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Director's Report to the National Advisory Council on Drug Abuse - February, 2005

Research Findings - Research on Medical Consequences of Drug Abuse

Nutritional Status of Hispanic Drug Abusers Co-infected with HIV

Malnutrition in drug abusers has been attributed to poor diet. However, previous studies are conflicting. Many studies have not considered possible concurrent HIV disease. The purpose of this study was to determine the relationship between drug abuse and dietary intake in Hispanic Americans with and without HIV infection. In this study, dietary intake was measured using 3-day food records and 24-hour dietary recalls in three groups: HIV-positive drug abusers, HIV-negative drug abusers and HIV-positive persons who do not use drugs ('non-drug abusers'). The baseline data from a prospective cohort study of the role of drug abuse in HIV/AIDS weight loss and malnutrition conducted in Boston, Massachusetts, USA was examined. The first 284 participants to enroll in the study served as subjects. Results indicated that HIV-positive drug abusers had a body mass index (BMI) that was significantly lower than that of HIV-positive non-drug abusers. Reported energy, fat and fiber intakes did not differ between groups. All groups had median reported intakes of vitamin A, vitamin B6, vitamin B12, selenium and zinc that were in excess of the dietary reference values (DRI). Intakes of alpha-tocopherol were below the DRI, but did not differ from intakes of the general US population. However, increasing levels of drug abuse were associated with lower reported intakes of vitamin B6, vitamin B12, selenium and zinc. Overall, this study does not support the notion that dietary intake can explain the lower BMI of HIV-positive drug abusers. Further studies examining non-dietary determinants of nutritional status in drug abusers are warranted. Forrester, J.E., Tucker, K.L. and Gorbach, S.L. Dietary Intake and Body Mass Index in HIV-positive and HIV-negative Drug Abusers of Hispanic Ethnicity. Public Health Nutr. 7(7), pp. 863-870, 2004.

Immunology of HCV Infection

Persons with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) co-infection are at increased risk for progression to cirrhosis compared with persons with HCV alone, but the reasons for this are unclear. In chronic HCV, the mechanism of liver injury is presumed to be due to HCV-specific T cell destruction of hepatocytes, so it is paradoxical that immunosuppressed hosts have higher rates of fibrosis progression. Intrahepatic cellular immune responses to HCV antigens were assessed to determine whether there were qualitative or quantitative differences in subjects with and without HIV. Expanded, CD4-enriched, liver-infiltrating lymphocytes from 18 subjects with chronic HCV and 12 subjects with HIV/HCV were cultured in the presence of HCV core protein, nonstructural proteins NS3 and NS5, and recall antigens tetanus toxoid and Candida. Secretion of interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin (IL) 10 was determined using enzyme-linked immunosorbent spot assay. There were no significant differences in liver biopsy grade or stage for HIV/HCV versus HCV groups. There were no significant differences between groups in the secretion of IFN-gamma or TNF-alpha in response to HCV or recall antigens. However, there was a significant increase in IL-10 secretion in response to NS3 and NS5 in subjects with HCV compared with HIV and HCV co-infection. In conclusion, subjects with co-infection have an alteration of intrahepatic HCV-specific IL-10 cytokine response that may have implications for HCV-related disease progression. Graham, C.S., Curry, M., He, Q., Afdhal, N., Nunes, D., Fleming, C., Horsburgh, R., Craven, D., Sherman, K.E. and Koziel, M.J. Comparison of HCV-specific Intrahepatic CD4+ T Cells in HIV/HCV Versus HCV. Hepatology. 40(1), pp. 125-132, 2004.

Injection Drug Use and Crack Cocaine Smoking: Independent and Dual Risk Behaviors for HIV Infection

Previous studies have examined the practices of injecting drugs or smoking crack cocaine as high-risk, but independent, factors for HIV transmission. To explore the independent and dual risks of injection practices and crack smoking, this study examined HIV seroprevalence rates among distinct drug user groups, based on patterns of daily administration. A sample of 3,555 drug users and neighborhood controls in urban Miami, FL and rural Belle Glade and Immokalee, FL were partitioned into four mutually-exclusive groups: 1) injection drug users (IDUs); 2) crack-cocaine smokers; 3) dual users who both smoked crack and injected drugs; and 4) non-drug-user controls. HIV seroprevalence rates were 45.1% for IDUs, 30.5% for dual users, 20.1% for crack smokers and 7.3% for controls. Multivariate logistic regression analysis found that when compared with controls, odds ratios for HIV seropositivity were 9.81 for IDUs, 5.27 for dual users, and 2.24 for crack smokers. These findings provide evidence of: 1) behavioral and structural co-factors that influence HIV exposure patterns among drug users; and 2) the substantially higher risk of HIV infection among IDUs compared with other drug users (such as smoking crack). Intervention strategies must be tailored for the specific drug use subpopulations to optimize efficacy. McCoy, C.B., Lai, S., Metsch, L.R., Messiah, S.E. and Zhao, W. Injection Drug Use and Crack Cocaine Smoking: Independent and Dual Risk Behaviors for HIV Infection. Ann Epidemiol. 14(8), pp. 535-542, 2004.

Drug Abuse and Neuropathogenesis

Dendritic cells (DC) are the critical mediators of various immune responses and are the first line of defense against any infection including HIV. They play a major role in harboring HIV and the subsequent infection of T cells and passage of virus through the blood-brain barrier (BBB). The recently discovered DC-specific, CD4-independent HIV attachment receptor, DC-SIGN, and T-cell suppressing factor, indolamine 2,3-dioxygenase (IDO), are known to play a critical role in the immuno-neuropathogenesis of HIV infection. Since brain microvascular cells (BMVEC) express dendritic cell (DC)-specific C type ICAM-3 grabbing nonintegrin (DC-SIGN), it is possible that DC-SIGN may play a critical role in human immunodeficiency virus-type 1 (HIV-1) infection and migration of infected DC across BBB. Matrix metalloproteinases (MMPs) are proteolytic enzymes known to be responsible for maintenance, turnover and integrity of the extracellular matrix. The results show that cocaine upregulates IDO and DC-SIGN expression by DC. Further, cocaine upregulates DC-SIGN and MMPs in BMVEC supporting the hypothesis that cocaine causes membrane permeability facilitating endothelial transmigration of infected DC in to the CNS. Targeting DC-SIGN and IDO with specific monoclonal antibodies, inexpensive synthetic antagonists, antisense oligonucleotides and siRNA may lead to development of novel treatment strategies particularly in high-risk populations such as cocaine users. Nair, M.P., Schwartz, S.A., Mahajan, S.D., Tsiao, C., Chawda, R.P., Whitney, R., Don Sykes, B.B. and Hewitt, R. Drug Abuse and Neuropathogenesis of HIV Infection: Role of DC-SIGN and IDO. J Neuroimmunol., 157(1-2), pp. 56-60, 2004.

Drug Abuse and Progression of HIV Disease

Recreational drug use has been proposed to affect the course of human immunodeficiency virus (HIV) infections. To investigate the effects of substance abuse on HIV infections, authors compared virus-specific cytotoxic T lymphocyte (CTL) responses and the expression of IL-16, TGF-beta1, and CXCR4 in three different cohorts of HIV-infected patients: (1) long-term nonprogressors (LT-NPs) of HIV infection who do not use recreational drugs; (2) nondrug using normal progressors (NPs), and (3) drug using NPs. The results show that LT-NPs manifest increased CTL activity and IL-16 expression and decreased expression of TGF-beta1 and CXCR4 compared to NPs, regardless of recreational drug usage. Furthermore, drugs using NPs showed significantly lower levels of CTL and IL-16 expression and increased TGF-beta1 and CXCR4 expression compared to nondrugs using NPs. The results suggest that recreational drug use may reduce CTL and IL-16 expression and increase the expression of TGF-beta1 and CXCR4, all of which may facilitate progression of HIV infections. Nair, M.P., Mahajan, S., Hewitt, R., Whitney, Z.R., Schwartz, S.A. Association of Drug Abuse with Inhibition of HIV-1 Immune Responses: Studies with Long-term of HIV-1 Non-progressors. J Neuroimmunol. 147(1-2), pp. 21-25, 2004.

Effect of Hard-Drug Use on CD4 Cell Percentage, HIV RNA Level, and Progression to AIDS-Defining Class C Events Among HIV-Infected Women

In vitro and animal studies suggest that cocaine and heroin increase HIV replication and suppress immune function, whereas epidemiologic studies are inconclusive regarding their effect on HIV infection progression. The authors prospectively examined the association between illicit-drug use and 4 outcome measures (CD4 cell percentage, HIV RNA level, survival to class C diagnosis of HIV infection, and death) in a national cohort of HIV-infected women. Women enrolled between 1989 and 1995 were followed for 5 years and repeatedly interviewed about illicit ("hard")-drug use. Up to 3 periodic urine screens validated self-reported use. Outcomes were compared between hard-drug users (women using cocaine, heroin, methadone, or injecting drugs) and nonusers, adjusting for age, antiretroviral therapy, number of pregnancies, smoking, and baseline CD4 cell percentage. Of 1148 women, 40% reported baseline hard-drug use during pregnancy. In multivariate analyses, hard-drug use was not associated with change in CD4 cell percentage (P = 0.84), HIV RNA level (P = 0.48), or all-cause mortality (relative hazard = 1.10; 95% confidence interval, 0.61-1.98). Hard-drug users did, however, exhibit a higher risk of developing class C diagnoses (relative hazard = 1.65; 95% confidence interval, 1.00-2.72), especially herpes, pulmonary tuberculosis, and recurrent pneumonia. Hard-drug-using women may have a higher risk for nonfatal opportunistic infections. Thorpe, L.E., Frederick, M., Pitt, J., Cheng, I., Watts, D.H., Buschur, S., Green, K., Zorrilla, C., Landesman, S.H. and Hershow, R.C. Effect of Hard-Drug Use on CD4 Cell Percentage, HIV RNA Level, and Progression to AIDS-Defining Class C Events Among HIV-Infected Women. J Acquir Immune Defic Syndr. 37(3), pp. 1423-1430, 2004.

Drug Use and Disease Progression among HIV-Infected Women

Investigators from the Women and Infants HIV Transmission Study (WITS) have examined the relationship between drug use and four outcome measures: two markers of HIV disease progression (CD4 cell percentage, and HIV RNA level), and two clinical outcomes (progression to a first AIDS-defining class C event, and mortality. WITS is a multi-site longitudinal study of the health of HIV-infected mothers and their children, as well as mother-to-child HIV transmission. It is jointly supported by NIAID, NICHD, and NIDA. A woman was categorized as a ‘hard drug' user if she reported use of cocaine, crack, heroin, or other opiates (including methadone), if she reported engaging in injection drug use, or if her urine was positive for any of these drugs. Three time periods were examined for hard drug use (once during pregnancy, and two later points). Each woman was followed for up to five years. Outcomes were compared between hard drug users and nonusers, adjusting for age, antiretroviral therapy, number of pregnancies, smoking, and baseline CD4 cell percentage. Of 1148 women, 40% reported baseline hard drug use during pregnancy. In multivariate analyses, hard drug use was not associated with change in CD4 cell percentage, HIV RNA level, or all-cause mortality. Hard drug users did exhibit a higher risk of developing class C diagnoses, especially herpes, pulmonary tuberculosis, and recurrent pneumonia, leading to a conclusion that HIV-infected women who use hard drugs may be at higher risk for nonfatal opportunistic infections. The investigators consider a number of reasons why a relationship was not found between hard-drug use and CD4 cell percentage or HIV RNA level, given findings of relationships of cocaine and heroin to HIV replication and immune function in animal and in vitro studies, but they also point out that their findings are consistent with most prior epidemiologic evidence. Thorpe, L.E., Frederick, M., Pitt, J., et al. Effect of Hard-Drug Use on CD4 Cell Percentage, HIV RNA Level, and Progression to AIDS-Defining Class C Events among HIV-Infected Women. JAIDS, 37(3), pp. 1423-1430, 2004.

Adult Trauma and HIV Status among Latinas

Latinas have unique cultural factors that can contribute to their health. Recent immigration, documentation status, and language barriers can impact their lives in various ways. Additional stressors and experiencing traumatic events can impact psychological adjustment and substance use. This study tests the differential contribution of adult trauma and other life stressors to psychological adjustment and substance use among Latinas who differ in their HIV status and level of acculturation. A community sample of 121 (87 HIV-positive and 34 HIV-negative) 18 to 50 year old Latinas participated in this study using baseline and one-year follow-up data. Path analyses examined the influence of acculturation, HIV status, and adult trauma, including intimate partner violence (IPV) and sexual assault, on subsequent changes in psychological adjustment (depression) and substance use one year later. Demographic variables of age, education, and relationship status were controlled and further analyses examined the interactive influence of HIV status and acculturation and trauma on the outcomes. Findings indicate that both acculturation and HIV status were related to the outcome variables, but did not influence these over time, emphasizing the developmental stability of these processes. Education was the most prominent variable in protecting these women from HIV, depression, and intimate partner violence (IPV), but placed them at greater risk for illicit drug use. The primary predictors of change in the outcome variables were domestic and sexual trauma that were exacerbated by HIV positive status. Newcomb, M.D., and Carmona, J.V. Adult Trauma and HIV Status among Latinas: Effects Upon Psychological Adjustment and Substance Use. AIDS and Behavior, 8, pp. 417-428, 2004.

Correlates of Hepatitis C Infection in Homeless Men

This study was conducted as a secondary analysis of data collected by Dr. Adeline Nyamathi and her team of outreach workers in the Los Angeles Skid Row area, where there is a high concentration of homeless people. Homeless individuals are at risk for numerous health problems including Hepatitis C virus (HCV). HCV is primarily caused by sharing of equipment associated with injection drug use (IDU). In the current study, authors assessed differences among HCV-negative and HCV-positive homeless men residing in Los Angeles (N = 198; about 50% HCV positive) on a number of risk factors and behaviors. Findings revealed several significant correlates of HCV-positive status. HCV-positive status was significantly and positively associated with a history of substance use (both IDU and non-IDU), recent risky IDU-related behaviors including equipment sharing, other forms of sharing (e.g., toothbrushes, razors), homelessness severity, tattoos, sexually transmitted diseases, a jail/prison history, and greater age. Lifetime alcohol problems were not associated with HCV. Although associations of HCV with current IDU-related behaviors such as needle-sharing are not surprising, it is particularly alarming that these risky behaviors were recent. Those who work among homeless populations should be aware not only of the high likelihood of HCV infection in this population but also of the transmission risk due to continued IDU sharing behaviors. Substance abuse treatment should be implemented to hinder the spread of HCV in this vulnerable population. Stein, J.A. and Nyamathi, A. Correlates of Hepatitis C Infection in Homeless Men: A Latent Variable Approach. Drug and Alcohol Dependence, 75, pp. 89-95, 2004.

Cross-sectional and Longitudinal Associations in Coping Strategies and Physical Health Outcomes among HIV-positive Youth

This study assessed whether coping styles had an influence on physical health outcomes either concurrently or longitudinally in a sample of HIV-positive youth. In the case of people living with HIV/AIDS, empirical studies have indicated that coping skills buffer stress, have a mental health benefit, increase adherence to medication, and are associated with a better quality of life. Whether this benefit extrapolates to physical health is more questionable. Coping styles were characterized as positive, passive, depressive withdrawal, and escapist. A cross-sectional latent variable analysis (N = 279) assessed associations among environmental stress, self-esteem, social support, coping styles, AIDS symptoms, and CD4 count. A more restricted longitudinal analysis (N = 174) tested associations among earlier environmental stress, self-esteem, coping styles, and AIDS symptoms at follow-up. CD4 count was not associated with coping styles in the cross-sectional analysis. Concurrent AIDS symptoms were significantly predicted by depressive withdrawal and environmental stress. A passive coping style modestly predicted more AIDS symptoms longitudinally. The authors concluded that correlates of perceived health and well-being of persons with HIV/AIDS are important to investigate in addition to more objective measures such as CD4 count that may not be amenable to change through coping style interventions alone. Stein, J.A., and Rotheram-Borus, M.J. Cross-sectional and Longitudinal Associations in Coping Strategies and Physical Health Outcomes Among HIV-positive Youth. Psychology and Health, 19, pp. 321-336, 2004.

The Efficacy of an Integrated Risk Reduction Intervention for HIV-positive Women with Child Sexual Abuse Histories

Child sexual abuse (CSA) is associated with HIV risk behaviors1 and more prevalent among women living with HIV than in the general population2. This randomized Stage II clinical trial tested the impact of a culturally congruent psychoeducational intervention designed to reduce sexual risks and increase HIV medication adherence for HIV-positive women with CSA histories. An ethnically diverse sample of 147 women were randomized to two conditions: an 11-session Enhanced Sexual Health Intervention (ESHI) or an attention control. Results based on "intent to treat" analyses of pre-post changes are reported in the article. Additional analyses explored whether the observed effects might depend on "intervention dose," i.e., number of sessions attended. Women in the ESHI condition reported greater sexual risk reduction than women in the control condition. Although there were no differences between women in the ESHI and control groups on medication adherence, women in the ESHI condition who attended 8 or more sessions reported greater medication adherence at post-test than control women. The findings provide initial support for this culturally- and gender-congruent psychoeducational intervention for HIV-positive women with CSA, and highlight the importance of addressing the effects of CSA on sexual risk reduction and medication adherence in preventive interventions for women. Wyatt, G.E., Longshore, D., Chin, D., Carmona, J.V., Loeb, T.B., Myers, H.F., Warda, N., Liu, H., and Rivkin, I. The Efficacy of an Integrated Risk Reduction Intervention for HIV-positive Women with Child Sexual Abuse Histories. AIDS and Behavior, 8, pp. 453-462, 2004.

Co-Occurring Hepatitis C, Substance Use, and Psychiatric Illness: Treatment Issues and Developing Integrated Models of Care

Hepatitis C virus (HCV) infection is transmitted by injection drug use and associated with psychiatric conditions. Patients with drug use or significant psychiatric illness have typically been excluded from HCV treatment trials noting the 1997 National Institutes of Health Consensus Statement on HCV that indicated active drug use and major depressive illness were contraindications to treatment of HCV infection. However, the 2002 NIH Consensus Statement recognized that these patients could be effectively treated for HCV infection and recommended that treatment be considered on a case-by-case basis. Treating HCV infection in these patients is challenging, with drug use relapse possibly leading to psychosocial instability, poor adherence, and HCV re-infection. Interferon therapy may exacerbate preexisting psychiatric symptoms. Co-occurring human immunodeficiency virus or hepatitis B virus provide additional challenges, and access to ancillary medical and psychiatric services may be limited. Patients with co-occurring HCV infection, substance use, and psychiatric illness can complete interferon treatment with careful monitoring and aggressive intervention. Clinicians must integrate early interventions for psychiatric conditions and drug use into their treatment algorithm. Few programs or treatment models are designed to manage co-occurring substance use, psychiatric illness, and HCV infection and therapy. The National Institute on Drug Abuse convened a panel of experts to address the current status and the long-range needs through a 2-day workshop, Co-occurring Hepatitis C, Substance Abuse, and Psychiatric Illness: Addressing the Issues and Developing Integrated Models of Care. This conference report summarizes current data, medical management issues, and strategies discussed. Sylvestre, D.L., Loftis, J.M., Hauser, P., Genser, S., Cesari, H., Borek, N., Kresina, T.F., Seeff, L. and Francis, H. Co-occurring Hepatitis C, Substance Use, and Psychiatric Illness: Treatment Issues and Developing Integrated Models of Care. J Urban Health, 81(4), pp. 719-734, 2004.

The Utility of Indirect Predictors of Hepatitis C Viremia

Although the majority of injection drug users (IDUs) have been exposed to hepatitis C (HCV), only 60-85% remain chronically viremic and at risk for HCV-induced progressive liver damage or transmitting HCV to others. Access to direct viral testing to establish the presence or absence of viremia is limited due to its expense. This study of 500 current and former IDUs examines the utility of demographic and biochemical features as a means of indirectly predicting HCV viremia. Retrospective chart and laboratory review were the methods employed for data collection. Overall, 409 (81.8%) were viremic at the time of presentation. HCV viremia did not correlate with the presence of active drug or alcohol use, drug of abuse, duration of drug use, or length of injecting career, but was more common in males and African-Americans. An elevated ALT, found in 36% of patients, was the best biochemical predictor: 95.6% of these patients were viremic. Other predictors of viremia included thrombocytopenia, hypoalbuminemia, elevated GGT, and total bilirubin level, with a stepwise increase in viremia seen as the number of abnormal biochemical predictors increased. The absence of HCV viremia was more difficult to predict. Viremia was found in 66.3% of those lacking all biochemical predictors and even in 43.8% of those in the lowest 10th percentile of ALT. Although indirect demographic and laboratory parameters may be used to help predict viremia in 40% of HCV-exposed IDUs, they are inadequate substitutes for direct viral testing and instead should be used only as an adjunct to education and referrals in high-risk patients. Sylvestre, D.L. and Clements, B.J. The Utility of Indirect Predictors of Hepatitis C Viremia. Drug Alcohol Depend, 74(1), pp. 15-19, 2004.

Risk Factors for Hepatitis C Virus Infection among Blood Donors in Northern Thailand

The epidemiology, virology, and risk factors for hepatitis C virus (HCV) infection among blood donors in northern Thailand have not been extensively evaluated. The researchers performed a prospective matched case-control study of blood donors who tested positive for HCV and were confirmed by recombinant immunoblot assay or nucleic acid testing. Infected donors were matched with one to four HCV-uninfected donors for sex, age +/- 5 years, and donation at the same site within 15 days of the HCV-positive donor. Married donors were invited to bring their spouse for HCV testing. Among 166 matched sets, a history of intravenous drug use (IDU), reported by 58 HCV infected donors (35.5%) and 2 HCV-negative donors, was strongly associated with HCV infection (odds ratio [OR], 107.6; 95% confidence interval, 14.8-780.7). In multivariate analysis among donors without a history of IDU, significant risk factors included a history of a blood transfusion (OR, 28.8), immediate family with a history of hepatitis/jaundice (OR, 4.4), six or more lifetime sexual partners (OR, 2.7); the frequency of blood donation was negatively associated with HCV infection (OR, 0.89). Six of 45 spouses of HCV-infected donors, and none of 44 spouses of uninfected donors, were HCV positive (p = 0.005). Data indicate that illicit IDU and a history of transfusion are important risk factors for HCV infection in Thailand. Also, these data suggest there may be some risk of transmission by sex or other close contact between spouses. Thaikruea, L., Thongsawat, S., Maneekarn, N., Netski, D., Thomas, D.L. and Nelson, K.E. Risk Factors for Hepatitis C Virus Infection among Blood Donors in Northern Thailand. Transfusion, 44(10), pp. 1433-1440, 2004.

Marijuana Withdrawal

The authors review the literature examining the validity and significance of cannabis withdrawal syndrome. Findings from animal laboratory research are briefly reviewed, and human laboratory and clinical studies are surveyed in more detail. Converging evidence from basic laboratory and clinical studies indicates that a withdrawal syndrome reliably follows discontinuation of chronic heavy use of cannabis or tetrahydrocannabinol. Common symptoms are primarily emotional and behavioral, although appetite change, weight loss, and physical discomfort are also frequently reported. The onset and time course of these symptoms appear similar to those of other substance withdrawal syndromes. The magnitude and severity of these symptoms appear substantial, and these findings suggest that the syndrome has clinical importance. Diagnostic criteria for cannabis withdrawal syndrome are proposed. Budney, A.J., Hughes, J.R., Moore, B.A. and Vandrey, R. Review of the Validity and Significance of Cannabis Withdrawal Syndrome. Am J Psychiatry,161(11), pp. 1967-1977, 2004.

Nuclear Receptor Activation and Interaction with Morphine

Nervous system disease in HIV infection is associated with toxic damage induced by effects from proinflammatory responses and oxidative stress, and such effects may be more prominent among opioid abusers. In these studies, the effects of activating retinoid receptor (retinoic acid receptor (RAR) and retinoid X receptor (RXR)) and peroxisome proliferator activated receptor (PPAR) gamma, which belong to the steroid-lipid nuclear receptor family, on tumor necrosis factor (TNF)-alpha production and inducible nitric oxide synthase (iNOS) gene expression by stimulated U937 and SVG cells, respectively, were examined. Also studied were the effects of morphine on these responses. These studies showed that, in stimulated cells, the observed responses were suppressed by activation of the nuclear receptors as compared to non-stimulated control cells. Moreover, in phytohemagglutinin (PHA)-stimulated U937 cells, morphine reversed the TNF-alpha suppression that was induced by LG101305 and ciglitazone. Preliminary data in SVG cells suggest a tendency for morphine to have a similar effect on LG101305-exposed SVG cells stimulated with a combination of lipopolysaccharide (LPS) and interferon-gamma, whereas this effect was not induced when these cells were incubated with ciglitazone. Therefore, specific nuclear receptor activation may be potentially beneficial in the treatment of neurological disease associated with HIV infection and may show specific interactions with opioids. The mechanisms that underlie these effects require further study. Royal, W. III, Leander, M., Chen, Y.E., Major, E.O. and Bissonnette, R.P. Nuclear Receptor Activation and Interaction with Morphine. J Neuroimmunol., 157(1-2), pp. 61-65, 2004.

Cocaine Use and Renal Disease

Cocaine has anaesthetic, vasoconstrictive and CNS stimulatory effects. Presently, it is used clinically as a local anaesthetic and abused as a recreational drug. It has been implicated in both acute and chronic renal failure and has been reported to affect every aspect of the nephron. This article reviews the spectrum of cocaine-induced kidney disease and attempts to give insight into the pathophysiological mechanisms involved. Gitman, M.D. and Singhal, P.C. Cocaine-Induced Renal Disease. Expert Opin Drug Saf. 3(5), pp. 441-448, 2004.

Gender Differences in Triazolam Pharmacokinetics

Sixty-one healthy men and women, aged 20 to 75 years, received single 0.25-mg doses of triazolam, a cytochrome P450 (CYP) 3A substrate benzodiazepine, and placebo in a double-blind crossover study. Among women, age had no significant effect on area under the triazolam plasma concentration curve (AUC) (Spearman r=0.14, P=.44) or clearance (r =-0.09, P=.62). Among men, AUC increased (r=0.43, P < .02) and clearance declined (r=-0.42, P <.02) with increasing age. Gender differences in triazolam kinetics were not apparent. Compared with placebo, triazolam impaired digit-symbol substitution test performance, increased observer-rated sedation, impaired delayed recall of information learned at 1.5 hours after dosing, and increased electroencephalographic beta amplitude. Among men, mean values of relative digit-symbol substitution test decrement (P <.002) and observer-rated sedation (P <.05) were significantly greater in elderly subjects compared with young subjects. Age-dependent differences among women reached significance for observer-rated sedation (P <.02). A combination of higher plasma levels and increased intrinsic sensitivity explained the greater pharmacodynamic effects of triazolam in elderly subjects. Although the findings are consistent with reduced clearance of triazolam in elderly men, individual variability was large and was not explained by identifiable demographic or environmental factors. Greenblatt, D.J., Harmatz, J.S., von Moltke, L.L., Wright, C.E. and Shader, R.I. Age and Gender Effects on the Pharmacokinetics and Pharmacodynamics of Triazolam, A Cytochrome P450 3A Substrate. Clin Pharmacol Ther., 76(5), pp. 467-479, 2004.

Inhibition of Cytochrome P450 by Ginkgo Biloba

The extraction, isolation and characterization of 29 natural products contained in Ginkgo biloba have been described, which we have now tested for their in-vitro capacity to inhibit the five major human cytochrome P450 (CYP) isoforms in human liver microsomes. Weak or negligible inhibitory activity was found for the terpene trilactones (ginkgolides A, B, C and J, and bilobalide), and the flavonol glycosides. However 50% inhibitory activity (IC50) was found at concentrations less than 10 microg L(-1) for the flavonol aglycones (kaempferol, quercetin, apigenin, myricetin, tamarixetin) with CYP1A2 and CYP3A. Quercetin, the biflavone amentoflavone, sesamin, as well as (Z,Z)-4,4'-(1,4-pentadiene-1,5-diyl)diphenol and 3-nonadec-8-enyl-benzene-1,2-diol, were also inhibitors of CYP2C9. The IC50 of amentoflavone for CYP2C9 was 0.019 microg mL(-1) (0.035 microM). Thus, the principal components of Ginkgo biloba preparations in clinical use (terpene trilactones and flavonol glycosides) do not significantly inhibit these human CYPs in-vitro. However, flavonol aglycones, the biflavonol amentoflavone and several other non-glycosidic constituents are significant in-vitro inhibitors of CYP. The clinical importance of these potential inhibitors will depend on their amounts in ginkgo preparations sold to the public, and the extent to which their bioavailability allows them to reach the CYP enzymes in-situ. von Moltke, L.L., Weemhoff, J.L., Bedir, E., Khan, I.A., Harmatz, J.S., Goldman, P. and Greenblatt, D.J. Inhibition of Human Cytochrome P450 by Components of Ginkgo Biloba. J Pharm Pharmacol., 56(8), pp. 1039-1044, 2004.


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