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Background: Opioids are considered the cornerstone of pain management: they show good efficacy as a first-line therapy for moderate to severe cancer pain. Since pharmacokinetic/pharmacodynamic information about the tissue-specific effect and toxicity of opioids is still scarce, their quantification in post-mortem autoptic specimens could give interesting insights. Methods: We describe an ultra-high-performance liquid chromatography coupled with tandem mass spectrometry method for the simultaneous quantification of methadone, morphine, oxycodone, hydrocodone, oxymorphone, hydromorphone and fentanyl in several tissues: liver, brain, kidney, abdominal adipose tissue, lung and blood plasma. The presented method has been applied on 28 autoptic samples from different organs obtained from four deceased PLWH who used opioids for palliative care during terminal disease. Results: Sample preparation was based on tissue weighing, disruption, sonication with drug extraction medium and a protein precipitation protocol. The extracts were then dried, reconstituted and injected onto the LX50 QSight 220 (Perkin Elmer, Milan, Italy) system. Separation was obtained by a 7 min gradient run at 40 °C with a Kinetex Biphenyl 2.6 µm, 2.1 × 100 mm. Concerning the analyzed samples, higher opioids concentrations were observed in tissues than in plasma. Particularly, O-MOR and O-COD showed higher concentrations in kidney and liver than other tissues (>15–20 times greater) and blood plasma (>100 times greater). Conclusions: Results in terms of linearity, accuracy, precision, recovery and matrix effect fitted the recommendations of FDA and EMA guidelines, and the sensitivity was high enough to allow successful application on human autoptic specimens from an ethically approved clinical study, confirming its eligibility for post-mortem pharmacological/toxicological studies.

The human LINE-1/L1 ORF2 protein is a multifunctional enzyme which plays a vital role in the life cycle of the human L1 retrotransposon. The protein consists of an endonuclease domain, followed by a central reverse transcriptase domain and a carboxy-terminal C-domain with unknown function. Here, we explore the nucleic acid binding properties of the 180-amino acid carboxy-terminal segment (CTS) of the human L1 ORF2p in vitro. In a series of experiments involving gel shift assay, we demonstrate that the CTS of L1 ORF2p binds RNA in non-sequence-specific manner. Finally, we report that mutations destroying the putative Zn-knuckle structure of the protein do not significantly affect the level of RNA binding and discuss the possible functional role of the CTS in L1 retrotransposition., Highlights • The 180-aa C-terminal segment (CTS) of human L1 ORF2p was expressed and purified from bacteria. • The nucleic acid binding properties of the CTS of L1ORF2p were examined in vitro. • The CTS of L1 ORF2p is an RNA binding domain. • The CTS of L1 ORF2p binds RNA in non-sequence-specific manner in the low nanomolar range. • Disruption of the putative Zn-knuckle structure does not significantly affect RNA binding.

Objective: To review the clinical features, risk factors, diagnosis, and management of abacavir hypersensitivity reaction (HSR). Data Sources: A MEDLINE (1950–October 2007) and EMBASE (1980–October 2007) search using key words abacavir, HIV, human immunodeficiency virus, hypersensitivity reaction, HLA-B*5701, and patch tests was conducted. Conference abstracts and article bibliographies were reviewed to identify relevant studies. Study Selection and Data Extraction: Studies that investigated the clinical and immunogenetic risk factors for abacavir hypersensitivity and the benefit of genetic screening, as well as articles that focused on the clinical presentation, assessment, and management of abacavir HSR, were considered for this review. Data Synthesis: Abacavir hypersensitivity is an immune-mediated reaction that typically occurs within the first 6 weeks of therapy. Signs and symptoms of abacavir HSR are nonspecific, which makes the diagnosis challenging, particularly in medically complex patients. Patch testing may improve the diagnosis and confirmation of abacavir HSR, but it remains experimental. Clinical management is aimed at supportive therapy and discontinuation of abacavir. Rechallenge with abacavir is contraindicated due to the risk of precipitating a life-threatening reaction. Appropriate patient education and a clear communication plan are essential for the safe use of this medication. Identification of patients at risk of developing abacavir hypersensitivity through routine genetic screening for human leukocyte antigen (HLA) HLA-B*5701 represents a significant advance in the field of pharmacogenomics, with an apparent 100% negative predictive value when used to screen for abacavir HSR. Preliminary data suggest that pharmacogenetic testing for HLA-B*5701 is cost effective. However, until routine testing is available, pharmacovigilance is necessary for the safe and effective use of abacavir. Conclusions: Serious adverse events associated with the use of abacavir can be avoided by appropriate recognition and management of the HSR. Screening patients for HLA-B*5701 prior to initiation of abacavir represents a tool to further decrease the risk of HSRs as well as unnecessary discontinuation of this drug.

Substance use is highly prevalent in HIV-infected individuals in the United States, and clinical management is complicated by the need for antiretroviral treatment, addiction therapy, variable medication adherence, and co-morbidities. The interrelation between HIV and substance use prompted our investigation to examine substance use and self-reported medication adherence in patients receiving the HIV-1 protease inhibitors, atazanavir (ATV) or lopinavir (LPV). ATV and LPV pharmacokinetics were determined by measuring plasma concentrations in subjects with active substance use (SU group) or with no active substance use (NSU group). No difference in adherence was observed between groups (p0.05). The mean SU ATV trough was 0.550+/-0.45 microg/mL; the mean NSU ATV trough was 0.780+/-0.590 microg/mL (p0.05). The mean SU LPV trough was 4.02+/-2.39 microg/mL; the mean NSU LPV trough was 6.67+/-0.910 microg/mL (p = 0.01). Co-factors found to be associated with variation in ATV and LPV concentrations included concurrent methadone use, cigarette smoking, and substance use status. These data indicate that chronic HIV treatment may be assisted with plasma concentration monitoring to identify those patients who may require dosage modification and/or regimen adjustment in order to optimize antiretroviral effects.

BACKGROUND It is recommended to boost atazanavir with ritonavir (ATV/r) when it is combined with tenofovir disoproxil fumarate (TDF) because of drug interactions. For tolerability, unboosted atazanavir (ATV) is sometimes coadministered with TDF. The objective of this study was to evaluate the impact of this interaction on the proportion of patients achieving target ATV C troughs and genotypic inhibitory quotients (GIQ). MATERIALS AND METHODS A therapeutic drug monitoring database was screened to evaluate ATV concentrations. Differences in C trough and GIQ values among 4 antiretroviral drug combinations were evaluated. RESULTS Three hundred eight C troughs, 91 GIQs, and 92 viral loads were evaluated for 238, 68, and 69 patients, respectively. Patients receiving ATV/r and TDF compared with ATV and TDF were more likely to have a therapeutic C trough (odds ratio, 2.27; 95% confidence interval: 1.46-3.52; P < 0.001). Among patients on unboosted ATV, the odds of having a therapeutic ATV C trough did not differ between groups with TDF versus without TDF. Although ritonavir increased the GIQ in patients receiving TDF (odds ratio, 3.38; 95% confidence interval: 1.30-8.81; P = 0.013), a similar proportion of patients on TDF and either ATV/r or ATV achieved a therapeutic GIQ. CONCLUSIONS In patients receiving TDF, ritonavir increased the ATV C trough and GIQ and patients on ATV/r were more likely to have therapeutic C troughs. However, among subjects without ritonavir boosting, TDF compared with other nucleosides did not influence the odds of achieving a therapeutic ATV C trough. These data suggest that ritonavir boosting of ATV is prudent, particularly in patients with resistance mutations.

Background Studies suggest knowledge gaps about epinephrine use and vaccination of persons with egg allergy. Objective We compared the perception of Canadian allergists and nonallergists on issues related to epinephrine use and vaccination of persons with egg allergy. Methods Canadian allergists, pediatricians, general practitioners/family physicians and emergency room physicians were recruited through medical associations and surveyed on these issues. Multivariate logistic regression models were used to identify determinants of specific responses. Results One-hundred fourteen allergists and 613 nonallergists participated. For most issues with accepted best practices, allergists were more likely to adhere to recommendations. Allergists versus nonallergists were more likely to recommend intramuscular epinephrine for anaphylaxis (odds ratio [OR] = 3.8; 95% CI, 1.43-10.11). Older physicians (OR = 0.98; 95% CI, 0.97-0.99), Canadian-Paediatric-Surveillance-Program participants (OR = 0.48; 95% CI, 0.24-0.96), family physicians (OR = 0.39; 95% CI, 0.16-0.96), and general practitioners (OR = 0.14; 95% CI, 0.04-0.52) were less likely to recommend intramuscular use. However, in severe anaphylaxis, >25% of both groups would not give epinephrine for patients presenting with breathing difficulties or hypotension. Use of epinephrine for severe anaphylaxis was less likely in older physicians (OR = 0.97; 95% CI, 0.95-0.99), female physicians (OR = 0.60; 95% CI, 0.39-0.89), and those practicing in Ontario (OR = 0.56; 95% CI, 0.36-0.86), Manitoba (OR = 0.42; 95% CI, 0.19-0.90), or Nova-Scotia (OR = 0.31; 95% CI, 0.12-0.78). Allergists (OR = 6.22; 95% CI, 3.60-10.72) and physicians treating mainly children (OR = 3.41; 95% CI, 1.87-6.25), or practicing in Quebec (OR = 1.68; 95% CI, 1.12-2.55) were more likely to recommend measles-mumps-rubella vaccination in a community facility. Conclusion Knowledge gaps about mode and indications for epinephrine administration and vaccination policies need to be addressed in future education programs to ensure prompt epinephrine use and to avoid unnecessary restriction of vaccines.

Over the past decade, there have been numerous advances in HIV therapy, with 6 drug classes comprising 24 indivi dual antiretroviral agents now available. For patients who are adherent with therapy and who have an undetectable viral load, HIV has become a chronic, manageable disease in an aging and genetically diverse population. The core goals of management remain maximal suppression of viral replication and promotion of immune reconstitution through combination antiretroviral therapy. Secondary goals of therapy include promoting long-term adherence, avoiding drug interactions, minimizing toxic effects, simplifying treatment regimens, decreasing drug costs, managing comorbid conditions, and preventing transmission of HIV by achieving undetectable viral load. Consequently, the pharmacist’s role has evolved and expanded to help patients and other health care providers to achieve these goals. Pharmacists are recognized as established and integral members of HIV health care teams across Canada and the United States. Pharmacists’ involvement in the care of HIVpositive patients has been associated with improved patient outcomes, including enhanced adherence, reduced pill burden and dosing frequency, greater increases in CD4 cell counts, higher rates of viral suppression, and decreases in medication errors. Guidelines and position statements on the role of the pharmacist in caring for patients with HIV/AIDS have been published by various national and international organizations, but there have been no updates since combination antiretro viral therapy came into use, about a dozen years ago. This paper provides current guidelines for a pharmacist’s role in the many aspects of caring for patients with HIV/AIDS, including selecting and reviewing therapy, tailoring treatment for specific populations, counselling patients, monitoring response to therapy, guiding transitions of care, and undertaking scholarly and professional activities. The target audience for these guidelines includes new HIV pharmacy practitioners, pharmacists with an interest in HIV but limited experience or therapeutic knowledge in this area, and pharmacy students. This paper may also serve as a model of pharmacy practice for ambulatory care in other therapeutic areas. A literature search was conducted using the electronic databases MEDLINE and PubMed from 2000 to March 2012. The following search terms were used: HIV, antiretrovirals, adverse drug reactions, drug interactions, adherence, pediatric, perinatal transmission, therapeutic drug monitoring, pharmacist, hepatitis B, hepatitis C, seamless care, and medication reconciliation. In addition, conference abstracts were searched for relevant studies. Updated guidelines for treatment of HIV and related conditions, landmark studies, and comprehensive review articles were selected for inclusion.

Therapeutic drug monitoring (TDM) is a strategy whereby the plasma concentration of one or more drugs is measured and drug doses are adjusted accordingly to achieve concentrations within an acceptable therapeutic range. The goal of TDM is to maximize pharmacologic efficacy and minimize the drug’s toxic effects, and hence to contribute to optimizing the patient’s outcomes. In general, TDM is indicated if the following conditions are present: there is a direct relationship between drug exposure and pharmacologic response, the drug has a narrow therapeutic index and is used to treat a condition for which drug failure or toxicity is associated with substantial morbidity or mortality, and there is limited intrapatient but wide interpatient pharmaco kinetic variation. Differences in pharmacokinetic factors among patients are multifactorial and may include age, sex, ethnic background, pregnancy, and body weight, as well as comorbid conditions causing variations in hepatic function, renal function, drug absorption, and drug disposition. In some cases, genetic polymorphisms in the cytochrome P450 enzymes may explain the large interpatient variability for certain antiretroviral agents. For example, certain CYP2B6 and CYP2A6 polymorphisms are independent predictors of plasma concentrations of efavirenz. Moreover, the potential for complex or unpredictable drug–drug or drug–food interactions can significantly affect plasma drug concentrations. Finally, TDM depends on the availability of an accurate and feasible analytical method for a given drug. Among antiretroviral agents, the protease inhibitors and the non-nucleoside reverse transcriptase inhibitors (NNRTIs) are considered suitable candidates for TDM. Evidence exists of a relation between exposure to antiretrovirals and virologic response and, in more limited instances, between exposure to the drug and toxic effects. Recent data have suggested that intraindividual variation is limited (19.0% for NNRTIs and 38.1% for protease inhibitors). Preliminary data have also suggested that trough levels of maraviroc, a chemokine (C–C motif) receptor 5 (CCR5) antagonist, are predictive of virologic outcome, although TDM experience with this agent is extremely limited. In retrospective and prospective studies, observed interindividual variability in drug concentrations has been 45% to 112% for protease inhibitors and 75% for NNRTIs. Thus, a given dose of a particular antiretroviral agent may result in unacceptable toxic effects in some patients while yielding subtherapeutic concentrations in others. TDM represents a tool by which the effectiveness of these agents in clinical practice can be optimized through dosage adjustments tailored to patient-specific pharmacokinetic and pharmaco dynamic parameters. The current article reviews the literature on antiretroviral TDM, describes the development of an antiretroviral TDM program in Canada, and illustrates the role of the pharmacist in the clinical application of TDM. Given current evidence and personal experience, the authors support the use of antiretro viral TDM as a clinical tool in special patient populations and for specific clinical situations.

Abacavir is a nucleoside reverse transcriptase inhibitor (NRTI) that is used in combination antiretroviral therapy in HIV-infected patients. It is currently recommended as a preferred or an alternative NRTI in antiretroviral-naive patients. The major toxicity of abacavir is a hypersensitivity reaction (HSR), which occurs in approximately 5% of treated patients. There is a strong association between the human leukocyte antigen (HLA)-B*5701 allele and abacavir HSR, which has allowed for rapid acceptance of genetic screening for HLA-B*5701 in clinical use. Canadian clinicians working in hospital centers with HLA typing capacity opted to launch a pilot project in 2006 to offer the screening test as standard of care to HIV-infected patients. Currently, more than 11,000 HLA-B*5701 tests have been performed, among which 6.3% are positive. Continued efforts have been made to ensure that testing is available to all HIV-infected patients to widen the patients' therapeutic options. HLA-B*5701 screening shows clinical use and preliminary data suggest cost-effectiveness.

(2005). A Rainforest Expedition with The Student Rainforest Fund. Journal of Herbal Pharmacotherapy: Vol. 5, No. 3, pp. 103-105.