pyrimidinones and Substance-Related-Disorders

MDMA (3,4-methylenedioxymethamphetamine, also popularly known as "ecstasy") is a popular recreational drug that produces loss of serotonin axons in animal models. Whether MDMA produces chronic reductions in serotonin signaling in humans remains controversial.. To determine whether MDMA use is associated with chronic reductions in serotonin signaling in the cerebral cortex of women as reflected by increased serotonin(2A) receptor levels.. Cross-sectional case-control study comparing serotonin(2A) receptor levels in abstinent female MDMA polydrug users with those in women who did not use MDMA (within-group design assessing the association of lifetime MDMA use and serotonin(2A) receptors). Case participants were abstinent from MDMA use for at least 90 days as verified by analysis of hair samples. The serotonin(2A) receptor levels in the cerebral cortex were determined using serotonin(2A)-specific positron emission tomography with radioligand fluorine 18-labeled setoperone as the tracer.. Academic medical center research laboratory.. A total of 14 female MDMA users and 10 women who did not use MDMA (controls). The main exclusion criteria were nondrug-related DSM-IV Axis I psychiatric disorders and general medical illness.. Cortical serotonin(2A) receptor nondisplaceable binding potential (serotonin(2A)BP(ND)).. MDMA users had increased serotonin(2A)BP(ND) in occipital-parietal (19.7%), temporal (20.5%), occipitotemporal-parietal (18.3%), frontal (16.6%), and frontoparietal (18.5%) regions (corrected P < .05). Lifetime MDMA use was positively associated with serotonin(2A)BP(ND) in frontoparietal (β = 0.665; P = .007), occipitotemporal (β = 0.798; P = .002), frontolimbic (β = 0.634; P = .02), and frontal (β = 0.691; P = .008) regions. In contrast, there were no regions in which MDMA use was inversely associated with receptor levels. There were no statistically significant effects of the duration of MDMA abstinence on serotonin(2A)BP(ND).. The recreational use of MDMA is associated with long-lasting increases in serotonin(2A) receptor density. Serotonin(2A) receptor levels correlate positively with lifetime MDMA use and do not decrease with abstinence. These results suggest that MDMA use produces chronic serotonin neurotoxicity in humans. Given the broad role of serotonin in human brain function, the possibility for therapeutic MDMA use, and the widespread recreational popularity of this drug, these results have critical public health implications.

Topics: Adolescent; Adult; Amphetamine-Related Disorders; Cerebral Cortex; Female; Fluorine Radioisotopes; Functional Neuroimaging; Humans; N-Methyl-3,4-methylenedioxyamphetamine; Positron-Emission Tomography; Pyrimidinones; Radioligand Assay; Receptor, Serotonin, 5-HT2A; Serotonin Antagonists; Substance-Related Disorders; Time Factors

Topics: Antiviral Agents; Enzyme Inhibitors; Hepacivirus; Hepatitis B virus; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Immunoglobulins; Interferons; Mental Disorders; Nucleosides; Pyrimidinones; Substance-Related Disorders; Telbivudine; Thymidine

Atazanavir (ATV) and lopinavir (LPV) are widely used HIV-1 protease inhibitors. Like with other protease inhibitors, careful monitoring of potential drug-drug and drug-disease interactions in clinical practice is necessary. The aim of this study was to assess the impact of substance use and hepatitis virus coinfection on plasma ATV and LPV trough concentrations in HIV-positive substance users and nonusers. Individuals established on ATV (300 mg and 100 mg ritonavir daily) or LPV (400 mg and 100 mg ritonavir twice daily)-containing regimens completed two clinical visits (trough and directly observed therapy) during which dosing characteristics, concomitant medication, and substance use were recorded. Trough plasma concentrations (22-26 hours for ATV and 10-14 hours for LPV) were measured using LCMSMS. The influence of substance use was evaluated by Kruskal-Wallis test. Substance use was associated with a marked decrease in trough LPV concentrations during the trough visit (median, 5.536 and 3.791 microg/mL for nonsubstance users and substance users, respectively, P = 0.029). Significantly lower LPV trough levels were also noted among patients with active hepatitis C virus coinfection evaluated as an independent variable (median, 2.253 and 5.927 microg/mL for active and inactive/no hepatitis C virus infection, respectively, P = 0.032). Substance use and hepatitis virus coinfection had limited effects on ATV trough levels. In this cohort, despite the wide interindividual variability of ATV and LPV trough concentrations, significant associations between substance use and active hepatitis C virus infection and low LPV trough concentrations were observed. Further work is needed to assess the optimal dosing regimen when using LPV in HIV-infected substance users.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Drug Administration Schedule; Drug Monitoring; Female; Hepatitis C; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Oligopeptides; Pyridines; Pyrimidinones; Substance-Related Disorders; United States

1,6-Dimethyl-3-carbethoxy-4-oxo-6,7,8,9-tetrahydro-homopyrimidazol (rimazolium, MZ-144) proved to be effective in all the analgesic assays used (independently of the nociceptive stimulus applied) (hot plate, tail flick, writhing tests, Randall-Selitto test, tail clip, surgical pain) differing in this respect from the nonsteroidal antiinflammatory analgetics. The analgesic, antiinflammatory and gastrointestinal effects of rimazolium, morphine and prostaglandin synthesis inhibitors were compared. The prostaglandin (PG) mediated pain (acetylcholine-, adenosine triphosphate- and acetic acid-induced writhing) was inhibited by all the three types of compounds, however, pain reaction where PGs are not involved (MgSO4-writhing) was inhibited only by rimazolium and morphine but not, or only slightly, by PG synthesis inhibitors. While the analgesic effect of rimazolium alone was not reversed by naloxone, the full analgesia evoked by the ineffective doses of morphine and rimazolium combinations was completely naloxone reversible (pA2 = 8.6). In addition, rimazolium produced weak analgesia by intrathecal administration, and its concomitant s.c. administration enhanced the analgesic effect of intrathecally administered morphine. Furthermore, chronic treatment with rimazolium failed to influence its analgesic activity, and no tolerance developed and no naloxone precipitated withdrawal syndrome could be seen. In addition, rimazolium did not substitute for morphine in morphine dependent rats, after morphine withdrawal, thus indicating that rimazolium lacks the capacity of producing opiate-like physiological dependence. Also rimazolium fails to show any indication of narcotic-like abuse liability by any of clinical assessments. Rimazolium, morphine and indometacin inhibited the carrageenin-induced edema formation. Gastrointestinal lesions produced by indometacin were depressed by rimazolium and enhanced by morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Cats; Dogs; Drug Tolerance; Guinea Pigs; Indomethacin; Macaca mulatta; Male; Mice; Pyrimidinones; Rabbits; Rats; Reaction Time; Stomach Ulcer; Substance Withdrawal Syndrome; Substance-Related Disorders

Azidomorphines, new semi-synthetic isomorphine alkaloids and homopyrimidazols (1, 5-diazanaphtalenes), two new families of compounds favourably enlarging the scope of analgetics, were developed. Azidomorphine, a 40--50 times more potent analgetic in man than morphine, showed a remarkably great dissociation between analgetic potency and dependence capacity and proved to exert significantly less unfavourable effects than either morphine or pentazocine. Probon (Rymazolium), the first compound of the homopyrimidazol series, introduced to therapy as a new minor analgetic, potentiated the analgetic and antagonized the respiratory depressant effect of morphine and its derivatives. In patients with chronic intractable pain, a combination of azidomorphine (0.5 mg) and Probon (150 mg) achieved total pain relief without noticeable euphoria and none of the patients subjected to nalorphine-precipitation showed signs of abstinence according to the Himmelsbach scoring system. Since both the azidomorphines and the homopyrimidazols are unexploited new families, further progress in detail structure-activity relationship studies seems quite promising.

Topics: Analgesics; Animals; Drug Synergism; Haplorhini; Humans; Hydromorphone; Macaca mulatta; Male; Morphine; Morphine Derivatives; Oxymorphone; Pyrimidines; Pyrimidinones; Rats; Respiration; Substance-Related Disorders