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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Cocaína: aspectos farmacológicos / Cocaine: pharmacologic aspects

Existen diferentes formas de abuso de la cocaína (hojas de coca, sulfato de cocaína, clorhidrato de cocaína y cocaína base o crack) que condicionan la farmacocinética; la actividad farmacológica, la toxicidad y el grado de adicción de la droga. En nuestro medio, la cocaína se fuma o se esnifa fundamentalmente, pero también se usa por vía intravenosa. La cocaína atraviesa las membranas celulares de forma rápida. Esnifada o administrada por vía intravenosa se encuentran niveles de cocaína en el cerebro en 30 segundos, mientras que fumada sólo tarda 5 segundos en tener efectos centrales. La cocaína es rápidamente metabolizada, generalmente por hidrólisis enzimática para producir benzolyecgonina, ecgonina metil ester y posteriormente ecgonina. Sin embargo, en presencia de etanol, la cocaína es transesterificada a cocaetileno que posee actividad farmacológica y tóxica. La cocaína es un potente inhibidor de la recaptación tipo I de noradrenalina, dopamina y serotonina, lo que facilita la acumulación de esos neurotransmisores en la hendidura sináptica. Las acciones farmacológicas se caracterizan por manifestaciones de actividad noradrenérgica y dopaminérgica fundamentalmente, que afecta a los distintos aparatos; la intoxicación aguda se manifiesta por una hiperactividad de estos sistemas (AU)

The routes of administration of cocaine are different depending on the cocaine source (leaves, sulphate, hydrochloride and crack), and this affects not only its pharmacokinetics but also its pharmacological effects, as well as other aspects such as toxicity, tolerance, dependence and withdrawal effects of this drug. In our country, cocaine is mainly smoked or inhaled, and intravenous administration can be also used. Cocaine is rapidly absorbed by many routes. Cocaine produces central effects in 30 seconds after nasal or intravenous administration and in only 5 seconds when cocaine is smoked. The major route for cocaine metabolism involves hydrolysis of its ester groups producing benzoylecgonine, ecgonine methyl ester and ecgonine as metabolites. An important metabolic interaction occurs when cocaine and alcohol are taken concurrently; cocaine is then transesterified to cocaethylene, which is toxic. Cocaine is a potent inhibitor of catecholamine uptake by noradrenergic, dopaminergic and serotoninergic nerve terminals and strongly enhances the effects of these neurotransmitters Pharmacological and toxic effects are derived from its actions on the catecholaminergic system (AU)

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.

Oxidative stress in HIV-1-infected injection drug users.

Low serum antioxidant levels observed in many HIV-infected populations could be largely due to an increase in oxidative stress (defined as a disturbance in the equilibrium status of prooxidant/antioxidant systems of intact cells). In HIV infection, oxidative stress may be caused by both overproduction of reactive oxygen intermediates (ROIs) and a simultaneous deficiency of antioxidant defenses. Furthermore, injection drug use has been associated with increased levels of oxidative stress in animal models. Currently, there is widespread use of self-prescribed antioxidant supplementation among the HIV-infected population and a prevailing belief that high-dose supplementation is beneficial, or at the very least, not harmful. Data from our studies show that HIV-positive injection drug users (IDUs) who are on antiretroviral combination therapies including a protease inhibitor have significantly higher mean serum levels of several antioxidants, independent of dietary and supplemental intake, compared with both HIV-negative IDUs and HIV-positive IDUs not taking protease inhibitors. This suggests that oxidative stress may be reduced in patients taking protease inhibitors. Preliminary data suggest that the future of antioxidant supplementation therapy, if any, will be one in which different doses of supplements are recommended for HIV-infected patients on the various antiretroviral treatment regimens. More research is needed to determine the interactions among injection drug use, oxidative stress, antiretroviral therapy, and the use of antioxidant supplements in HIV infection. Until more is known, caution should be exercised when using or recommending high-dose antioxidant supplementation in HIV-infected individuals, particularly in those on protease inhibitors, since moderate levels of oxidative stress are involved in a number of useful physiologic processes.

Interaction of methadone with didanosine and stavudine.

For opiate-dependent injection drug users infected with HIV, methadone therapy may facilitate adherence to complex highly active antiretroviral therapy (HAART) regimens. Current HAART regimens include one or more nucleoside analogues. We investigated the effects of methadone on the pharmacokinetics of the tablet formulation of didanosine (ddI) and of stavudine (d4T) in 17 study subjects on stable methadone therapy and in 10 untreated controls. Methadone treatment reduced the measured areas under the time-concentration curve (AUC0-6) by 63% for ddI (p =.04) and by 25% for d4T (p =.005) and the extrapolated AUCs for the full dosing interval (AUC0-12) by 57% for ddI (p =.11) and by 23% for d4T (p =. 02). Peak drug concentrations (Cmax) were reduced by 66% (p =.007) and 44% (p =.001) for ddI and d4T, respectively. The effects on AUC and Cmax appeared to result primarily from decreases in bioavailability. Methadone also delayed drug absorption. Trough levels for methadone did not differ significantly from those in historical controls, suggesting that ddI and d4T did not substantially alter methadone disposition. The results suggest that larger doses of the tablet formulation or an alternate formulation may be needed when didanosine is given to study subjects treated with methadone.

Improved antioxidant status among HIV-infected injecting drug users on potent antiretroviral therapy.

Low serum antioxidant levels in HIV-infected people have been attributed to altered metabolism associated with excess oxidative stress. We conducted a study to examine serum antioxidant levels in 175 HIV-positive and 210 HIV-negative injecting drug users (IDUs) in Baltimore, Maryland. At the time of data collection, 30 of the HIV-positive IDUs were receiving antiretroviral therapies (ART) including a protease inhibitor (PI), 43 ART without a PI, 22 monotherapies, and 80 not on any ART. Serum antioxidants examined included retinol, alpha-tocopherol and gamma-tocopherol, alpha-carotene and beta-carotene, lycopene, lutein/zeaxanthin, and beta-cryptoxanthin. Mean serum levels of lycopene and lutein/zeaxanthin were significantly lower in HIV-positive IDUs than HIV-negative IDUs. Contrary to the findings in other studies, however, levels of the remaining antioxidants in HIV-positive study subjects were not lower than in HIV-negative study subjects. In fact, serum alpha-tocopherol levels were significantly higher in HIV-positive IDUs than HIV-negative IDUs (medians = 744 microg/dl and 718 microg/dl, respectively; p = .04). Among HIV-positive study subjects, there were significant differences in antioxidant levels by ART regimen. In multivariate models adjusting for injecting drug use, dietary intake, supplement intake, gender, and alcohol intake, significant overall differences by ART regimen were observed for alpha-tocopherol, beta-carotene, and beta-cryptoxanthin. Serum levels of these three antioxidants were significantly higher in the PI group than in the other three ART groups combined (p = .0008, 0.02, and 0.02, respectively). These data provide indirect evidence of the effectiveness of PIs in lowering oxidative stress levels in HIV-positive IDUs.