Brain viral burden, neuroinflammation and neurodegeneration in HAART-treated HIV positive injecting drug users.

The long-term impact of chronic human immunodeficiency virus (HIV) infection on brain status in injecting drug users (IDU) treated with highly active antiretroviral therapy (HAART) is unknown. Viral persistence in the brain with ongoing neuroinflammation may predispose to Alzheimer-like neurodegeneration. In this study, we investigated the brains of ten HAART-treated individuals (six IDU and four non-DU), compared with ten HIV negative controls (six IDU and four non-DU). HIV DNA levels in brain tissue were correlated with plasma and lymphoid tissue viral loads, cognitive status, microglial activation and Tau protein and amyloid deposition. Brain HIV proviral DNA levels were low in most cases but higher in HIV encephalitis (n = 2) and correlated significantly with levels in lymphoid tissue (p = 0.0075), but not with those in plasma. HIV positive subjects expressed more Tau protein and amyloid than HIV negative controls (highest in a 58 year old), as did IDU, but brain viral loads showed no relation to Tau and amyloid. Microglial activation linked significantly to HIV positivity (p = 0.001) and opiate abuse accentuated these microglial changes (p = 0.05). This study confirms that HIV DNA persists in brains despite HAART and that opiate abuse adds to the risk of brain damage in HIV positive subjects. Novel findings in this study show that (1) plasma levels are not a good surrogate indicator of brain status, (2) viral burden in brain and lymphoid tissues is related, and (3) while Tau and amyloid deposition is increased in HIV positive IDU, this is not specifically related to increased HIV burden within the brain.

Heavy injection drug use is associated with lower percent body fat in a multi-ethnic cohort of HIV-positive and HIV-negative drug users from three U.S. cities.

BACKGROUND: The clinical implications of lower body weight in drug using populations are uncertain given that lower mean weights may still fall within the healthy range. OBJECTIVES: To determine the effect of type, mode and frequency of drug use on underlying body composition after accounting for differences in body shape and size. METHODS: We conducted a cross-sectional analysis of 511 participants from the Tufts Nutrition Collaborative (TNC) Study. Data included measures of body composition, a 24-hour dietary recall, and a detailed health history and lifestyle questionnaire. Multivariate regression analysis was used to determine the independent effect of drug use on percent body fat (BF) after adjusting for BMI and waist circumference. RESULTS: Heavy injection drug users (IDUs) had a 2.6% lower percent BF than non-users after adjusting for BMI, waist circumference, and other confounders. (p = 0.0006). Differences in percent BF were predominantly due to higher lean mass, rather than lower fat mass. Cocaine and heroin had similar effects on body composition. CONCLUSIONS: In the U.S., where the general population is prone to over-nutrition, the average percent BF for heavy injectors does not fall into a range low enough to suggest harmful effects. However, in populations with substantial levels of under-nutrition, small differences in percent BF among drug users will have a greater impact on health status. SCIENTIFIC SIGNIFICANCE: Differences in BMI, weight and body composition are not always straightforward. Accounting for underlying nutritional status and relative differences in fat and FFM is critical when interpreting results. diagnosed patients and prevent them from returning to prison.

Analysis of the effects of injecting drug use and HIV-1 infection on 18F-FDG PET brain metabolism.

UNLABELLED: Injecting drug use (IDU) is a major risk factor for contracting HIV-1 infection. Both HIV and IDU are neurotoxic, and their coexistence may lead to increased dysfunction of brain metabolic processes. The objective of this research was to investigate the effects of HIV-1 infection and IDU on (18)F-FDG PET brain metabolism. METHODS: (18)F-FDG PET brain imaging, with a standard clinical protocol, was performed on 59 subjects who belonged to 3 groups: HIV-positive/IDU-positive (n = 17), HIV-negative/IDU-positive (n = 13), and HIV-negative/IDU-negative controls (n = 29). A voxel-based analysis of the (18)F-FDG PET brain images was performed using statistical parametric mapping. The images were spatially normalized to a standard (18)F-FDG template, proportionally scaled to compensate for count differences, and then appropriately smoothed. Statistical 2-sample t tests were performed to determine regional metabolic distribution differences in the 3 groups. RESULTS: Diffuse hypermetabolism in the subcortical and deep white matter, the basal ganglia, and the thalami was observed in HIV-1 infection. IDU resulted in increased brainstem metabolism and decreased activity in cortical structures including bilateral medial frontal lobes and the right inferior frontal and temporal cortices. The cortical hypometabolism was more extensive in HIV-1-infected subjects, involving the left temporoparietal and right parietal cortices and bilateral medial frontal lobes. CONCLUSION: Voxel-based analysis of (18)F-FDG PET brain images demonstrated statistically significant differences in regional metabolism for the 3 studied groups. It also showed that HIV-1 infection may have a synergistic effect with IDU, resulting in more extensive cortical hypometabolism. Correlation of these findings with other quantitative approaches and neurocognitive functioning is warranted.

Methylphenidate disintegration from oral formulations for intravenous use by experienced substance users.

BACKGROUND AND AIMS: Methylphenidate (MPH) is a prescription stimulant used to treat attention-deficit hyperactivity disorder. MPH is currently the preferred substance among most intravenous (i.v.) substance users in Iceland. Four types of MPH preparations were available in Iceland at the time of study: Immediate-release (IR), sustained-release (SR), osmotic controlled-release oral delivery (OROS) tablet and osmotic-controlled release (OCR). MPH OROS has previously been rated the least desirable by i.v. users and we hypothesized that this was associated with difficulty of disintegrating MPH from OROS formulation. The aim of the study was to measure the amount of MPH and the viscosity of the disintegrated solutions that were made from the four MPH formulations by four i.v.-users and non-users. METHODS: A convenience sample of four i.v. substance users and 12 non-users. Non-users imitated the methods applied by experienced i.v. substance users for disintegrated MPH formulations. RESULTS: Both groups managed to disintegrate over 50% of MPH from IR and SR formulations but only 20% from OROS (p<0.0001). The viscosity of the disintegrated MPH was significantly higher for MPH OROS and MPH OCR and the preparation was significantly more time-consuming than for the other MPH samples. No differences were observed between users and non-users. CONCLUSIONS: To our knowledge, this is the first investigation of viscosity and the amount of disintegrated MPH from prescription drugs for i.v. use. The results indicate that the ease of disintegration, amount of MPH and viscosity may explain the difference in popularity for i.v. use between different MPH formulations.

Escalation of i.v. cocaine self-administration and reinstatement of cocaine-seeking behavior in rats bred for high and low saccharin intake.

RATIONALE: Rats selectively bred for high saccharin (HiS) intake consume more alcohol, acquire intravenous (i.v.) cocaine self-administration more rapidly, and show more dysregulated patterns of cocaine self-administration than their low saccharin-consuming (LoS) counterparts. OBJECTIVES: The purpose of the present study was to determine whether HiS and LoS rats also differ in the escalation, maintenance, extinction, and reinstatement of i.v. cocaine self-administration. MATERIALS AND METHODS: Two experiments were conducted in separate groups of rats. In the first experiment, HiS and LoS female rats were allowed to self-administer cocaine [0.4 mg/kg; fixed ratio (FR) 1] under short (ShA, 2 h per day) or long (LgA, 12 h per day) access conditions for 21 days. Session lengths were subsequently equated (2 h), and FR1-maintained cocaine self-administration was examined. In the second experiment, additional groups of HiS and LoS female rats were given access to cocaine (0.4 mg/kg; FR 1) self-administration during 2-h sessions for 10 days. Subsequently, saline was substituted for cocaine, and responding was extinguished. After a 14-day extinction period, saline- and cocaine-[5, 10, and 15 mg/kg, intraperitoneal (i.p.)] induced reinstatement of drug-seeking behavior was measured. RESULTS: HiS LgA rats escalated their cocaine intake more rapidly than LoS rats, and during the 2 h sessions after escalation cocaine self-administration was significantly higher in HiS LgA rats, compared to LoS LgA rats. HiS rats responded on the cocaine-paired lever more than LoS rats during maintenance, extinction, and cocaine-(15 mg/kg) induced reinstatement. CONCLUSIONS: These results suggest that HiS and LoS rats have distinct drug-seeking and drug-taking profiles. The HiS and LoS rats differ along a wide range of behavioral dimensions and represent an important model to study the interactions of excessive intake of dietary substances and vulnerability to drug abuse.

Norepinephrine secretion in the hypothalamic paraventricular nucleus of rats during unlimited access to self-administered nicotine: An in vivo microdialysis study.

Norepinephrine (NE) secretion within the hypothalamic paraventricular nucleus (PVN) is pivotal to endocrine and behavioral responses. Activation of NE afferents to PVN also is necessary for the hypothalamo-pituitary-adrenal axis response to passively administered nicotine. The mode of drug delivery is a critical determinant of the dynamics of neurotransmitter secretion, yet the PVN NE response to nicotine self-administration (SA) is unknown. Herein, rats housed in operant chambers had unlimited 23 hr access to self-administered nicotine. In vivo microdialysis of PVN NE was performed, collecting consecutive 7 min samples over 9 hr sessions during three phases of nicotine SA: acquisition (day 1); early maintenance, once stable rates of SA were achieved (day 9.2 +/- 0.6); later maintenance (day 18.6 +/- 0.8). On d1, nicotine animals had an increased percentage of SA episodes (SAEs) in which NE levels were elevated (80 vs 30% with saline; p < 0.01). By early maintenance, a fourfold increase in such episodes was observed in nicotine animals (p < 0.01), and the overall NE level was greater (1.30 +/- 0.24 vs 0.63 +/- 0.07 pg/10 microl in saline; p < 0.05); NE increased during the first, but not the last, SAE. The pattern was similar during later maintenance, although NE responsiveness declined (overall NE level, 0.96 +/- 0.19 in nicotine vs 0.52 +/- 0.08 pg/10 microl in saline; p < 0.05). Therefore, nicotine SAEs were associated with sustained increases in NE secretion during all three phases of SA. However, the reduced NE responsiveness observed both within the dialysis session in each phase and by later versus early maintenance is consistent with progression of partial daily desensitization of PVN NE secretion to nicotine SA. Therefore, in rats chronically self-administering nicotine, the drug stimulates sustained PVN NE secretion that may alter neuroendocrine and behavioral responses mediated by the PVN. Compared with studies of chronic human smokers, our nicotine SA model may reflect the CNS noradrenergic responses that occur during human cigarette smoking.

Cocaine and heroin ('speedball') self-administration: the involvement of nucleus accumbens dopamine and mu-opiate, but not delta-opiate receptors.

RATIONALE: The combined administration of heroin and cocaine ('speedball') is common among intravenous drug users. Dopamine receptors in the nucleus accumbens play a key role in cocaine self-administration; however, their role in speedball self-administration is unknown, as is the role of opiate receptors in this region. OBJECTIVES: The effect of blocking dopamine D1, D2, mu-opiate or delta-opiate receptors in the nucleus accumbens on the intravenous self-administration of combined heroin and cocaine was examined in rats. METHODS: Rats with bilateral cannulae implanted into the nucleus accumbens were trained to self-administer intravenous speedball (ratio of cocaine/heroin, 17:1) under a progressive ratio (PR) schedule. Prior to their self-administration session, rats were then microinjected with the dopamine D1 receptor antagonist SCH 23390 (1 and 6 nmol side(-1)), the D2 receptor antagonist raclopride (3 and 10 nmol side(-1)), the mu-opiate receptor antagonist CTOP (0.1, 0.3 and 1.0 nmol side(-1)), the delta-opiate receptor antagonist naltrindole (1.0, 3.0 and 10 nmol side(-1)) or a cocktail of SCH 23390 (1 nmol side(-1)) and CTOP (0.1 nmol side(-1)) into the nucleus accumbens. RESULTS: Microinjection of SCH 23390, raclopride or CTOP into the nucleus accumbens produced dose-dependent decreases in breakpoints under the PR schedule, while naltrindole was without effect. The highest dose of SCH 23390 also significantly reduced locomotor activity measured during speedball self-administration. The combination of SCH 23390 and CTOP significantly reduced breakpoints, while not affecting locomotor activity. CONCLUSIONS: These results indicate that dopamine and mu-opiate receptors, but not delta-opiate receptors, in the nucleus accumbens are involved in the reinforcing effects of speedball. Combined administration of D1 and mu-opiate receptor antagonists may be more selective at reducing the reinforcing effects of speedball self-administration than either drug alone.

Oxycodone/naloxone preparation can cause acute withdrawal symptoms when misused parenterally or taken orally.

CONTEXT: Oral oxycodone/naloxone preparations are designed to reduce the incidence of constipation associated with oxycodone use. The low oral bioavailability (< 2%) of naloxone makes the precipitation of the acute opioid withdrawal symptoms unlikely following oral oxycodone/naloxone exposure. The incidence of acute opioid withdrawal symptoms following both oral and intravenous administration of oxycodone/naloxone preparations has not been described. OBJECTIVE: The aim of the study was to investigate the incidence and circumstances associated with oxycodone/naloxone-induced acute opioid withdrawal. METHODS: An observational case series of acute opioid withdrawal following oxycodone/naloxone administration were selected from all calls received by the Victoria Poisons Information Centre from January 2012 to December 2014. Data collected included patient demographics, reported symptoms, type of caller, intentional or accidental exposure and advice given. RESULTS: There were 107 reported exposures to oxycodone/naloxone preparations. Route of exposure was oral in 92 (86%) and intravenous injection of crushed tablets in 14 (14%) of cases, respectively. Nine callers had a history of long-standing opioid treatment and developed withdrawal symptoms with oral oxycodone/naloxone. Temporal relationship between first dose, increased dose and chewing tablets was described. There were 14 exposures to crushed oxycodone/naloxone tablets injected intravenously; all precipitated an acute withdrawal state. DISCUSSION: The development of opioid withdrawal symptoms with intravenous injection of oxycodone/naloxone is likely a result of bypassing first-pass metabolism. Withdrawal symptoms after ingesting increased dose, first dose or chewing oxycodone/naloxone suggests that there is a systemic absorption of naloxone in opioid-dependent callers. CONCLUSION: Oxycodone with naloxone tablets can lead to acute opioid withdrawal symptoms if crushed and injected parentally. First dose, increased dose and chewing of these opioid-naloxone combination tablets in opioid-dependent people can also result in acute opioid withdrawal symptoms or diminished pain relief.

Retinoids and drugs of abuse: implications for neurological disease risk in human immunodeficiency virus type 1 infection.

Among injection drug users, human immunodeficiency virus (HIV) type 1 infection may be associated with an increased risk of nervous system disease. For HIV-infected drug users with vitamin A deficiency, the overall risk of HIV-related morbidity and mortality may also be higher. In previous studies, levels of retinol, retinol-binding protein, and transthyretin in samples from such individuals were examined and found to be lower than such levels in seronegative control subjects. Also, in studies using an activated mononuclear cell line, all-trans retinoic acid and 9-cis retinoic acid suppressed production of the tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. However, simultaneous exposure of the cells to morphine at a concentration similar to that to which drug users are exposed resulted in increased production of these cytokines. Therefore, morphine may alter the immunomodulatory effects of retinoids, thereby potentially affecting the clinical outcome of studies involving retinoid administration to HIV-infected drug users and increasing the risk for the development of HIV-related complications, including neurological disease.

PET study of competition between intravenous cocaine and [11C]raclopride at dopamine receptors in human subjects.

OBJECTIVE: Animal data suggest that the strong euphoriant effects of cocaine are related to the drug's enhancement of available dopamine at the synaptic cleft. The authors' goal was to determine whether this mechanism is the same in humans because the development of putative pharmacological agents for treatment of cocaine dependence depends on this knowledge. METHOD: Positron emission tomography with [11C]raclopride was used to examine the effects of the intravenous administration of 48 mg of cocaine (a typical "street" dose) on the occupancy of dopamine 2 receptors in the putamen of 11 self-identified intravenous drug abusers. RESULTS: All 11 subjects reported subjective stimulation and euphoria in response to cocaine administration. Radioligand occupancy at dopamine receptors was decreased significantly after cocaine administration, suggesting that higher dopamine concentrations were competing at the receptor site. CONCLUSIONS: These results support the concept of dopamine system involvement in human cocaine abuse.

Inflammatory and immune mediators in crevicular fluid from HIV-infected injecting drug users.

Gingival crevicular fluid (GCF) levels of the polymorphonuclear leukocyte (PMN) lysosomal enzyme beta-glucuronidase (beta G), the pro-inflammatory cytokine interleukin 1 beta (IL-1 beta), and immunoglobulins (IgA, IgG, and IgM) were examined in 16 HIV seropositive (HIV+) and 10 HIV seronegative (HIV-) injecting drug users (IDU). Each subject received a periodontal examination including assessment of probing depth, attachment level, bleeding on probing, and plaque and calculus accumulation. GCF was collected from the mesial surfaces of premolar and molar teeth using filter paper strips. Although HIV+ subjects had a significantly lower number of peripheral blood CD4+ T cells/mm3 compared to HIV- subjects, there were no significant differences in mean probing depth, percentage of sites exhibiting bleeding on probing, or plaque and calculus accumulation between HIV- and HIV+ subjects. When the GCF components were analyzed, we found no significant differences between HIV- and HIV+ subjects in GCF levels of beta G, IL-1 beta, IgA or IgM, but GCF levels of IgG were significantly increased in HIV+ subjects. When sites were categorized by probing depth, no differences in the levels of beta G, IgA, IgG, and IgM existed between sites with probing depth < or = 3 mm compared to sites with probing depth > or = 4 mm in both HIV- and HIV+ IDU. However, levels of IL-1 beta in GCF were increased in the deeper sites (> or = 4 mm) in HIV+ IDU when compared to sites with PD < or = 3 mm. Analyzing GCF constituents in relation to the CD4 cell number, no differences were found between subjects with < or = 400 or > 400 CD4 cells/mm3 with respect to the levels of IL-1 beta, IgG, and IgM. However, the level beta G was significantly decreased in the HIV+ IDU with < or = 400 CD4 cells when compared to those with > 400 CD4 cells/mm3, while levels of IgA were significantly higher in HIV+ subjects with < or = 400 CD4 cells/mm3. Our results suggest that levels of IgG, and in immunodeficient subjects IgA were increased in GCF of HIV+ IDU while decreased levels of beta G were found in immunodeficient HIV+ IDU. These findings may be local manifestations of systemic alterations and suggest that analysis of GCF may provide insight into the immune and inflammatory responses of HIV-infected individuals to periodontal microorganisms.

[Evaluation of the carbohydrate metabolism in the drug addict]. / Valoración del metabolismo hidrocarbonado en el drogadicto.

A prospective study to determine the carbohydrate metabolism in 23 intravenous drug users (IVDU) was carried out. 13 of them had no infection complications (group A), while the other 10 had acute associated infectious (group B). Both groups showed basal glycemia, insulin and glycosylated hemoglobin levels, similar to the control determinations. There were no correlations between these parameters and the hepatic function test alterations or the immunological changes in the IVDU. Our results showed that there were no alterations in the carbohydrates metabolism of the IVDU with a normal nutritional state, in spite of the well-known hypoglycemic effects of opiates in the experimental animal mode.

The effect of methamphetamine and heroin price on polydrug use: A behavioural economics analysis in Sydney, Australia.

BACKGROUND: A key aim of supply-side drug law enforcement is to reduce drug use by increasing the retail price of drugs. Since most illicit drug users are polydrug users the effectiveness of this strategy depends on the extent to which drug users reduce their overall consumption of drugs. The literature shows that drug users do reduce their consumption of a drug when its price increases. However the extent of that decrease and the implications for the use of other drugs vary across studies. METHODOLOGY: A sample of 101 Australian methamphetamine users was surveyed using a behavioural economics approach. Participants were given a hypothetical fixed drug budget, presented with a range of drug price lists and asked how many units of each drug they would purchase. Methamphetamine and heroin prices were varied independently across trials. RESULTS: While demand for both methamphetamine and heroin was found to be price elastic, elasticity estimates were influenced by the nature of participants' drug dependence. The group least responsive to changes in methamphetamine price were those dependent only on methamphetamine, while the group most responsive were dependent only on heroin. Similar findings emerged in relation to changes in heroin price. Cross-price elasticity analysis showed limited substitution into other drugs as the price of methamphetamine increased. In contrast, for heroin, there was significant substitution into pharmaceutical opioids and to a lesser extent, benzodiazepines and methamphetamine. However, for the most part, the decreases in methamphetamine or heroin consumption outweighed any substitution into other drugs. CONCLUSION: The reduction in overall drug consumption and expenditure in response to price increases in heroin and methamphetamine observed in this sample lend support to supply-side enforcement strategies that aim to increase retail drug price. Notably, this analysis highlights the importance of accounting for the nature of users' drug dependence in estimating price responsiveness.

Tumor necrosis factor-alpha levels in HIV-1 seropositive injecting drug users.

TNF-alpha is a highly pleiotropic cytokine and plays an important role in regulating HIV-1 replication. It may compromise the integrity of the blood-brain-barrier and, thus, may contribute to the neurotoxicity of HIV-1-infection. Both intravenous drug abuse (IDU) and HIV infection can increase TNF-alpha activity, but little information is available on the effects of a combination of these factors on TNF-alpha. We investigated plasma TNF-alpha levels and mRNA in the peripheral monocytes of 166 men and women in three groups: HIV-1-positive IDUs, HIV-1-negative IDUs, and HIV-negative non-IDU control participants. HIV-1-positive IDUs had higher TNF-alpha levels than HIV-1-negative IDUs who, in turn, had higher levels than controls. TNF-alpha mRNA expression in peripheral monocytes was significantly increased in both HIV-1-positive and negative IDUs compared to controls. These findings show that the effects of HIV infection and intravenous drug use may be additive in increasing TNF-alpha levels. Given the multiple effects of TNF-alpha in HIV infection, additional investigation of its role is needed.

Teicoplanin pharmacokinetics in intravenous drug abusers being treated for bacterial endocarditis.

The pharmacokinetics of teicoplanin were determined after multiple 30-min intravenous infusions of 10 to 15 mg/kg every 12 to 24 h in 11 intravenous drug abuse (IVDA) patients being treated for bacterial endocarditis. Multiple serum samples were obtained over 7 to 14 days. Twenty-four-hour urine collections were obtained on days 1 and 5. Serum concentration-time data were analyzed by using multiple-dose pharmacokinetic analysis (NONLIN84). Results were compared with pharmacokinetic parameters derived from previous studies in normal healthy volunteers following multiple intravenous infusions of teicoplanin (3 to 6 mg/kg/day). Total and renal clearances of teicoplanin in IVDA patients were found to be significantly greater and more highly variable than those observed previously in normal healthy volunteers. As a result, predicted steady-state trough concentrations in serum may vary up to fivefold. The mechanism responsible for this variation appears to be related to the glomerular filtration rate. In IVDA patients, individualized teicoplanin dosage may be required in the treatment of bacterial endocarditis.

Vancomycin pharmacokinetics in burn patients and intravenous drug abusers.

The pharmacokinetics of vancomycin were evaluated in 34 patients (10 burn patients, 14 intravenous drug abusers [IVDA], and 10 controls). Multiple serum samples were drawn following a 1-h vancomycin infusion at steady state over an 8- to 12-h dosing interval. Pharmacokinetic parameters were derived by noncompartmental analysis. There were no significant differences among the groups with respect to age, weight, serum creatinine, volume of distribution, or protein binding. Burn patients had a significantly higher creatinine clearance than did IVDA or controls. Vancomycin clearances averaged 142.8, 98.0, and 67.7 ml/min in burn patients, IVDA, and controls, respectively. The renal clearance of vancomycin was also higher in burn patients than in the other groups. IVDA tended to have a higher vancomycin clearance (31% higher) than did controls, but the difference was not statistically significant. Vancomycin clearance was much higher in burn patients requiring dosage individualization and close monitoring. A considerable amount of vancomycin was eliminated through renal tubular secretion, making dosage predictions based on creatinine clearance more difficult. Further work with IVDA will be needed to determine if they represent a group requiring aggressive vancomycin dosages.