuranyl aryl groups provided several highly active (arylalkyl)imidazole anticonvulsants. These structurally diverse aryl moieties, and comparable anticonvulsant activities, lend credence to the hypothesis that the pharmacophore of this class of anticonvulsants is the alkylimidazole portion of the molecule, with the lipophilic aryl portion enabling penetration of the blood-brain barrier. We focused our SAR studies on the (fluorenylalkyl)imidazole series. A representative compound from this series is 1-(9H-fluoren-2-yl)-2-(1H-imidazol-1-yl)ethanone. This agent was twice as potent as nafimidone in inhibiting maximal electroshock seizures in mice (po ED50's = 25 and 56 mg/kg, respectively) and considerably less toxic in the rat (po LD50's = 4550 and 504 mg/kg, respectively). The tertiary alcohol alpha-(9H-fluoren-2-yl)-alpha-methyl-1H-imidazole-1-ethanol was as potent as denzimol in mice (po ED50's = 10 and 12 mg/kg, respectively). This series of imidazole anticonvulsants was highly selective; while many compounds displayed potent antielectroshock activity, little or not activity was observed against pentylenetetrazole-induced clonic seizures or in the horizontal screen test for ataxia. All active compounds that we tested in this series, as well as denzimol and nafimidone, potentiated hexobarbital-induced sleeping time in mice, probably by imidazole-mediated inhibition of cytochrome P-450. The SAR's for the anticonvulsant activity and the sleeping time potentiation were similar. The propensity of these (arylalkyl)imidazole anticonvulsants to interact strongly with cytochrome P-450 and thereby impair the metabolism of other antiepileptic drugs may severely limit their clinical utility as anticonvulsants.

Effects of mu- and kappa-opioid receptor agonists on urinary output in mice.

The effects of ethylketazocine, morphine, bremazocine and naloxone were determined on urinary output and weight loss in Cox mice. Morphine and fentanyl were also studied in Harlan mice. Bremazocine, ethylketazocine and morphine markedly increased urinary output and weight loss within 5 hr after injection. Naloxone antagonized the diuretic actions of morphine (5 mg/kg) and bremazocine (0.06 mg/kg) over a similar dose range (0.3--10 mg/kg). By comparison with the other agonists, fentanyl had little effect on urinary output or weight loss. These results suggest that kappa agonist activity increases urinary output in mice just as reported for rats. The data also suggest that in mice morphine has some kappa agonist activity, whereas fentanyl does not.

Enhanced binding of radioligands to receptors of gamma-aminobutyric acid and benzodiazepine by a new anticonvulsive agent, LY81067.

A diaryltriazine, LY81067, effectively protects against pentylenetetrazole- and picrotoxin-induced convulsions in mice, with ED50 values of 5.7 and 5.8 mg/kg i.p., respectively. LY81067 enhances the binding of both 3H-GABA and 3H-flunitrazepam to specific sites in rat brain membranes. The degree of enhancement by LY81067 varies from one brain region to another and is different for the binding of 3H-GABA and 3H-flunitrazepam. In cortical membranes, LY81067 increases the affinity of 3H-GABA for both high and low affinity sites and increases the number of sites. LY81067 increases the affinity of 3H-flunitrazepam for its binding sites without greatly increasing the number of sites. Like the pyrazolopyridines, the enhancement of 3H-flunitrazepam binding by LY81067 is dependent on chloride or related anions and is reversed by picrotoxin, suggesting that LY81067 exerts its anticonvulsant effects by binding to or near picrotoxin binding sites. The differential effects of LY81067 on the enhancements of 3H-GABA and 3H-flunitrazepam binding in several brain regions suggest extensive multiplicity of GABA/benzodiazepine/picrotoxin/anioin receptor complexes.

Inhibition of drug metabolism by fluoxetine.

Fluoxetine hydrochloride (Lilly 110140: 3-p-trifluoromethylphenoxy-3-phenyl-N-methyl-propylamine hydrochloride) inhibited the metabolism of hexobarbital and ethinamate in rodents and prolonged the hypnotic effects of these drugs.