International Research

Alumni of the NIDA International Program research training and exchange programs authored or coauthored the following articles indexed by PubMed:

Former NIDA INVEST Drug Abuse Research Fellows

Audiovestibular Dysfunction in Alcohol Dependence. Are We Worried?
Verma, R.K., Panda, N.K., Basu, D., and Raghunathan, M. Am J Otolaryngol. 27(4), pp. 225-228, July-August 2006. INVEST Fellow: Debasish Basu, India, 2001-2002. The purpose of this research was to study the audiovestibular function in patients of long-term alcohol dependence and compare these changes with social users of alcohol and complete abstainers. This was a prospective study of 20 randomly selected patients of long-term alcohol dependence fulfilling International Statistical Classification of Diseases, 10th Revision criteria of alcohol dependence. Audiovestibular function in this group was compared with social users of alcohol and complete abstainers. Statistically significant elevations of thresholds were found at higher frequencies (4000 and 8000 Hz ) in the alcohol-dependent group (P < .001). Alcohol-dependent patients had elevated thresholds at 4 and 8 kHz. Brainstem-evoked response audiometry showed prolongation of latencies of waves I, III, and V alone with interpeak latencies of I-III and III-V. One third of alcohol-dependent patients had abnormal electronystagmographic (ENG) findings. Abnormal ENG findings were only seen in alcohol-dependent patients with vertigo. There was no significant correlation between duration of alcohol dependence and abnormal ENG. Authors concluded that elevated thresholds at higher frequencies can be the only abnormality in alcohol-dependent patients. Presence of vertigo in alcohol-dependent patient may be associated with abnormal ENG findings. There is no correlation of duration of dependence and ENG abnormalities.

Antidepressant-Like Effects of mGluR1 and mGluR5 Antagonists in the Rat Forced Swim and the Mouse Tail Suspension Tests
Belozertseva, I.V., Kos, T., Popik, P., Danysz, W., and Bespalov, A.Y. Eur Neuropsychopharmacol. April 19, 2006 [Epub ahead of print]. INVEST Fellow: Anton Bespalov, Russia, 1994-1995. Drugs that act to reduce glutamatergic neurotransmission such as NMDA receptor antagonists exert antidepressant-like effects in a variety of experimental paradigms, but their therapeutic application is limited by undesired side effects. In contrast, agents that reduce glutamatergic tone by blocking type I metabotropic glutamate receptors have been suggested to have more a favorable side-effect profile. The present study aimed to compare the effects of mGluR1 antagonist (EMQMCM; JNJ16567083, 3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate, 0.156-10 mg/kg) and mGluR5 antagonist (MTEP, [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine, 1.25-10 mg/kg) in two behavioral screening assays commonly used to assess antidepressant-like activity. In the modified forced swim test in rats, imipramine (used as a positive control) decreased immobility (MED 40 mg/kg) and increased the duration of escape-oriented (climbing and diving; MED 20 mg/kg) behaviors. Both EMQMCM and MTEP decreased the floating duration (MED 1.25 and 2.5 mg/kg) and increased the duration of mobile behaviors (paddling and swimming; MED 2.5 and 5 mg/kg). EMQMCM but not MTEP increased the duration of escape behaviors (climbing and diving; MED 1.25 mg/kg). In the mouse tail suspension test, EMQMCM (5 but not 2.5, 10 and 25 mg/kg), 2-methyl-6-(phenylethynyl)-pyridine (MPEP, 10 but not 1 mg/kg) and MTEP (MED 25 mg/kg) decreased immobility scores. For EMQMCM, the dose-effect relationship was biphasic. With the exception of EMQMCM (10 mg/kg), locomotor activity in mice was not affected by treatments. The present study therefore suggests that acute blockade of mGluR5 and also of mGluR1 exerts antidepressant-like effects in behavioral despair tests in rats and mice.

Prevalence and Correlates of Drug Use Disorders in Mexico
Medina-Mora, M.E., Borges, G., Fleiz, C., Benjet, C., Rojas, E., Zambrano, J., Villatoro, J., and Aguilar-Gaxiola, S. Rev Panam Salud Publica. 19(4), pp. 265-276, April 2006. INVEST Fellow: Guilherme Borges, Mexico, 1997-1998. The objective of this study was to describe the prevalence of drug use disorders, the correlates of drug use, and the utilization of specialized treatment services for drug users among the Mexican urban population 18-65 years old. The data were collected in 2001 and 2002 in the Mexican National Comorbidity Survey. The sample design was stratified probabilistically for six geographical areas of the country in a multistage process for census count areas, city blocks, groups of households, and individuals. The data were weighted, taking into account the probability of selection and the response rate. The information was collected using a computerized version of the World Mental Health Survey edition of the Composite International Diagnostic Interview. The weighted response rate for individuals was 76.6%. Overall, 2.3% of the population reported any illicit use of drugs in the preceding 12 months; marijuana and cocaine were the substances most often used. Low levels of education were significantly associated with use, abuse, and dependence. Use of any drug was significantly more common among those who were in the youngest age group (18-29 years), were male, or were living in the Northwest region of the country. Overall, 1.4% had a lifetime history of drug abuse or dependence, with this being much more common for men (2.9%) than for women (0.2%). The 12-month prevalence of drug abuse or dependence was 0.4% overall (0.9% for men, and 0.0% for women). The rate of treatment during the preceding 12 months for those with the 12-month criteria for abuse or dependence was 17.1%; 14.8% were seen in specialized treatment centers; 2.8% reported having attended self-help groups. A noticeable number of Mexicans have a drug use disorder, but demand for treatment is limited, in part due to stigma. These results indicate that there is an urgent need to organize the specialized services for persons with a substance abuse disorder according to the prevalence of dependence on different substances and the variation in prevalence in the different regions of the country.

Multicentre Study of Acute Alcohol Use and Non-Fatal Injuries: Data from the WHO Collaborative Study on Alcohol and Injuries
Borges, G., Cherpitel, C., Orozco, R., Bond, J., Ye, Y., Macdonald, S., Rehm, J., and Poznyak, V. Bull World Health Organ. 84(6), pp. 453-460, June 2006. INVEST Fellow: Guilherme Borges, Mexico, 1997-1998. The objectives of this study were to study the risk of non-fatal injury at low levels and moderate levels of alcohol consumption as well as the differences in risk across modes of injury and differences among alcoholics. Data are from patients aged 18 years and older collected in 2001-02 by the WHO collaborative study on alcohol and injuries from 10 emergency departments around the world (n = 4320). Authors used a case-crossover method to compare the use of alcohol during the 6 hours prior to the injury with the use of alcohol during same day of the week in the previous week. The risk of injury increased with consumption of a single drink (odds ratio (OR) = 3.3; 95% confidence interval = 1.9-5.7), and there was a 10-fold increase for participants who had consumed six or more drinks during the previous 6 hours. Participants who had sustained intentional injuries were at a higher risk than participants who had sustained unintentional injuries. Patients who had no symptoms of alcohol dependence had a higher OR. Since low levels of drinking were associated with an increased risk of sustaining a non-fatal injury, and patients who are not dependent on alcohol may be at higher risk of becoming injured, comprehensive strategies for reducing harm should be implemented for all drinkers seen in emergency departments.

Acute Alcohol Use and the Risk of Non-Fatal Injury in Sixteen Countries
Borges, G., Cherpitel, C.J., Orozco, R., Bond, J., Ye, Y., Macdonald, S., Giesbrecht, N., Stockwell, T., Cremonte, M., Moskalewicz, J., Swiatkiewicz, G., and Poznyak, V. Addiction. 101(7), pp. 993-1002, July 2006. INVEST Fellow: Guilherme Borges, Mexico, 1997-1998. The aims of this study were to determine the relative risk (RR) of non-fatal injury associated with alcohol consumption in a series of emergency departments (EDs), possible effect modifiers and the impact of contextual variables on differences across sites. The case-crossover method was used to obtain RR estimates of the effect of alcohol on non-fatal injuries. Meta-analysis was used to evaluate the consistency and magnitude of RR across sites, and the extent to which contextual variables explain differences in effect sizes. Study participants were probability samples of 11,536 injured patients attending 28 EDs studies in 16 countries (1984-2002). The majority of the sample was male (65%) and > 30 years old (53%). Exposed cases were those that consumed alcohol 6 hours prior to the injury. Usual alcohol consumption served as the control period. Drinking within 6 hours prior to the injury was reported by 21% of the sample. The estimated (random) pooled relative risk for patients who reported alcohol use within 6 hours prior to injury was 5.69 (95% confidence interval = 4.04-8.00), ranging from 1.05 in Canada to 35.00 in South Africa. Effect size was not homogeneous across studies, as societies with riskier consumption patterns had a higher relative risk for injury. Heavier drinkers also showed lower RR. Authors concluded that acute alcohol was a risk factor for non-fatal injuries in most sites. Policy measures addressed to the general population are recommended, especially in societies with riskier consumption patterns.

Effects of Topiramate on the Prepulse Inhibition of the Acoustic Startle in Rats
Frau, R., Orru, M., Fa, M., Casti, A., Manunta, M., Fais, N., Mereu, G., Gessa, G., and Bortolato, M. Neuropsychopharmacology. [Epub ahead of print] June 14, 2006. INVEST Fellow: Marco Bortolato, Italy, 2004-2005. The anticonvulsant topiramate (TPM) has been recently proposed as a novel adjuvant therapy for bipolar disorder and schizophrenia, yet its efficacy remains controversial. As both disorders are characterized by gating deficits, authors tested the effects of TPM on the behavioral paradigm of prepulse inhibition (PPI) of the acoustic startle response, a validated animal model of sensorimotor gating. TPM (10, 18, 32, 58, 100 mg/kg, intraperitoneal, i.p.) enhanced PPI in rats in a dose-dependent fashion, prevented the PPI reduction mediated by the dopaminergic agonist apomorphine (0.25 mg/kg, subcutaneous, s.c.) and potentiated the effects of the antipsychotic drugs haloperidol (0.05, 0.1 mg/kg, i.p.) and clozapine (2.5, 5 mg/kg, i.p.). Conversely, TPM elicited no significant effect on the PPI disruption mediated by the NMDA receptor antagonist dizocilpine (0.05, 0.1 mg/kg, s.c.) and surprisingly antagonized the attenuation of dizocilpine-induced PPI disruption mediated by clozapine (5 mg/kg, i.p.). Results suggest that TPM may exert diverse actions on the neural substrates of sensorimotor gating. While the pharmacological mechanisms of such effects are still elusive, these findings might contribute to shed light on some controversies on the therapeutic action of TPM, and point to this drug as a putative novel adjuvant therapy for some clusters of gating disturbances. Neuropsychopharmacology advance online publication, 14 June 2006; doi:10.1038/sj.npp.1301115.

Toxicological Analysis in Rats Subjected to Heroin and Morphine Overdose
Strandberg, J.J., Kugelberg, F.C., Alkass, K., Gustavsson, A., Zahlsen, K., Spigset, O., and Druid, H. Toxicol Lett. [Epub ahead of print] May 16, 2006. INVEST Fellow: Henrik Druid, Sweden, 2000-2001. In heroin overdose deaths the blood morphine concentration varies substantially. To explore possible pharmacokinetic explanations for variable sensitivity to opiate toxicity authors studied mortality and drug concentrations in male Sprague-Dawley rats. Groups of rats were injected intravenously (i.v.) with heroin, 21.5mg/kg, or morphine, 223mg/kg, causing a 60-80% mortality among drug-naive rats. Additional groups of rats were pre-treated with morphine for 14 days, with or without 1 week of subsequent abstinence. Brain, lung and blood samples were analyzed for 6-acetylmorphine, morphine, morphine-3-glucuronide and morphine-6-glucuronide. i.v. morphine administration to drug-naive rats resulted in both rapid and delayed deaths. The brain morphine concentration conformed to an exponential elimination curve in all samples, ruling out accumulation of morphine as an explanation for delayed deaths. This study found no support for formation of toxic concentration of morphine-6-glucuronide. Spontaneous death among both heroin and morphine rats occurred at fairly uniform brain morphine concentrations. Morphine pre-treatment significantly reduced mortality upon i.v. morphine injection, but the protective effect was less evident upon i.v. heroin challenge. The morphine pre-treatment still afforded some protection after 1 week of abstinence among rats receiving i.v. morphine, whereas rats given i.v. heroin showed similar death rate as drug-naive rats.

Signal Transduction Induced by Opioids in Immune Cells: A Review
Martin-Kleiner, I., Balog, T., and Gabrilovac, J. Neuroimmunomodulation. 13(1), pp. 1-7 [Epub ahead of print] April 3, 2006. INVEST Fellow: Irena Martin-Kleiner, Croatia, 1995-1996. New data regarding signal transduction triggered by opioid ligands in immune cells are reviewed, and the signal transduction in neuronal cells is documented. Similar signaling pathways are induced by opioids in immune as well as neuronal cells. Opioids altered second messenger cAMP, intracellular calcium, and second messenger-induced kinases in immune cells. Met-enkephalin, preferentially delta-opioid, was bimodally regulated, while kappa-opioids inhibited these second messengers. delta-, kappa- and mu-opioids altered nitric oxide secretion, inducing cGMP as the second messenger in immune cells. Coupling of opioid agonists to opioid receptors activated mitogen-activated protein/extracellular signal-regulated protein kinases and various transcription factors in immune cells. Activator protein 1 (AP-1), c-fos, and nuclear factor-kappaB (NF-kappaB) are transcription factors shared by neuronal and immune cells. delta-Opioids activated AP-1, c-fos, activating transcription factor 2, Ikaros-1 and Ikaros-2 transcription factors in immune cells. Induction of kappa-opioid receptor gene by retinoic acid resulted in increased binding of Sp1 transcription factor to the promoter of the kappa-opioid receptor. mu-Opioids inhibited synthesis of common transcription factors AP-1, c-fos, NF-kappaB, and nuclear factor of activated T cells in activated or stimulated immune cells, whereas mu-opioids activated NF-kappaB, GATA-3, and Kruppel-like factor 7 transcription factors in non-stimulated immune cells.

Leber's Hereditary Optic Neuroretinopathy (LHON) Associated with Mitochondrial DNA Point Mutation G11778A in Two Croatian Families
Martin-Kleiner, I., Gabrilovac, J., Bradvica, M., Vidovic, T., Cerovski, B., Fumic, K., and Boranic, M. Coll Antropol. 30(1), pp. 171-174, March 2006. INVEST Fellow: Irena Martin-Kleiner, Croatia, 1995-1996). Leber's hereditary optic neuroretinopathy (LHON) is manifested as a bilateral acute or subacute loss of central vision due to optic atrophy. It is linked to point mutations of mitochondrial DNA, which is inherited maternally. The most common mitochondrial DNA point mutations associated with LHON are G3460A, G11778A and T14484C. These mutations are linked with the defects of subunits of the complex I (NADH-dehydrogenase-ubiquinone reductase) in mitochondria. The G11778A mitochondrial DNA point mutation is manifested by a severe visual impairment. In this paper two Croatian families with the LHON G11778A mutation are presented. Three LHON patients from two families were younger males which had the visual acuity of 0.1 or below, the ophthalmoscopy revealed telangiectatic microangiopathy and papilloedema, while Goldmann kinetic perimetry showed a central scotoma. The mothers and female relatives were LHON mutants without symptoms, whereas their sons suffered from a severe visual impairment. Molecular diagnosis helps to explain the cause of LHON disease.

Personal, Interpersonal, and Cultural Predictors of Stages of Cigarette Smoking Among Adolescents in Johannesburg, South Africa
Brook, J.S., Morojele, N.K., Brook, D.W., Zhang, C., and Whiteman, M. Tob Control. 15 Suppl 1:i48-53, June 2006. INVEST Fellow: Neo Morojele, South Africa, 1998-1999. This study examined the personal, parental, peer, and cultural predictors of stage of smoking among South African urban adolescents. A cross-sectional design was employed. A stratified random approach based on census data was used to obtain the sample. Analyses were conducted using logistic regression. The study took place in communities in and around Johannesburg, South Africa. Participants consisted of 731 adolescents in the age range of 12-17 years old. The sample was 47% male and 53% female, and contained four ethnic classifications: white, black, Indian, and "coloured" (a South African term for mixed ancestry). A structured, in-person interview was administered to each participant in private by a trained interviewer, after obtaining consent. The dependent variables consisted of three stages of smoking: non-smoking, experimental smoking, and regular smoking. The independent measures were drawn from four domains: personal attributes, parental, peer, and cultural influences. Factors in all four domains significantly predicted three different stages of smoking. Personal attributes (internalizing and externalizing) distinguished among the three stages. Parental factors (for example, affection) reduced the odds of being a regular smoker compared with an experimental smoker or non-smoker, but did not differentiate experimental smokers from non-smokers. Findings from the peer domain (for example, peer substance use) predicted an increase in the risk of being a regular smoker compared with an experimental smoker or non-smoker. In the cultural domain, ethnic identification predicted a decrease in the risk of being a regular smoker compared with an experimental smoker, whereas discrimination and victimization predicted an increase in the risk of being an experimental smoker compared with a non-smoker. All the domains were important for all four ethnic groups. Four psychosocial domains are important in distinguishing among the three stages of smoking studied. Some predictors differentiated all stages of smoking, others between some of the stages of smoking. Therefore, intervention and prevention programs which are culturally and linguistically sensitive and appropriate should consider the individual's stage of smoking.

South African Adolescents: Pathways to Risky Sexual Behavior
Brook, D.W., Morojele, N.K., Zhang, C., and Brook, J.S. AIDS Educ Prev. 18(3), pp. 259-272, June 2006. INVEST Fellow: Neo Morojele, South Africa, 1998-1999. This study tested a developmental model of pathways to risky sexual behavior among South African adolescents. Participants comprised 633 adolescents, 12-17 years old, recruited from households in Durban, South Africa. Data were collected using in-person interviews. Topics included adolescents' sexual behaviors, household poverty levels, vulnerable personality and behavioral attributes, parent-child relations, and deviant peers. Structural equation modeling was used to assess the pathways to risky sexual behavior among the adolescents. The goodness-of-fit index (GFI) was .93. One major pathway indicated that family poverty was associated with difficulty in the parent-child relationship. This was related to vulnerable personality and behavioral attributes and to association with deviant peers, which, in turn, were related to risky sexual behavior. Findings suggest that poverty, parent-child relations, personality and behavioral vulnerabilities, and peer influences should be among factors addressed by prevention and intervention programs to reduce sexual risk behaviors by South African adolescents.

Therapeutic Drug Monitoring (TDM) of Psychotropic Drugs: A Consensus Guideline of the AGNP-TDM Group
Baumann, P., Hiemke, C., Ulrich, S., Eckermann, G., Kuss, H.L., Laux, G., Muller-Oerlingenhausen, B., Rao, M.L., Riederer, P., Zernig, G. and AGNP-TDM. Rev Med Suisse. 2(67), pp. 1413-1418, 1420-1422, 1424-1426, May 24, 2006. INVEST Fellow: Gerald Zernig, Austria, 1993-1994. In psychiatry, therapeutic drug monitoring (TDM) is an established procedure for most psychotropic drugs. However, as its use in everyday clinical practice is far from optimal, the AGNP-TDM group has worked out consensus guidelines to assist psychiatrists and laboratories involved in drug analysis. Based on a thorough analysis of available literature, 5 levels of recommendation were defined with regard to TDM of psychoactive drugs, from 1) (strongly recommended) to 5) (not recommended). A list of indications for TDM, alone or in combination with pharmacogenetic tests is presented. Instructions are given with regard to preparation of TDM, analytical procedures, reporting and interpretation of results and the use of information for patient treatment. Using the consensus guideline will help to ensure optimal clinical benefit of TDM.

Activation of Muscarinic and Nicotinic Acetylcholine Receptors in the Nucleus Accumbens Core is Necessary for the Acquisition of Drug Reinforcement
Crespo, J.A., Sturm, K., Saria, A., and Zernig, G. J Neurosci. 26(22), pp. 6004-6010, May 31, 2006. INVEST Fellow: Gerald Zernig, 1993-1994. Neurotransmitter release in the nucleus accumbens core (NACore) during the acquisition of remifentanil or cocaine reinforcement was determined in an operant runway procedure by simultaneous tandem mass spectrometric analysis of dopamine, acetylcholine, and remifentanil or cocaine itself. Run times for remifentanil or cocaine continually decreased over the five consecutive runs of the experiment. Intra-NACore dopamine, acetylcholine, and drug peaked with each intravenous remifentanil or cocaine self-administration and decreased to pre-run baseline with half-lives of approximately 10 min. As expected, remifentanil or cocaine peaks did not vary between the five runs. Surprisingly, however, drug-contingent dopamine peaks also did not change over the five runs, whereas acetylcholine peaks did. Thus, the acquisition of drug reinforcement was paralleled by a continuous increase in acetylcholine overflow in the NACore, whereas the overflow of dopamine, the expected prime neurotransmitter candidate for conditioning in drug reinforcement, did not increase. Local intra-accumbens administration by reverse microdialysis of either atropine or mecamylamine completely and reversibly blocked the acquisition of remifentanil reinforcement. Findings suggest that activation of muscarinic and nicotinic acetylcholine receptors in the NACore by acetylcholine volume transmission is necessary during the acquisition phase of drug reinforcement conditioning.

Dopamine D4 Receptor Polymorphism Modulates Cue-elicited Heroin Craving in Chinese
Shao, C., Li, Y., Jiang, K., Zhang, D., Xu, Y., Lin, L., Wang, Q., Zhao, M., and Jin, L. Psychopharmacology (Berl). 186(2), pp. 185-190, June 2006. Epub 2006 Apr 27. [Epub ahead of print]. INVEST Fellow: Min Zhao, China, 2001-2002. Subjective craving, which contributes to the continuation of drug use in active abusers and the occurrence of relapse in detoxified abusers, is considered to be a central phenomenon in addiction. Dopamine pathway has been implicated in the mechanism underlying the cue-elicited craving for a variety of addictive substances. The objective of this study was to test the hypothesis that heroin addicts carrying D4 dopamine receptor gene (DRD4) variable number tandem repeat (VNTR) long type allele would have higher craving after exposure to a heroin-related cue. Craving was induced by a series of exposure to neutral and heroin-related cue and were assessed in a cohort of Chinese heroin abusers (n=420) recruited from the Voluntary Drug Dependence Treatment Center at Shanghai. Significantly stronger cue-elicited heroin craving was found in individuals carrying DRD4 VNTR long type allele than the non-carriers (F=31.040, p<0.001). As for baseline craving and mean change in craving responding to neutral stimuli, no significance was found (1.06+/-0.34 vs 1.07+/-0.36, F=0.067, p =0.797 and 0.42+/-0.34 vs 0.45+/-0.37, F=0.277, p=0.599, respectively). The results of this study suggest that DRD4 VNTR polymorphism contributes to cue-elicited craving in heroin dependence, indicating DRD4 VNTR represents one of potential genetic risk factors for cue-induced craving.

HIV Sexual Risk Behaviors Among Injection Drug Users in Shanghai
Zhao, M., Du, J., Lu, G.H., Wang, Q.Y., Xu, H., Zhu, M., and McCoy, C.B. Drug Alcohol Depend. 82 Suppl 1, pp. S43-47, April 2006. INVEST Fellow: Min Zhao, China, 2001-2002. This study investigated the sexual risk behaviors among injection drug users (IDUs) in order to inform the development of sexual risk reduction interventions for IDUs. A cross-sectional survey of IDUs (n=141) was conducted in an in-patient detoxification treatment center in Shanghai, China, to collect information on demographics; drug use history; sexual risk behavior; HIV/AIDS knowledge, attitudes, and other psychosocial variables; and HIV, HBV, and HCV seroprevalence. Factors associated with HIV sexual risk behaviors and HBV and/or HCV infection were analyzed. Sexual risk behaviors among IDUs were common: the majority (77%) of the participants had not used a condom consistently in the previous 3 months, 25.5% had multiple partners, 48.2% had IDU partners, and 75.9% did not know their partner's HIV status. IDUs who were married (OR=4.83, p<0.05) or did not intend to use condoms in the future (OR=0.21, p<0.05) were more likely to have unprotected sex. The prevalence of HBV and HCV infection was 31.9% and 51.8%, respectively, but no one tested positive for HIV. IDUs with an injection history of 3 years or more (OR=5.86, p<0.05) and with an overdose history (OR=3.21, p<0.05) were more likely to be infected with HBV and/or HCV. Sexual risk behaviors among IDUs in Shanghai are common, and many IDUs are vulnerable for transmission of disease. Prevention efforts with IDUs should address sexual risk behaviors in addition to needle-sharing behaviors.

Antifungal Susceptibility Testing and Antifungal Traditional Chinese Medicines Screening of Oral Candida Isolated from Head and Neck Cancer Patients Treated with Radiotherapy or Chemotherapy [Article in Chinese]
Zhao, M., Zhou, Z.T., Zhang, W.D. Hua, Xi Kou Qiang Yi Xue Za Zhi. 24(2), pp. 131-134, April 2006. INVEST Fellow: Min Zhao, China, 2001-2002. The objective of this study was to evaluate the sensitivity and resistance of pathogenic oral Candida spp. isolated from head and neck cancer patients treated with radiotherapy or chemotherapy to antifungal agents. To screen antifungal agents from Chinese traditional and herbal drugs by NCCLS M27-A2 method. Using YBC Test Kit to identify 20 clinical oral Candida isolated from head and neck cancer patients treated with radiotherapy or chemotherapy. The in vitro susceptibilities of 20 oral Candida spp. to 5-flucytosine (5-FC), itraconazole (ITR), fluconazole (FLU), the extracts of 6 Chinese traditional and herbal drugs (caltrop, honeysuckle flower, dandelion, green tea, pine bark, red trefoil) and utility components of 7 Chinese traditional and herbal drugs (sophorcarpidine, aloperine, archin, glycyrrhizic acid, glycosides of white peony root, glycosides of baikal skullcap root, hydrochloric berberine) were determined by NCCLS M27-A2 method. The proportion of no-C. albicans in all Candida spp. were 25%. All strains were sensitive to 5-flucytosine, 25% stains were resistant to fluconazole and 40% strains were resistant to itraconazole. In all agents from Chinese traditional and herbal drugs, glycosides of white peony root and hydrochloric berberine (C20H18CINO4) exhibited antifungal activity, especially to C. glabrates. The proportion of no-C. albicans in all oral Candida spp. isolated from head and neck cancer patients treated with radiotherapy or chemotherapy was high. NCCLS M27-A2 micro-dilution method is a reliable and reproducible method and can be used to screen antifungal agents from Chinese traditional and herbal drugs.

Former Hubert H. Humphrey Drug Abuse Research Fellows

Factors Associated with Drug and Alcohol Use Among University Students [Article in Portuguese]
Silva, L.V., Malbergier, A., Stempliuk, Vde A., and Andrade, A.G. Rev Saude Publica. 40(2), pp. 280-288, April 2006. Epub 2006 March 29. HHH Fellows: Artur Guerra de Andrade, Brazil, 1991-1992; and Vladimir Stempliuk, Brazil, 2003-2004. Recent studies show an alarming rate of alcohol and drug use among university students. The objective of this study was to assess the level of association between lifestyle and socioeconomic status and the prevalence of alcohol, tobacco, medicine, and "illicit drug" use in the last 12 months among university students. The sample included 926 undergraduate students in the Biology Department of a university in Sao Paulo who completed an anonymous, self-applied questionnaire in 2000 and 2001. Anova and Chi-square tests were applied to verify the correlation between substance use and variables. Among students who reported having a religion, alcohol consumption was 83.1%, tobacco use 20.7%, and "illicit drugs" 24.6% during this period. Among students who reported not having a religion, reported alcohol use was higher in the last 12 months: alcohol (89.3%), tobacco (27.7%) and "illicit drugs" (37.7%). Monthly family income was related to alcohol and "illicit drug" use (p<0.001 for both). The students who used tobacco and "illicit drugs" reported more free time during the week than students who didn't smoke during the period of time analyzed (p=0.033 and p=0.008, respectively). Psychoactive drug use was common among students, indicating a need for policies to be implemented with the goal of reducing consumption. Students with higher family income and without religion should be considered to be at higher risk for alcohol and drug use among this group.

Human Vitamin B12 Absorption Measurement by Accelerator Mass Spectrometry Using Specifically Labeled (14)C-Cobalamin
Carkeet, C., Dueker, S.R., Lango, J., Buchholz, B.A., Miller, J.W., Green, R., Hammock, B.D., Roth, J.R., and Anderson, P.J. Proc Natl Acad Sci U S A. 103(15), pp. 5694-5699, April 11, 2006. Epub 2006 Apr 3. HHH Fellow: Józef Langó, Hungary, 1997-1998. There is a need for an improved test of human ability to assimilate dietary vitamin B(12). Assaying and understanding absorption and uptake of B(12) is important because defects can lead to hematological and neurological complications. Accelerator mass spectrometry is uniquely suited for assessing absorption and kinetics of carbon-14 ((14)C)-labeled substances after oral ingestion because it is more sensitive than decay counting and can measure levels of (14)C in microliter volumes of biological samples with negligible exposure of subjects to radioactivity. The test authors describe employs amounts of B(12) in the range of normal dietary intake. The B(12) used was quantitatively labeled with (14)C at one particular atom of the dimethylbenzimidazole (DMB) moiety by exploiting idiosyncrasies of Salmonella metabolism. To grow aerobically on ethanolamine, Salmonella enterica must be provided with either preformed B(12) or two of its precursors, cobinamide and DMB. When provided with (14)C-DMB specifically labeled in the C2 position, cells produced (14)C-B(12) of high specific activity (2.1 GBq/mmol, 58 mCi/mmol) (1 Ci = 37 GBq) and no detectable dilution of label from endogenous DMB synthesis. In a human kinetic study, a physiological dose (1.5 microg, 2.2 kBq/59 nCi) of purified (14)C-B(12) was administered and showed plasma appearance and clearance curves consistent with the predicted behavior of the pure vitamin. This method opens new avenues for study of B(12) assimilation.

Mirtazapine for Patients with Alcohol Dependence and Comorbid Depressive Disorders: A Multicentre, Open Label Study
Yoon, S.J., Pae, C.U., Kim, D.J., Namkoong, K., Lee, E., Oh, D.Y., Lee, Y.S., Shin, D.H., Jeong, Y.C., Kim, J.H., Choi, S.B., Hwang, I.B., Shin, Y.C., Cho, S.N., Lee, H.K., and Lee, C.T. Prog Neuropsychopharmacol Biol Psychiatry. April 17, 2006. [Epub ahead of print] HHH Fellow: Chung Tai Lee, South Korea, 1994-1995. Major depressive disorder and alcohol dependence are common and serious mental illnesses. There is a great interest in discovering useful treatments for both mood symptoms and alcohol abuse in those patients with depressive disorders and comorbid alcohol dependence. The primary purpose of this study was to evaluate the effectiveness and tolerability of mirtazapine for the treatment of patients with alcohol dependence comorbid with a depressive disorder in an open label, naturalistic multicentre treatment setting. The 17-item Hamilton Depression Rating Scale (HDRS), the Hamilton Anxiety Rating Scale (HARS) and the Clinical Global Impression-Severity (CGI-S) scale were measured at baseline and at weeks 4 and 8 for the assessment of treatment effectiveness. Alcohol craving was measured using the Obsessive Compulsive Drinking Scale (OCDS) and the Visual Analog Scale for Craving (VAS). This study showed a statistically significant reduction of the scores on the HDRS (13.9+/-7.3, p<0.0001), HARS (10.8+/-7.2, p<0.0001) and the CGI-S (1.7+/-1.0, p<0.0001) from baseline to the endpoint (week 8). The OCDS and VAS scores were also decreased significantly by 42.3% and 53.2% (9.0+/-10.0, p<0.0001; 2.5+/-2.4, p<0.0001, respectively). The number of patients with a 50% reduction or more in the HDRS and HARS scores was 103 (72.0%) and 106 (74.1%) at the endpoint, respectively. Adverse events related to mirtazapine were observed in 10% or more of the patients in this study. In conclusion, the results from this naturalistic study suggest that the use of mirtazapine for the patients with alcohol dependence comorbid with depressive disorder is accompanied by clinical improvement in their mood and alcohol craving.

Assessing Prescribing and Patient Care Indicators for Children Under Five Years Old With Malaria and Other Disease Conditions in Public Primary Health Care Facilities
Nsimba, S.E. Southeast Asian J Trop Med Public Health. 37(1):206-214, January 2006. HHH Fellow: Stephen Nsimba, Tanzania, 2005-2006. A prospective descriptive observational study using WHO indicator forms and questionnaire was carried out in Kibaha district public primary health care facilities. Authors assessed knowledge about drugs in mothers/guardians of sick children under age five years immediately after consulting clinicians and after receiving drugs from the dispenser. The questionnaires had closed- and open-ended questions. Interviews were administered by trained nurses and the authors. The prescribing, dispensing practices, including drug labeling and instructions given to mothers/guardians on how to use drugs at home, in these health facilities which are under the Essential Drugs Program (EDP), was assessed. A total of 652 prescriptions from mothers/ guardians with sick children under age five years were observed, recorded and analyzed. Prescribing indicators were used as stipulated by the WHO/DAP/93.1 how to investigate drug use in health facilities. The diagnosis for malaria cases made by the clinicians on average per facility were as follows: malaria alone 25, diarrhea alone 3, pneumonia alone 3, malaria and diarrhea 4 cases, malaria and pneumonia 2 cases and malaria and other conditions 14 cases. The average number of drugs per prescription in these facilities was 2.3 and the percentage generic prescribing was 87.0, antibiotics 30.5, and injections 26.2, with 93.5 % of all prescribed drugs being within the Essential Drugs List (EDL). The overall average dispensing time was 1.4 minutes per patient, of the drugs prescribed, 54.7 % were dispensed, whereas 21.4 % of drugs dispensed to mothers/guardians were adequately labeled, and 37.2 % of mothers knew how to administer drugs correctly to their sick children after receiving the drugs from the dispenser. These results suggest the need for educational intervention for prescribers (health care providers) on rational prescribing of drugs, such as antimalarials, antibiotics, injections, proper dispensing, and adequate labeling drugs in packets, while the dispensing time for drugs was too short. It is necessary to correct these malpractices of irrational prescribing and dispensing drugs for treatment of malaria and other childhood illnesses in public primary health care facilities (PHC). Furthermore, inadequate physical examination and short consultation time needs to be improved. There is a need to advise the Ministry of Health to develop health education programs on a regular basis for all health care providers in the country and mothers/guardians of children in general public/rural communities on how to use/administer antimalarials and other drugs at home. All these can be achieved through well planned health education training programs.

HIV Seroprevalence Among Drug Users: An Analysis of Selected Variables Based on 10 Years of Data Collection in Porto Alegre, Brazil
Pechansky, F., Woody, G., Inciardi, J., Surratt, H., Kessler, F., Von Diemen, L., and Bumaguin, D.B. Drug Alcohol Depend. 82 Suppl 1, pp. S109-113, April 2006. HHH Fellow: Flavio Pechansky, Brazil, 1993-1994. Data from five studies were pooled to describe associations between drug use and HIV. The Risk Assessment. Battery in Porto Alegre, Brazil, was used to collect data from 1449 subjects in 5 separate studies conducted between 1995 and 2004. The subjects were divided into categories based on their pattern of drug use: (1) injection drug users (IDUs), (2) crack smokers, (3) frequent drug users, and (4) infrequent cocaine/alcohol/marijuana users. The sample consisted primarily of young males with low education and income levels. Half of the subjects reported frequent condom use, and exchanges involving drugs, sex, and money were infrequent (although more common in groups 1 and 2). The overall seroprevalence was 20.6%, and the prevalence was different across the four groups, showing a linear decrease from group 1 (57.1%) to group 4 (11.7%). The IDU and crack-smoking groups showed similarities in their risk levels when compared with the other two groups, and individuals in group 1, 2, and 3 were more likely to report having had four or more sex partners. After controlling for all other risk factors, IDU, males having sex with males, and crack use were highly associated with HIV (OR 7.30, 95% CI: 5.10.10.40; OR 3.04, 95%CI: 1.89,4.80; OR 2.03, 95%CI: 1.40, 2.92, respectively). The findings confirm that poverty, low education, and IDU remain risk factors for HIV in Porto Alegre, Brazil, and the study identities crack smoking as a new risk factor.

Poor Educational Attainment and Sexually Transmitted Infections Associated with Positive HIV Serostatus Among Female In-Patient Substance Abusers in Trinidad and Tobago
Reid, S.D. Drug Alcohol Depend. 82 Suppl 1, pp. S81-84, April 2006. HHH Fellow: Sandra Reid, Trinidad and Tobago, 1992-1993. Female crack cocaine users are at high risk for HIV infection. Data from 121 female substance abusers admitted to an all-female rehabilitation center in Trinidad and Tobago between 1996 and 2002 were reviewed retrospectively to determine human immunodeficiency virus (HIV) seroprevalence and associated risk factors. HIV seroprevalence was 19.8%, which is six times higher than in the general population. The univariate analysis identified the following factors associated with HIV infection: poor educational attainment, history of a sexually transmitted infection (STI), and use of crack cocaine. In the multivariate analysis, only poor educational attainment and history of an STI were independently associated with HIV seroprevalence. Female substance abusers, especially female crack cocaine users, are at high risk of acquiring and transmitting the HIV virus. To reduce risk of HIV infection, rehabilitation programs should address risky sexual behaviors and screen for STIs, and they also should improve educational attainment, develop skills, and provide vocational training.

Acute Hepatic Injury and Renal Failure After Ingestion of Snake Gallbladder
Chao, T.C., Wu, M.L., Tsai, W.J., Ger, J., and Deng, J.F. Clin Toxicol (Phila). 44(4), pp. 387-390, 2006. HHH Fellow: Wei-Jen Tsai, Taiwan, 1992-1993. Ingestion of snake gallbladder has been practiced in ancient Chinese civilizations to improve vision and relieve arthritic pain. Although little is known about the composition of snake gallbladder, ingestion is still practiced in some Chinese cultures. Adverse effects of ingesting snake gallbladder have not yet been reported. Here, authors present a case of acute hepatic injury and delayed-onset renal failure after ingestion of snake gallbladders. The patient subsequently recovered after supportive care, combined with plasma exchange and hemodialysis. He was the only survivor of the four victims suffering from intoxication of snake gallbladder in the last three years in our hospital.

U.S. - Netherlands Supplement-Supported Research Suggests Word Association Tasks and Working Memory Capacity Are Associated With Drug Use
Working with funding provided through the U.S. - Netherlands Binational Agreement, research teams led by Dr. Alan W. Stacy, University of Southern California, and Dr. Reinout Wiers, University of Maastricht, have reported that word association tasks appear to be more effective predictors of drug use than other major tests of implicit cognition, such as reaction time measures, and that adolescents with high levels of drug-related associations are at risk of using more drugs if they have lower versus higher levels of working memory capacity. The researchers also demonstrated the feasibility and utility of neuro-cognitive, laboratory-based batteries in small-group settings in the field. Their successful implementation of brief interventions for at-risk adolescents in a school setting could serve as a model for other high school intervention programs, especially for students who do not respond to group interventions. The group most recently published results in the Journal of Adolescent Medicine and Health (18, 53-67, 2006) and Evaluation and the Health Professions (29, 89-125, 2006), and presented their findings at a conference organized by the Dutch National Institute for Drug Abuse, Maastricht, the Netherlands, in March 2006. They have also completed a chapter, "Brief motivational interviewing and drug related problems," in Adolescence and Alcohol: An International Perspective (in press), edited by I. Kandel, J. Merrick, and L. Sher.

DISCA Researcher Examines Role of NMDA Receptors on Dopamine Efflux
2005 NIDA Distinguished International Scientist Dr. Luc Deneroy and colleagues at UniversitŽ Claude Bernard de Lyon, France, have published their research discussing how NMDA receptors inhibit the mild hypoxia-induced dopamine efflux in the rat striatum. The short communication appeared in Synapse, 59(7) 458 - 461.