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Director's Report to the National Advisory Council on Drug Abuse - February, 2009



Research Findings - Research on Medical Consequences of Drug Abuse and Co-Occurring Infections (HIV/AIDS, HCV)

HIV-1 Expression Induces Tubular Cell G2/M Arrest and Apoptosis

Human renal biopsy studies suggest the presence of HIV-1 and associated signs of injury in renal tubular epithelial cells. Because renal epithelial cells lack conventional HIV-1 receptors, the modus operandi of HIV-1 in the induction of tubular cell injury remains a mystery. In the present study, the authors evaluated the role of HIV-1 gene expression in human proximal tubular cell apoptosis and cell cycle progression. HIV-1- or vector-transduced cells were assayed for cellular injury and cell cycle defect. HIV-1-transduced cells showed the progressive loss of viability in a time-dependent manner. Similarly, HIV-1-transduced cells showed greater apoptosis when compared with vector-transduced cells. A higher number of HIV-1 expressing cells showed cell cycle arrest at G2/M phase and enhanced tubular cell expression of phospho-p53 (ser15), phospho- cdc-2(Tyr 15), and phospho-chk-2 (Thr 68). These findings suggest that in addition to the activation of apoptotic pathway, HIV-1- induced G2/M arrest may also contribute to tubular cell injury. Vashistha, H., Husain, H., Kumar, D., Yadav, A., Arora, S., Singhal. P.C., and Failure, R. Renal Failure 30(6) pp. 655-664, 2008.

Drug Use and Weight Loss in HIV-infected Hispanic Men

Weight loss is an independent risk factor for mortality in HIV but the role of drug use in HIV-related weight loss is not well described. The authors conducted this study to determine the role of drug use in HIV-related weight loss. Men (n=304), all of whom were Hispanic, were recruited into one of three groups: HIV-infected drug users; HIV-non-infected drug users; and HIV-infected non-drug users. Body mass index (BMI) was measured at successive visits. The groups were re-categorized based on self-reported drug use at the current visit into: (1) users of cocaine alone; (2) users of cocaine and opiates; (3) users of opiates alone; (4) former drug users; and (5) those who denied ever using drugs (all HIV-infected). The effect on BMI of the duration of use of the specific drug types was evaluated using repeated-measures analyses. Longer duration of exclusive opiate use or mixed cocaine and opiate use did not affect BMI in the men, regardless of HIV status. Exclusive cocaine use was associated with a decline in BMI among HIV-infected men (-0.070 kg/m(2) per month duration of use; SE=0.033; p=0.037) but not among HIV-uninfected men (0.024 kg/m(2) per month; SE=0.023; p=0.29). Adjustment for marijuana, cigarette and alcohol use in all men, or for CD4 count, viral load or HIV medication use in the HIV-infected men, did not alter the conclusions. The authors conclude that the use of opiates or combined opiates and cocaine does not increase the risk of weight loss in the presence or absence of HIV infection. Exclusive Cocaine Use May Exacerbate Weight Loss in HIV-infection. Forrester, J.E., Tucker, K.L., Skinner, S., and Terrin, N. AIDS Care 20(7), pp. 868-875, August 2008.

Risk Factors for Proteinuria in HIV-infected and -uninfected Hispanic drug Users

Proteinuria may be an early marker of chronic kidney disease in human immunodeficiency virus (HIV)-infected patients with coexisting chronic hepatitis and/or drug use. Minorities are at greater risk of chronic kidney disease. Data are limited about risk factors for proteinuria in Hispanic drug users with and without HIV infection. In this cross-sectional study a community-recruited Hispanic cohort was employed to study the role of drug use in HIV-associated malnutrition composed of 4 groups (106 HIV-infected drug users, 96 HIV-uninfected drug users, 38 HIV-infected non-drug users, and 47 healthy controls). Patients on renal replacement therapy were excluded. Predictors were: HIV infection, chronic hepatitis, history of hypertension or diabetes, and intravenous drug use (never, prior, or current). The presence of proteinuria was defined as urine dipstick result of 1+ or greater. Multivariable logistic regression was used to identify independent risk factors for proteinuria. Of 287 patients with available data, 24 (8.4%) had proteinuria. In univariate analyses, those with HIV infection; prior, but not current, intravenous drug use; and a history of hypertension or diabetes were more likely to have proteinuria. In multivariate analyses, significant risk factors for proteinuria were HIV infection (odds ratio, 9.2; 95% confidence interval, 1.9 to 45.8; P = 0.007); prior, but not current, intravenous drug use (odds ratio, 4.7; 95% confidence interval, 1.4 to 15.3; P = 0.01); and history of hypertension or diabetes (odds ratio, 8.2; 95% confidence interval, 3.1 to 21.7; P < 0.001). The cross-sectional study design used here makes it difficult to establish the temporal relationship. The number of outcomes in relation to the number of predictors is small. The authors concluded that HIV and prior intravenous drug use, but not chronic hepatitis or current intravenous drug use, were independently associated with proteinuria in this Hispanic population. Longitudinal studies to assess the development of proteinuria and chronic kidney disease in this high-risk population are warranted. Rhee, M.S., Schmid, C.H., Stevens L.A., and Forrester, J.E. Am. J. Kidney Dis. 52(4), pp. 683-690, 2008. Epub June 24, 2008.

Methamphetamine Enhances HIV-1 Infectivity in Monocyte Derived Dendritic Cells

The US is currently experiencing an epidemic of methamphetamine (Meth) use as a recreational drug. Recent studies also show a high prevalence of HIV-1 infection among Meth users. The authors report that Meth enhances HIV-1 infectivity of dendritic cells as measured by multinuclear activation of a galactosidase indicator (MAGI) cell assay, p24 assay, and LTR-RU5 amplification. Meth induces increased HIV-1 infection in association with an increase in the HIV-1 coreceptors, CXCR4 and CCR5, and infection is mediated by downregulation of extracellular-regulated kinase (ERK2) and the upregulation of p38 mitogen-activated protein kinase (MAPK). A p38 inhibitor (SB203580) specifically reversed the Meth-induced upregulation of the CCR5 HIV-1 coreceptor. The dopamine D2 receptor antagonist RS +/- sulpiride significantly reversed the Meth-induced upregulation of CCR5, demonstrating that the Meth-induced effect is mediated via the D2 receptor. These studies report for the first time that Meth fosters HIV-1 infection, potentially via upregulating coreceptor gene expression. Further, Meth mediates its regulatory effects via dopamine receptors and via downregulating ERK2 with a reciprocal upregulation of p38 MAPK. Elucidation of the role of Meth in HIV-1 disease susceptibility and the mechanism through which Meth mediates its effects on HIV-1 infection may help to devise novel therapeutic strategies against HIV-1 infection in high-risk Meth-using HIV-1-infected subjects. Nair, M.P., Saiyed, Z.M., Nair, N., Gandhi, N.H., Rodriguez, J.W., Boukli, N., Provencio-Vasquez, E., Malow, R.M., and Miguez-Burbano, M.J. J. Neuroimmune Pharmacol. October 29, 2008.

Routine HIV Testing in Jails is Critical for the Early Diagnosis of HIV Infection in Men

The authors emphasize the need for development of new HIV testing and referral strategies for use in jails that will increase the number of diagnoses of HIV and facilitate earlier referral and entry of HIV positive patients to care, when CD4 cell counts are higher and treatment is more effective. Late presentation for care has been associated with black race and male sex, as well as increased likelihood of being poor and uninsured, less educated, disproportionately incarcerated and high levels of HIV infection, addiction and mental health disorders. It is recommended that interventions with maximum potential public health impact, such as routine rapid HIV testing performed as part of medical intake for processing persons in jails, be prioritized. Flanigan, T. P., and Beckwith, C.G. Clin. Infect. Dis. 47(10), pp. 1366, Novmber 2008.

HIV/HCV: Role of Molecular Mimickry of Hepatitis C-virus (HCV) Protein with Platelet GPIIIa in Hepatitis C-related Immunologic Thrombocytopenia

HIV-1-ITP patients have a unique Ab against platelet GPIIIa49-66 capable of inducing oxidative platelet fragmentation in the absence of complement. HIV-1-seropositive drug abusers are more prone to develop immune thrombocytopenia (HIV-1-ITP) than non-drug abusers and have a higher coinfection with Hepatitis C virus than non-drug abusers (90% vs 30%). Molecular mimickry with a Hepatitis C protein was sought by screening a phage peptide library with anti-GPIIIa49-66 antibody as bait for peptides sharing homology sequences with HCV protein. Several phage peptide clones had 70% homology with HCV protein. Sera from dually infected thrombocytopenic patients with HCV and HIV-ITP reacted strongly with 4 nonconserved peptides from HCV core envelope 1. Reactivity correlated inversely with platelet count, r2=0.7, p<0.01. Ab raised against peptide PHC09 in GPIIIa-/- mice induced severe thrombocytopenia in wild-type mice. Affinity-purified IgG against PHC09 induced oxidative platelet fragmentation in vitro. Drug abusers dually infected with HCV and HIV-1 had a greater incidence and severity of thrombocytopenia as well as greater incidence and titer of anti- GPIIIa49-66/PHC09 Ab. NZB/W F1 mice injected with recombinant core envelope 1 developed Ab vs PHC09 and significantly decreased their platelet count, p<0.001. Thus, HCV core envelope 1 can induce thrombocytopenia by molecular mimicry with GPIIIa49-66. Note: ITP (idiopathic immune thrombocytopenic purpura) A condition in which the body produces antibodies against the platelets in the blood, the cells responsible for blood clotting. ITP is very common in persons infected with HIV. If left untreated, ITP can lead to uncontrolled bleeding. Zhang, W., Nardi, A.M., Li, Z., Borkowsky, W., and Karpatkin, S. Blood. Prepublished online, November 20, 2008.

Platelet Fragmentation Requires a Specific Structural Conformation of Human Monoclonal Antibody against 3 Integrin

The authors have described an autoantibody against 3 (GPIIIa49-66), a region of platelet integrin IIb3 that is unique. It induces platelet fragmentation in the absence of complement via antibody activation of platelet NADPH oxidase and 12-lipoxygenase to release reactive oxygen species, which destroy platelets. To study the mechanism of anti-GPIIIa antibody-induced platelet fragmentation, the authors screened a human single chain Fv antibody library with the GPIIIa49-66 peptide. Nine monoclonal antibodies were identified that were capable of binding to GPIIIa49-66. Surprisingly, binding avidity for GPIIIa49-66 did not correlate with activity of induction of platelet fragmentation. They therefore investigated the requirements for platelet fragmentation. Mutations were introduced into the heavy chain complementary-determining region-3 of clones 11, 43, and 54 by site-directed mutagenesis. The capability of these clones to induce platelet fragmentation or bind to GPIIIa49-66 subsequently changed. Molecular modeling of these clones with their mutants revealed that the ability to induce platelet fragmentation is affected by the side chain orientation of positively charged amino acids in the heavy chain of residues 99-102. Thus, a structural change in the conformation of anti- GPIIIa49-66 antibody contributes to its binding to the 3 integrin and subsequent antibody-induced platelet fragmentation and aggregate dissolution. Li, Z., Nardi, A.M., Wu, J., Pan, R., Zhang, W., and Karpatkin, S. J. Biol. Chem., 283(6), pp. 3224-3230, February 8, 2008.

Liver Fibrosis During an Outbreak of Acute Hepatitis C Virus Infection in HIV-Infected Men: A Prospective Cohort Study

Outbreaks of acute hepatitis C virus (HCV) infection are occurring in HIV-infected men who have sex with men. The authors evaluated risk factors and liver histopathology in 11 consecutively enrolled men with newly acquired HCV infection that was diagnosed on the basis of antibody seroconversion, new elevations in alanine aminotransferase level, and wide fluctuations in HCV RNA level. Ten patients reported unprotected anal intercourse, and 7 reported "club-drug" use, including methamphetamine. Liver biopsy showed moderately advanced fibrosis (Scheuer stage 2) in 9 patients (82%). No cause of liver damage other than acute HCV infection was identified. The specific pathways leading to periportal fibrosis in HIV-infected men with newly acquired HCV infection require investigation. Note: On the cover: Image showing a liver biopsy specimen from an HIV-infected man with acute hepatitis C virus infection obtained 8 weeks after presentation with clinical hepatitis. Fierer, S.D., Uriel, J.A., Carriero, C.D., Klepper, A., Dieterich, T.D., Mullen, P.M., Thung, N.S., Fiel, M.I., and Branch, D.A. The Journal of Infectious Diseases, 198(5), pp. 683, 1 September 2008.

Clinicopathologic Correlates of Hepatitis C Virus in Brain: A Pilot Study

Hepatitis C virus (HCV) has been detected in the brain tissues of 10 individuals reported to date; it is unclear what clinical factors are associated with this, and with what frequency it occurs. Accordingly, a pilot analysis utilizing reverse transcriptase-polymerase chain reaction (RT- PCR) to detect and sequence HCV in premortem plasma and postmortem brain and liver from 20 human immunodeficiency virus (HIV)-infected and 10 HIV-naive individuals was undertaken. RNA encoding the first 126 amino acids of the HCV E1 envelope protein and the majority of the E1 signal sequence was analyzed in parallel with an 80-base-long segment of the 5' untranslated region (UTR). Liver HCV was detected only in subjects with premortem HCV viremia (10 HIV-infected and 3 HIV-naive). Brain HCV was detected in 6/10 HCV/HIV-coinfected and 1/3 HCV-monoinfected subjects. In the setting of HIV, the magnitude of plasma HCV load did not correlate with the presence of brain HCV. However, coinfected patients with brain HCV were more often off antiretroviral therapy and tended to have higher plasma HIV loads than those with HCV restricted to liver. Furthermore, premortem cerebrospinal fluid (CSF) analysis revealed that HCV/HIV-coinfected patients with brain HCV had detectable CSF HIV, whereas those without brain HCV had undetectable CSF HIV loads (P = .0205). Neuropsychologic tests showed a trend for hierarchical impairment of abstraction/executive functioning in HIV/HCV coinfection, with mean T scores for HIV monoinfected patients 43.2 (7.3), for liver-only HCV 39.5 (9.0), and for those with HCV in brain and liver 33.2 (5.1) (P = .0927). Predominant brain HCV sequences did not match those of the plasma or liver in 4 of the 6 coinfected patients analyzed. The authors conclude that in the setting of HIV/HCV coinfection, brain HCV is a common phenomenon unrelated to the magnitude of HCV viremia, but related to active HIV disease and detectable CSF HIV. Furthermore, there is sequence evidence of brain compartmentalization. Differences in abstraction/executive function of HCV/HIV coinfected patients compared to HIV monoinfected warrant further studies to determine if neuropsychiatric effects are predicated upon brain infection. Murray. J., Fishman, S.L., Ryan, E., Eng, F.J., Walewski, J.L., Branch, A.D., and Morgello, S. Journal of Neurovirology, 14(1), pp. 17 - 27, January 2008.

HCV/ HIV Co-infection: Time to Re-evaluate the Role of HIV in the Liver?

Because of major advances in the treatment of HIV /AIDS, HIV-positive persons now live longer, healthier lives; however, hepatitis C virus (HCV) is increasingly recognized as a major cause of morbidity and mortality in this population. Among HCV-infected persons, HIV co-infection is associated with increased HCV RNA levels, increased hepatic inflammation and fibrosis, and more rapid progression to cirrhosis and end-stage liver disease. Compounding this problem are reduced HCV treatment response rates among HCV /HIV co-infected persons. Moreover, antiretroviral therapy used to suppress HIV replication is often associated with a paradoxical increase in HCV RNA levels, as well as hepatotoxicity. Despite the adverse clinical consequences of HCV/ HIV co-infection, the mechanisms by which these two viruses interact at the cellular level remain largely unexplored. This review focuses on the evidence demonstrating direct infection of hepatocytes by HIV, as well as the indirect mechanisms by which HIV may regulate HCV replication at the cellular level. A comprehensive understanding of virus-virus and virus-cell interactions is critical to the development of novel treatment strategies to combat HCV/ HIV co-infection. Blackard, L.T., and Sherman, K.E. Journal of Viral Hepatitis, 15, pp. 323-330, 2008.

Quality of Life, Symptomatology and Healthcare Utilization in HIV/HCV Co-infected Drug Users in Miami

HIV/HCV co-infection is becoming one of the main causes of death in HIV+ persons. The authors determined quality of life, clinical symptoms and health care utilization in HIV mono-infected and HIV/HCV co-infected chronic drug users. After consenting 218 HIV+ drug users, a physical examination and questionnaires on demographics, quality of life, drugs of abuse, and healthcare utilization were completed. Blood was drawn for HCV status, CD4 cell count, HIV viral load, CBC and chemistry. HIV/HCV co-infected participants had significantly higher risk of having poorer perceived outlook and health, presented significantly more frequent depression and physical symptoms, and used significantly more healthcare services than those infected with HIV only, after adjusting for age, gender, ethnicity, CD4 cell count, and viral load. Diminished quality of life in the HIV/HCV co-infected group was explained by increased frequency of depression, physical symptoms, healthcare utilization, and poor access to HCV treatment in this population. Baum, M.K., Jayaweera, D.T., Duan, R., Sales, S., Lai, S., Rafie, C., Regev, A., Page, J.B., Berkman, R., and Campa, A. J. Addict. Dis. 27(2), pp. 37-48, 2008.

Low Frequency of GB Virus C Viremia in a Cohort of HIV-1-infected Elite Suppressors

The persistence of GB virus C viremia in patients with chronic HIV-1 infection has been associated with increased survival. Elite suppressors are untreated HIV-1-infected patients who maintain viral loads of below 50 copies/ml. This study found that the frequency of GB virus C viremia in elite suppressors and chronically infected patients with progressive disease was not significantly different. Thus, GB virus C does not appear to explain the nonprogressive course seen in this cohort of elite suppressors. Blankson, J.N., Klinzman, D., Astemborski, J., Thomas, D.L., Kirk, G.D., and Stapleton, J.T. AIDS, 22(17), pp. 2398-2400, 2008.

HCV/ HBV, Liver Disease: Molecular and Bioinformatic Evidence of Hepatitis C Virus Evolution in Brain

HCV was present in the brains of 7 (54%) of 13 patients with viremia, as determined by 5' UTR and E1 (envelope 1) gene analysis. Brain HCV RNA consensus sequences differed from those in plasma and liver in 4 (57%) of 7 patients. The quality of HCVRNA from postmortem brain and liver was assessed and demonstrated to be suitable for sequence analysis. Quasispecies analysis revealed that several mutations present in clones from >1 brain region were absent in clones from liver and plasma. Brain-specific mutations defined several families of related sequences. The patterns of brain-specific mutations in these families were consistent with the evolution of HCV RNA from a common ancestor. Single-nucleotide-polymorphism analysis confirmed that a prominent brain-specific mutation constituted ~10% of HCV RNA in cerebellum and medulla but that this mutation was undetectable in the liver and plasma of the same patient. In conclusions, This study introduces novel methods for assessing RNA from postmortem samples. It increases the reported cases of HCV in the brain, provides the first E1 sequences from the brain, and contributes to the growing evidence that HCV replicates and evolves within the brain. Fishman, L.S., Murray, M.J., Eng, J.F., Walewski, L.J., Morgello, S., and Branch, D.A. The Journal of Infectious Diseases, 197, pp. 597-607, 2008.

Clinical Outcomes of Hepatitis C Treatment in a Prison Setting: Feasibility and Effectiveness for Challenging Treatment Populations

More than one-third of people in the United States with hepatic C virus (HCV) infection pass through the correctional system annually. Data are lacking on outcomes of treatment with pegylated interferon plus ribavirin (PEG-RBV) in correctional settings. During 2002-2006, the authors analyzed patients in the Connecticut Department of Correction who received PEG-RBV. They assessed the rates of sustained virological response, hospitalization, and use of medications to treat psychiatric disorders and anemia. Of 138 treatment-naive patients referred for treatment, 68 (49%) were approved. Overall, sustained virological response occurred in 47.1% of patients (for HCV genotype 1, 43.1%; for HCV genotypes 2 and 3, 58.8%). Only 9 patients (13%) discontinued treatment because of adverse effects. Multiple regression analysis revealed that not achieving a sustained virological response was correlated with HCV genotype 1 infection plus cirrhosis (adjusted odds ratio, 12.9; 95% confidence interval, 1.1-148) and baseline major depression (adjusted odds ratio, 3.4; 95% confidence interval, 1.01-11.6), but not with HIV infection, a baseline HCV RNA level >or=400,000 IU/mL, or black race. Compared with baseline, the rate of prescription of a new mood stabilizer (2.2 vs. 0.8 prescriptions per person-year) or an opioid (1.8 vs. 0.5 prescriptions per person-year) was higher during treatment, whereas there was no change in the rate of prescription of benzodiazepines and antipsychotic medications. These results support the feasibility and clinical effectiveness of PEG-RBV for the treatment of chronic HCV infection in correctional facilities. Maru, D.S., Bruce, R.D., Basu, S., and Altice, F.L. Clin. Infect. Dis. 47(7), pp. 952-961, October 2008.

Hepatitis C Virus-specific T-cell Immune Responses in Seronegative Injection Drug Users

T-cell responses to hepatits C virus (HCV) antigens have been reported in high-risk HCV seronegative persons, suggesting that an effective cellular immune response might be able to clear infection without the development of antibodies. Such findings, however, could be explained by waning antibody or cross-reactivity to other antigens. To address these issues, the authors evaluated HCV-specific T-cell responses in 26 young (age 18-33 years) aviremic, seronegative injection drug users (IDUs) (median duration of injection, 6 years) by interferon-gamma enzyme-linked immunospot (ELISpot) assay using 429 overlapping HCV peptides pooled in 21 mixes. Seventeen aviremic, seropositive IDUs (spontaneous resolvers) and 15 healthy people were used as positive and negative controls, respectively. The percentage of patients with HCV-specific cellular immune responses was similar in seronegative and seropositive aviremic IDUs (46%vs 59%, P = 0.4), while these responses were not detected in any of the negative controls. Among the seronegative IDUs, six (23%) had intermediate to very strong responses to 10-20 peptide mixes and another six (23%) had moderately strong responses for two to six mixes. The 12 seronegative IDUs with HCV-specific T-cell responses had higher demographical and behavioural risk profiles than the 14 IDUs without T-cell responses (estimated risk of HCV infection, 0.47 vs 0.26, P < 0.01). In conclusion, HCV-specific T-cell responses are common among high-risk, seronegative IDUs. The responses are broad and are associated with risk factors for HCV exposure, suggesting that they reflect true exposure to HCV in seronegative persons. Zeremski, M., Shu, M.A., Brown, Q., Wu, Y., DesJarlais, D.C., Busch, M.P., Talal, A.H., and Edlin, B.R. J. Viral Hepat. [Epub ahead of print] July 17, 2008.

The Inverse Relationship Between Chronic HBV and HCV Infections Among Injection Drug Users is Associated with Decades of Age and Drug Use

Infection with hepatitis C virus (HCV) may suppress co-infection with hepatitis B virus (HBV) during acute or chronic HBV infection. The authors examined relationships between HBV infection, HCV infection and other factors among injection drug users (IDUs) with antibodies to both viruses. Participants enrolled in a cross-sectional study during 1998-2000 were considered to have been infected with HBV if they had core antibody, to be chronically infected if they had hepatitis B surface antigen (HBsAg), to have been infected with HCV if they had HCV antibody and to be chronically infected if they had HCV RNA. Among 1,694 participants with antibody to both viruses, HBsAg prevalence decreased with increasing age among those positive for HCV RNA [from 4.55% in those 18-29 years to 1.03% in those >or=50 years old (P(trend) = 0.02)], but not among those who were negative for HCV RNA. Chronic HBV infection was less common overall among those with chronic HCV infection (odds ratio [OR], 0.25; P < 0.0001), but this inverse relationship was much stronger in the oldest (>50 years; OR = 0.15) than the youngest (18-29 years; OR = 0.81) participants (P(trend) = 0.03). Similar results were obtained when duration of injection drug use was substituted for age (P(trend) = 0.05). Among IDUs who have acquired both HBV and HCV, chronic HBV infection is much less common among those with chronic HCV infection, but this inverse relationship increases markedly with increasing years of age and injection drug use. Co-infection with HCV may enhance the resolution of HBsAg during the chronic phases of these infections. Tseng, F.C., Edlin, B.R., Zhang, M., Kral, A., Busch, M.P., Ortiz-Conde, B.A., Welzel, T.M., and O'Brien, T.R., J. Viral Hepat. 15(9), pp. 690-698, September 2008.

Hepatitis C Virus (HCV)-specific Immune Responses of Long-term Injection Drug Users Frequently Exposed to HCV

Injection drug users (IDUs) who successfully clear hepatitis C virus (HCV) have a reduced risk of developing chronic reinfection, despite their continuing exposure to the virus. To identify immunological correlates for this apparent protection, the authors studied HCV-specific immune responses in long-term IDUs (duration, >10 years). HCV-specific T cell responses were assessed in proliferation, enzyme-linked immunospot (ELISPOT), interferon (IFN)-gamma secretion, and cytotoxicity assays, whereas HCV-specific antibodies were assessed in enzyme immunoassays (EIAs), chemiluminescent assays, and in vitro neutralization assays. HCV-specific T cell proliferation and IFN-gamma production were more common in nonviremic EIA-positive IDUs (16 [94%] of 17 IDUs) than in viremic EIA-positive IDUs (9 [45%] of 20 IDUs) (P= .003). They were also noted in 16 (62%) of 26 nonviremic EIA-negative IDUs. In contrast, 19 (90%) of 21 viremic IDUs displayed neutralizing antibodies (nAbs), compared with 9 (56%) of 16 nonviremic EIA-positive IDUs (P= .04) and 0 of 24 nonviremic EIA-negative IDUs. Nonviremic IDUs with nAbs were older (P= .0115) than those without nAbs, but these groups did not differ in terms of either injection drug use duration or HCV-specific T cell responses. The authors concluded that the reduced risk of HCV persistence in IDUs previously recovered from HCV infection correlated with T cell responses, and prolonged antigenic stimulation appears to be required to maintain humoral responses. Mizuk, L.H., Busch, M.P., Carrington, M., McKeating, J.A., O'Brien, T.R., and Rehermann, B. J. Infect. Dis. 198(2), pp. 203-212, 2008.

MBL2 and Hepatitis C Virus Infection Among Injection Drug Users

Genetic variations in MBL2 that reduce circulating levels and alter functional properties of the mannose binding lectin (MBL) have been associated with many autoimmune and infectious diseases. The authors examined whether MBL2 variants influence the outcome of hepatitis C virus (HCV) infection. Participants were enrolled in the Urban Health Study of San Francisco Bay area injection drug users (IDU) during 1998 through 2000. Study subjects who had a positive test for HCV antibody were eligible for the current study. Participants who were positive for HCV RNA were frequency matched to those who were negative for HCV RNA on the basis of ethnicity and duration of IDU. Genotyping was performed for 15 single nucleotide polymorphisms in MBL2. Statistical analyses of European American and African American participants were conducted separately. The analysis included 198 study subjects who were positive for HCV antibody, but negative for HCV RNA, and 654 IDUs who were positive for both antibody and virus. There was no significant association between any of the genetic variants that cause MBL deficiency and the presence of HCV RNA. Unexpectedly, the MBL2 -289X promoter genotype, which causes MBL deficiency, was over-represented among European Americans who were HCV RNA negative (OR = 1.65, 95% CI 1.05-2.58), although not among the African Americans. This study found no association between genetic variants that cause MBL deficiency and the presence of HCV RNA. The observation that MBL2 -289X was associated with the absence of HCV RNA in European Americans requires validation. Brown, E.E., Zhang, M., Zarin-Pass, R., Bernig, T., Tseng, F.C., Xiao, N., Yeager, M., Edlin, B.R., Chanock, S.J., and O'Brien, T.R. BMC Infect. Dis. 8(57), pp. 1-8, 2008.

Hepatitis C Patients' Self-reported Adherence to Pegylated Interferon and Ribavirin

Prior research on adherence to Hepatitis C treatment has documented rates of dose reductions and early treatment discontinuation, but little is known about patients' dose-taking adherence. The aims of this study were to assess the prevalence of missed doses of pegylated interferon and ribavirin and examine the correlates of dose-taking adherence in clinic settings. 180 patients on treatment for Hepatitis C (23% co-infected with HIV) completed a cross-sectional survey at the site of their Hepatitis C care. Seven percent of patients reported missing at least one injection of pegylated interferon in the last four weeks and 21% reported missing at least one dose of ribavirin in the last 7 days. Dose-taking adherence was not associated with HCV viral load. The authors concluded that self-reported dose nonadherence to Hepatitis C treatment occurs frequently. Further studies of dose nonadherence (assessed by method other than self-report) and its relationship to HCV virologic outcome are warranted. Weiss, J.J., Bhatti, L., Dieterich, D.T., Edlin, B.R., Fishbein, D.A., Goetz, M.B., Yu, K., and Wagner, G.J. Aliment. Pharmacol. Ther. 28, pp. 289-293, 2008.

Interaction Between RANTES Promoter Variant and CCR5Delta32 Favors Recovery from Hepatitis B

Recovery from acute hepatitis B virus (HBV) infection occurs in 95% of adult-acquired infections. A 32-bp deletion in CCR5 (CCR5Delta32), which encodes for a nonfunctional receptor, increases the likelihood of recovery. Using 181 subjects with persistent HBV infection and 316 who had recovered, the authors tested the hypothesis that an epistatic interaction between functional polymorphisms in RANTES (a CCR5 ligand) and CCR5 impacts recovery. Specific models designed to assess individual contributions of compound genotypes demonstrated that the only combination associated with recovery from an HBV infection was RANTES -403A with CCR5Delta32 (odds ratio 0.36, p = 0.02). Because the phenotypic consequence of -403A is reported to be higher levels of RANTES, the authors propose a model in which excess RANTES in combination with low CCR5 favors recovery from an HBV infection, which will require validation through functional testing. Thio, C.L., Astemborski, J., Thomas, R., Mosbruger, T., Witt, M.D., Goedert, J.J., Hoots, K., Winkler, C., Thomas, D.L., and Carrington, M. J. Immunol. 181(11), pp. 7944-7947, 2008.

Exceeding the Limits of Liver Histology Markers

Alternatives to liver biopsy for staging liver disease caused by hepatitis C virus (HCV) have not appeared accurate enough for widespread clinical use. The authors characterized the magnitude of the impact of error in the "gold standard" on the observed diagnostic accuracy of surrogate markers. They calculated the area under the receiver operating characteristic curve (AUROC) for a surrogate marker against the gold standard (biopsy) for a range of possible performances of each test (biopsy and marker) against truth and a gradient of clinically significant disease prevalence. In the 'best' scenario where liver biopsy accuracy is highest (sensitivity and specificity of biopsy are 90%) and the prevalence of significant disease 40%, the calculated AUROC would be 0.90 for a perfect marker (99% actual accuracy) which is within the range of what has already been observed. With lower biopsy sensitivity and specificity, AUROC determinations >0.90 could not be achieved even for a marker that perfectly measured disease. The authors demonstrate that error in the liver biopsy result itself makes it impossible to distinguish a perfect surrogate from ones that are now judged by some as clinically unacceptable. An alternative gold standard is needed to assess the accuracy of tests used to stage HCV-related liver disease. Mehta, S.H., Lau, B., Afdhal, N.H., Thomas, D.L. J. Hepatol. 51, pp. 36-41, 2008.

Genetic Markers of IgG Influence the Outcome of Infection with Hepatitis C Virus

The authors examined the role that immunoglobulin GM and KM allotypes-genetic markers of gamma and kappa chains, respectively-play in the outcome of hepatitis C virus (HCV) infection in white Americans. A total of 119 persons who had cleared HCV and 111 with persistent HCV infection were genotyped for the presence of several GM and KM determinants. Persistent HCV infection was more than three times as likely (odds ratio, 3.50; P= .01) in subjects who were carriers of the GM3 allele than in those who were noncarriers. These results show that particular GM alleles may be important determinants of the outcome of HCV infection. Pandey, J.P., Namboodiri, A.M., Luo, Y., Wu, Y., Elston, R.C., Thomas, D.L., Rosen, H.R., and Goedert, J.J. J. Infect. Dis. 198(9), pp. 1334-1336, 2008.

Detection of Liver Disease in Injection Drug Users

Detection of liver disease among injection drug users is an important challenge because liver disease is common, usually unrecognized, and treatable in early stages. Many forms of liver disease occur in injection drug users (IDUs). However, commensurate with its exceedingly high prevalence among IDUs, much of the published literature (and accordingly the focus of this review) regards liver disease caused by chronic hepatitis C. Existing guidelines for detection of liver disease are presented in the context of the current standard of care. Since recent research shows these guidelines rarely contribute to the medical management of IDUs, special emphasis is given to novel approaches that, when coupled with advances in treatment, the authors believe could substantially reduce the medical and psychological consequences of injection drug use. Thomas, D.L., and Sulkowski, M.S. J. Addict. Dis. 27(2), pp. 19-24, 2008.

HCV E2 Protein Binds Directly to Thyroid Cells and Induces IL-8 Production: A New Mechanism for HCV Induced Thyroid Autoimmunity

HCV infection is well-known to be associated with autoimmune thyroiditis. However, the mechanisms by which HCV triggers thyroiditis are unknown. The authors hypothesized that HCV envelope proteins could induce thyroidal inflammation directly, thereby triggering thyroiditis by a bystander activation mechanism. To test this hypothesis they examined whether the HCV receptor CD81 was expressed and functional on thyroid cells. The authors found significant levels of CD81 mRNA by QPCR analysis, as well as CD81 protein by flow cytometric (FACS) analysis. Incubation of thyroid cells with HCV envelope glycoprotein E2 resulted in E2 binding to thyroid cells and activation of IL-8, an important pro-inflammatory cytokine. Intriguingly, thyroid cells incubated with E2 continued to proliferate normally and did not undergo apoptosis, as was reported in hepatocytes. The authors conclude that: (1) HCV envelope glycoprotein E2 can bind to CD81 receptors which are expressed on thyroid cells and induce a cascade of signaling pathway leading to IL-8 release; and (2) HCV may trigger thyroiditis in genetically susceptible individuals by bystander activation mechanisms. Akeno, N., Blackard, J.T., and Tomer, Y. Journal of Autoimmunity, 31(4), pp. 339-344, 2008.

Efficacy and Safety of Peginterferon alfa-2a/ribavirin in Methadone Maintenance Patients: Randomized Comparison of Direct Observed Therapy and Self-administration

The investigators assessed the safety, tolerability, and efficacy of peginterferon alfa-2a/ribavirin treatment in methadone maintenance patients previously untreated for Chronic Hepatitis C (CHC). Based on defined efficacy stopping rules, 77% (37/48) completed their targeted length of treatment, and 44% (21/48) achieved sustained virologic response (SVR). Over 60% and 50% of each group were > 80% compliant with the planned cumulative doses of peginterferon alfa-2a and ribavirin, respectively, and over 60% with overall treatment duration. SVR rates were 54% for Directly Observed Therapy (DOT) and 33% for Self Administration (SA); 23% and 38%, respectively, for genotype 1 and 91% and 25%, respectively, for genotypes 2 and 3. DOT and Caucasian race were found to be predictors of SVR. Peginterferon alfa-2a/ribavirin was found safe and successful for use in CHC patients receiving methadone maintenance. Bonkovsky, H.L., Tice, A.D., Yapp, R.G., Bodenheimer, H.C. Jr., Monto, A., Rossi, S.J., and Sulkowski. M. S. Am. J.Gastroenterol., 103(11), pp. 2757-2765, November 2008. Epub August 5, 2008.

Safety and Antiviral Activity of Albinterferon Alfa-2b in Prior Interferon Nonresponders With Chronic Hepatitis C

The safety/efficacy of albinterferon alfa-2b, a recombinant protein consisting of interferon alfa-2b fused to human albumin to increase drug exposure in Chronic Hepatitis C patients unresponsive to interferon-based regimens was evaluated for safety and efficacy. Among non-responders, higher doses of albinterferon showed significant early antiviral activity and low incidence of adverse events, with types of adverse events similar to those observed with interferon treatment. Nelson, D.R., Rustgi, V., Balan, V., Sulkowski, M.S., Davis, G.L., Muir, A.J., Lambiase, L.R., Dickson, R.C., Weisner, R.H., Fiscella, M., Cronin, P. W., Pulkstenis, E., McHutchison, J.G., and Subramanian, G.M. Clin. Gastroenterol. Hepatol. [Epub ahead of print], November 7, 2008.

Successful Treatment of Chronic Hepatitis C with Pegylated Interferon in Combination with Ribavirin in a Methadone Maintenance Treatment Program

Injection drug users (IDUs) constitute the majority of individuals with hepatitis C virus (HCV), however there are limited clinical outcome data regarding HCV treatment provided on-site in methadone maintenance settings. On-site HCV treatment with pegylated interferon and ribavirin was shown effective in methadone-maintained patients, with HCV treatment response rates nearly equivalent to previously published response rates for non-IDUs. Of 73 patients; 55% achieved end-of-treatment response and 45% achieved sustained viral response, despite high prevalences of ongoing drug use (49%), psychiatric comorbidity (67%), and HIV co-infection (32%). Methadone maintenance programs were shown as safe settings for the treatment of chronic hepatitis C. Litwin, A.H., Harris, K. A. Jr., Nahvi, S., Zamor, P.J., Soloway, I.J., Tenore, P.L., Kaswan, D., Gourevitch, M.N., and Arnsten, J.H., J. Subst. Abuse Treat. [Epub ahead of print]. November 25, 2008.

Naturally Occurring Dominant Resistance Mutations to Hepatitis C Virus Protease and Polymerase Inhibitors in Treatment-naive Patients

Resistance mutations to hepatitis C virus (HCV) nonstructural protein protease inhibitors in <1% of the viral quasispecies may still allow >1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naive individual, raising concerns about possible full drug resistance. The authors analyzed HCV genome sequences from 507 treatment-naive patients infected with HCV genotype 1 from the United States, Germany, and Switzerland, to investigate the prevalence of dominant resistance mutations against specifically targeted antiviral therapy for HCV (STAT-C) in the population. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication-competent, drug-resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo. Naturally occurring dominant STAT-C resistance mutations were found to be common in treatment-naive patients infected with HCV genotype 1. The authors suggest further development of drug resistance testing for individual tailoring of drug combinations when treatment options are limited, or unresponsivity to previous treatment. Kuntzen, T., Timm, J., Berical, A., Lennon, N., Berlin, A.M., et al., Hepatology, 48(6), pp. 1769-1778, December 2008.

Aldosterone Induces Mesangial Cell Apoptosis both In Vivo and In Vitro

Both clinical and experimental reports indicate that aldosterone contributes to the progression of renal failure independent of its hemodynamic effects. In the present study, the authors evaluated the effects of aldosterone on human mesangial cell (MC) growth. Aldosterone induced apoptotic and mitogenic effects on MCs. Aldosterone promoted MC Apoptosis in a dose- and time-dependent manner. Spironolactone, a mineralocorticoid receptor antagonist, inhibited aldosterone-induced MC Apoptosis. Similarly, antioxidants and free radical scavengers partially attenuated proapoaptotic effects of aldosterone. Aldosterone also enhanced dephosphorylation of phospho- Bad and accumulation of cytosolic cytochrome c in MCs. In in vivo studies, rats were randomly assigned to receive normal saline, aldosterone, or eplerenone + aldosterone for 28 days. Systolic blood pressure, urinary albumin excretion rate, serum creatinine, and aldosterone were measured. Aldosterone-infused rats developed elevated systolic blood pressure and albuminuria when compared with control rats. Aldosterone-treated rats also showed greater numbers of apoptosed MCs. This proapoptotic effect of aldosterone was inhibited by eplerenone, a selective aldosterone antagonist. These findings suggest that aldosterone, besides its hemodynamic effects, may also directly contribute to the occurrence of MC apoptosis. Mathew, T.J., Patni, H., Chaudhary, N.A., Liang, W., Gupta, A., Chander, N.P., Ding, G., and Singhal, C.P. Am. J. Physiol. Renal Physiol., 295, pp. F73-F81, 2008.

Angiotensin II Infusion Induces Nephrin Expression Changes and Podocyte Apoptosis

In in vitro studies, angiotensin (Ang) II has been demonstrated to promote podocyte apoptosis. The present study evaluates the effects of Ang II infusion in rats on podocyte nephrin expression and apoptosis and the molecular mechanisms involved in Ang II-induced proteinuria and mesangial expansion. Sprague-Dawley rats were randomly assigned to receive either normal saline or Ang II (400 ng.kg-1.min-1) by means of a mini-osmotic pump for variable time periods. Systolic blood pressure and urinary protein and albumin excretion rate measurements were carried out on days 7, 14, 21, and 28. The animals were sacrificed on days 14 and 28 and evaluated for serum creatinine, renal pathological changes, podocyte apoptosis, renal nephrin mRNA, and protein expression. The Ang II-infused rats developed hypertension and proteinuria. On day 14, the Ang II-infused rats showed narrowing of the slit diaphragm, an increase in podocyte nephrin mRNA and protein expression, and alterations in its distribution along the foot processes. On day 28, the Ang II-infused rats demonstrated the presence of apoptotic podocytes and decreased nephrin mRNA and protein expression. There was a negative correlation between nephrin expression and the numbers of apoptotic podocytes (r = -0.63, p < 0.05). These results suggest that changes in nephrin expression may play a role in the pathogenesis of Ang II-induced podocyte apoptosis. Jia, J., Ding, G., Zhu, J., Chen, C., Liang, W., Franki, N., and Singhal, C.P. Am. J. Nephrol. 28, pp. 500-507, 2008.

Ethical and Human Rights Imperatives to Ensure Medication-assisted Treatment for Opioid Dependence in Prisons and Pre-trial Detention

Opioid dependence is a complex medical condition affecting neurocognitive and physical functioning. Forced or abrupt opioid withdrawal may cause profound physical and psychological suffering, including nausea, vomiting, diarrhea, extreme agitation and/or anxiety. Opioid-dependent individuals are especially vulnerable at the time of arrest or initial detention, when they may, as a result of their chemical dependency, be coerced into providing incriminating testimony, or be driven to engage in risky behaviour (such as sharing needles in detention) in order to avoid painful withdrawal symptoms. Upon incarceration, many opioid-dependent prisoners are forced to undergo abrupt opioid withdrawal (both from legally prescribed agonist therapy such as methadone as well as illicit opioids). Physical and psychological symptoms attendant to withdrawal may impair capacity to make informed legal decisions, and cause prisoners to risk HIV and other blood-borne diseases by sharing injection equipment. Although prisons must provide at least the standard of care to prisoners that is available in the general population, medication-assisted treatment, endorsed by international health and drug agencies as an integral part of HIV prevention and care strategies for opioid-dependent drug users, is unavailable to most prisoners. Medication-assisted treatment is a well-studied and validated pharmacological therapy for the medical condition known as opioid dependence. The failure to ensure prisoner access to this medical therapy threatens fundamental human rights protections against cruel, inhuman or degrading treatment and rights to health and to life. It also poses serious ethical problems for health care providers, violating basic principles of beneficence and non-maleficence (i.e., do good/do no harm). Governments must take immediate action to ensure access to opioid substitution to prisoners to ensure fulfillment of ethical and human rights obligations. Bruce, R. D., and Schleifer, R.A. Int. J. Drug Policy., 1, pp. 17-23, 2008.

Historical Analysis: Heroin in Brown, Black and White: Structural Factors and Medical Consequences in the US Heroin Market

Heroin coming into the United States historically comes from three widely dispersed geographical regions: Southwest Asia, Southeast Asia and Mexico. A fourth source of US-bound heroin, from Colombia, originated in the early 1990s. The fact that the four heroin sources produce differing morphologies and qualities of heroin has not been critically examined. In addition, it is not well established how the contemporary competing dynamics of interdiction, or restriction of heroin flows across international boundaries, and neoliberal, e.g., global expansion of free trade, policies are affecting heroin markets. This paper highlights changes in the US heroin market, including source trends, the political economy of the now dominant source and the resultant effects on the heroin risk environment by US region. Using a structural and historical framework this paper examines two decades of secondary data sources, including government and drug control agency documents, on heroin flows together with published work on the political and economic dynamics in Latin America. Co-occurring neoliberal economic reforms may have contributed to paradoxical effects of US/Colombian interdiction efforts. Since entering the US market, heroin from Colombia has been distributed at a much higher quality and lower retail price. An increasingly exclusive market has developed with Mexican and Colombian heroin gaining market share and displacing Asian heroin. These trends have had dramatic effects on the risk environment for heroin consumers. An intriguing factor is that different global sources of heroin produce substantially different products. Plausible associations exist between heroin source/form and drug use behaviors and harms. For example, coldwater-soluble powdered heroin (sources: Asia, Colombia) may be associated with higher HIV prevalence in the US, while low-solubility "black tar" heroin (BTH; source: Mexico) is historically used in areas with reduced HIV prevalence. BTH is associated with soft tissue infections caused by Clostridium bacteria. The authors conclude that source and type of heroin are structural factors in the risk environment of heroin users: source dictates distribution and type predicts practice. How specific types of heroin are used and with what risk is therefore distributed geographically. Continued flux in the heroin market and its effects on the risk environment for drug users deserves further attention. Ciccarone, D. Int. J. Drug Policy, Available online 21 October, 2008.

Case Series of Buprenorphine Injectors in Kuala Lumpur, Malaysia

Diversion of buprenorphine has been described in settings where it is legally prescribed and has become an increasing concern in Malaysia; it resulted in banning of buprenorphine in Singapore where unsubstantiated case reports suggested that buprenorphine injection was associated with particularly poor outcomes. The authors therefore conducted a case series of qualitative interviews with buprenorphine injectors in Kuala Lumpur, Malaysia to examine further the issues surrounding buprenorphine injection as well as the abuse of midazolam in combination with buprenorphine. Interviews with 19 men do not suggest significant adverse health consequences from buprenorphine injection alone and injectors have adapted diverted buprenorphine as a treatment modality. A subset of these injectors, however, combined buprenorphine and midazolam for euphoric effects with resultant symptoms of a possible pharmacological interaction. Prospective cohort studies, rather than hospital-derived samples, are needed to better understand the safety of buprenorphine injection. Bruce, R.D., Govindasamy S.S.L., Haddad, M.S., Kamarulzaman, A., and Altice, F.L. Am. J. Drug Alcohol Abuse, 34(4), pp. 511-517, 2008.

Mechanism of Ritonavir Changes in Methadone Pharmacokinetics and Pharmacodynamics: II. Ritonavir Effects on CYP3A and P-Glycoprotein Activities

Ritonavir diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but the actual mechanisms are unknown. The authors determined short-term (2-day) and steady-state (2-week) ritonavir effects on intestinal and hepatic CYP3A4/5 (probed with intravenous (IV) and oral alfentanil (ALF) and with miosis) and P-glycoprotein (P-gp) (fexofenadine), and on methadone pharmacokinetics and pharmacodynamics in healthy volunteers. Acute ritonavir increased the area under the concentration-time curve (AUC) (0-infinity)/dose ratio (ritonavir/control) for oral ALF 25-fold. Steady-state ritonavir increased the AUC (0-infinity)/dose ratio for IV and oral ALF 4- and 10-fold, respectively; reduced hepatic extraction (from 0.26 to 0.07) and intestinal extraction (from 0.51 to 0); and increased bioavailability (from 37 to 95%). Acute ritonavir inhibits first-pass CYP3A >96%. Chronic ritonavir inhibits hepatic CYP3A (>70%) and first-pass CYP3A (>90%). Acute and steady-state ritonavir increased the fexofenadine AUC (0-infinity) 2.8- and 1.4-fold, respectively, suggesting P-gp inhibition. Steady-state compared with acute ritonavir caused mild apparent induction of P-gp and hepatic CYP3A, but net inhibition still predominated. Ritonavir inhibited both intestinal and hepatic CYP3A and drug transport. ALF miosis noninvasively determined CYP3A inhibition by ritonavir. Kharasch, E., Bedynek, P., Walker, A., Whittington, D., Hoffer, C. Clin. Pharmacol. Ther. Advance online publications July 9, 2008.

Molecular Characterization of CYP2B6 Substrates

CYP2B6 has not been as fully characterized at the molecular level as other members of the human cytochrome P450 family. As more widely used in vitro probes for characterizing the involvement of this enzyme in the metabolism of xenobiotics have become available, the number of molecules identified as CYP2B6 substrates has increased. In this study the authors have analyzed the available kinetic data generated by multiple laboratories with human recombinant expressed CYP2B6 and along with calculated molecular properties derived from the ChemSpider database, they have determined the molecular features that appear to be important for CYP2B6 substrates. In addition they have applied 2D and 3D QSAR methods to generate predictive pharmacophore and 2D models. For 28 molecules with K(m) data, the molecular weight (mean +/- SD) is 253.78+/-74.03, ACD/logP is 2.68+/-1.51, LogD(pH 5.5) is 1.51+/-1.43, LogD(pH 7.4) is 2.02+/-1.25, hydrogen bond donor (HBD) count is 0.57 +/-0.57, hydrogen bond acceptor (HBA) count is 2.57+/-1.37, rotatable bonds is 3.50+/-2.71 and total polar surface area (TPSA) is 27.63+/-19.42. A second set of 15 molecules without K(m) data possessed similar mean molecular property values. These properties are comparable to those of a set of 21 molecules used in a previous pharmacophore modeling study (Ekins et al., J. Pharmacol. Exp. Ther. 288(1), pp. 21-29, 1999). Only the LogD and HBD values were statistically significantly different between these different datasets. The authors have shown that CYP2B6 substrates are generally small hydrophobic molecules that are frequently central nervous system active, which may be important for drug discovery research. Ekins, S., Iyer, M., Krasowski, M.D., and Kharasch, E.D. Curr. Drug Metab., 9(5), pp. 363-373, June 2008.

Role of CYP2B6 in Stereoselective Human Methadone Metabolism

Metabolism and clearance of racemic methadone are stereoselective and highly variable, yet the mechanism remains largely unknown. Initial in vitro studies attributed methadone metabolism to cytochrome P4503A4 (CYP3A4). CYP3A4 was also assumed responsible for methadone clearance in vivo. Nevertheless, recent clinical data do not support a primary role for CYP3A4 and suggest that CYP2B6 may mediate methadone clearance. Expressed CYP2B6 and also CYP2C19 N-demethylate methadone in vitro. This investigation tested the hypothesis that CYPs 2B6, 3A4, and/or 2C19 are responsible for stereoselective methadone metabolism in human liver microsomes and in vivo. N-demethylation of racemic methadone and individual enantiomers by expressed CYPs 2B6, 2C19, and 3A4 was evaluated. Stereoselective microsomal methadone metabolism was quantified, compared with CYP 2B6 and 3A4 content, and probed using CYP isoform-selective inhibitors. A crossover clinical investigation (control, CYP2B6 and CYP3A4 induction by rifampin, CYP3A inhibition by troleandomycin and grapefruit juice) evaluated stereoselective methadone disposition. At clinical concentrations, methadone enantiomer N-demethylation by recombinant CYPs 2B6, 3A4, and 2C19 was S > R, S = R, and S << R. Greater stereoselective metabolism (S > R) occurred in livers expressing high levels of CYP2B6 compared with CYP3A4. Clopidogrel, troleandomycin, and (+)-N-3-benzyl-nirvanol, selective inhibitors of CYPs 2B6, 3A4, and 2C19, respectively, inhibited microsomal methadone metabolism by 50-60%, 20-30%, and less than 10%. Only inhibition by clopidogrel was stereoselective. Clinically, rifampin diminished both R- and S-methadone plasma concentrations, but troleandomycin and grapefruit juice altered neither R- nor S-methadone concentrations. Plasma R/S-methadone ratios were increased by rifampin but unchanged by CYP3A inhibition. These results suggest a significant role for CYP2B6, but not CYP3A, in stereoselective human methadone metabolism and disposition. Totah, R.A., Sheffels, P., Roberts, T., Whittington, D., Thummel, K., and Kharasch, E.D. Comment in: Anesthesiology 108(3), pp. 351-352; March 2008.

Self-Reported Substance Use and Sexual Behaviors among Adolescents in a Rural State

Research finds a strong association between substance use and risky sexual behavior but more needs to be known about this relationship. Few studies have examined this relationship among rural sixth- to eighth-grade students. As such, the purposes of this study were to provide a descriptive profile of rural sixth- to eighth-grade students' substance use behavior and sexual activity and to examine the relationship between substance use behaviors and sexual activity. Participants consisted of a convenience sample of 10,273 middle school students (sixth to eighth grade) attending 10 public schools in rural Tennessee. The middle school Youth Risk Behavior Survey was administered to these students during April and May 2004. Analysis found that a large percentage of students had tried cigarettes, alcohol, and inhalants. Additionally, it was found that sexual intercourse had been initiated by 18.8% of females and 25.4% of males. Of those students who reported ever having had sexual intercourse, 75% had reported the use of cigarettes and alcohol. In addition, approximately 50% of those students reported marijuana and inhalant use. The results suggest that substance use behavior has a relationship with the likelihood of initiating sexual activity. Additional longitudinal research with this population will be needed for explaining whether these select substance use behaviors are probable risk factors predisposing young rural adolescents to report engaging in sexual behaviors or a result of other factors. Dunn, M.S., Ilapogu, V., Taylor, L., Naney, C., Blackwell, R., Wilder, R., and Givens, C. J. Sch. Health. 78(11), pp. 587-593, November 2008.

Gender-related Differences in Muscle Injury, Oxidative Stress, and Apoptosis

Due to its alleged antioxidant properties, 17beta-estradiol (E2) may protect against muscle injury, oxidative stress, and apoptosis. This study sought to determine whether such mechanisms existed between genders for muscle injury, oxidative stress, and apoptosis after eccentric exercise. Eight men and eight women (no oral contraceptive use; midluteal phase of menstrual cycle) performed 7 x 10 eccentric repetitions of the knee extensors at 150% 1RM. Strength, soreness, and blood samples were taken before exercise and 6, 24, 48, and 72 h after exercise while muscle samples were collected before and 6 and 24 h after exercise. Blood samples were assayed for free E2, lactate dehydrogenase (LDH), superoxide dismutase (SOD), and 8-isoprostane (8-iso). Muscle samples were assayed for mitochondrial apoptosis (e.g., bax, bcl-2, cytochrome c, and cell death), total DNA content, and myofibrillar protein content. Men reported greater soreness levels at 24, 48, and 72 h after exercise, whereas strength changes were similar among genders. At baseline and independent of exercise, females had higher E2 (P < 0.001) and SOD in conjunction with lower 8-iso levels when compared with men. Bax increased in both genders, whereas bcl-2 increased only in women with no cytochrome c changes for either gender after exercise. The bax/bcl-2 ratio in women significantly decreased after 6 h (P = 0.03) and returned to baseline levels after 24 h. Men exhibited greater cell death at all time points (P < 0.05), whereas myofibrillar protein content and total DNA content decreased in both genders at 24 h after exercise. No changes in LDH were found (P > 0.05). Although more research is needed, differences between genders may provide greater endogenous protection against oxidative stress and apoptosis. Kerksick, C., Taylor, L., Harvey, A., and Willoughby, D. Med. Sci. Sports Exerc. 40(10), pp. 1772-1780, October 2008.

Heroin Transition Risk among Daily and Non-daily Cannabis Users Who are Non-injectors of Heroin

Non-injecting heroin use (NIU) has been identified as a potential precursor for the transition to injecting drug use (IDU). Heroin transition risks between two groups of Mexican American cannabis users (daily users (DU) vs. non-daily users (NDU)) who are NIUs were examined and compared. Three fourths of the cannabis NDU showed transition risk attributes. Heroin transition risk was positively associated with longer term heroin use. An inverse relationship was found with DU of cannabis and those reporting use of alcohol in the past month being less likely to be associated with heroin transition risks. Findings tentatively indicate that DU of cannabis may be interpreted as a form of self-regulation and potentially deterring problematic heroin use among Mexican American NIUs and possibly other polydrug users in similar social environments. The authors discuss alternative interpretations of these findings. Valdez, A., Cepeda, A., Neaigus, A., and Russell, A. Int. J. Drug Policy, 19(6), pp. 442-449, December 2008.

Crack-Cocaine Use Accelerates HIV Disease Progression in a Cohort of HIV-Positive Drug Users

HIV infection is prevalent among substance abusers. The effects of specific illicit drugs on HIV disease progression have not been established. The authors evaluated the relationship between substances of abuse and HIV disease progression in a cohort of HIV-1-positive active drug users. A prospective, 30-month, longitudinal study was conducted on 222 HIV-1 seropositive drug users in Miami, FL. History of illicit drug, alcohol, and medication use, CD4+ cell count, and viral load were performed every 6 months. Crack-cocaine users were 2.14 times [95% confidence interval (CI): 1.08 to 4.25, P = 0.029] more likely to present a decline of CD4 to <=200 cells per microliter, independent of antiretroviral use. Viral load over 30 months was significantly higher in crack users ([beta] = 0.315, P = 0.037) independent of highly active antiretroviral therapy (HAART) over time. The only multidrug combination that significantly increased the risk of disease progression was crack cocaine with marijuana (hazard ratio = 2.42; 95% CI: 1.042 to 5.617, P = 0.04). Of those on HAART, a significantly lower proportion of crack-cocaine users versus nonusers had controlled viral load (P < 0.001), suggesting lower medication adherence, whereas crack-cocaine users not on HAART showed a greater risk for HIV disease progression than nonusers (hazard ratio = 3.946; 95% CI: 1.049 to 14.85, P = 0.042). The authors conclude that crack-cocaine use facilitates HIV disease progression by reducing adherence in those on HAART and by accelerating disease progression independently of HAART. Baum, M.K., Rafie, C., Lai, S., Sales, S., Page, B., and Campa, A. JAIDS, November 25, 2008.


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