Multiple modes of hepatitis A virus transmission among methamphetamine users. (41/1448)

Methamphetamine users are at increased risk of hepatitis A, but modes of transmission are unclear. The authors conducted a case-control study among methamphetamine users during an outbreak in Iowa in 1997. Twenty-eight reported, laboratory-confirmed, hepatitis A cases did not differ from 18 susceptible controls with respect to age, sex, or number of doses used. When compared with controls in multivariate analysis, case-patients were more likely to have injected methamphetamine (odds ratio (OR) = 5.5, 95% confidence interval (CI): 1.1, 27), to have used methamphetamine with another case-patient (OR = 6.2, 95% CI: 0.95, 41), and to have used brown methamphetamine (OR = 5.5, 95% CI: 0.51, 59). Receptive needle sharing was reported by 10 of the 20 case-patients who injected. Methamphetamine use with another case-patient was also associated with hepatitis A in an analysis restricted to noninjectors (OR = 17, 95% CI: 1.0, 630). During this outbreak, hepatitis A may have been transmitted from person to person among methamphetamine users through the fecal-oral and the percutaneous routes. Methamphetamine users should be vaccinated against hepatitis A and should be given immune globulin if they used methamphetamine with a case-patient in the last 2 weeks. Persons who intend to continue using methamphetamine should be advised about safer practices.  (+info)

Inhibitory effect of the reversal agents V-104, GF120918 and Pluronic L61 on MDR1 Pgp-, MRP1- and MRP2-mediated transport. (42/1448)

The human multidrug transporter MDR1 P-glycoprotein and the multidrug resistance proteins MRP1 and MRP2 transport a range of cytotoxic drugs, resulting in multidrug resistance in tumour cells. To overcome this form of drug resistance in patients, several inhibitors (reversal agents) of these transporters have been isolated. Using polarized cell lines stably expressing human MDR1, MRP1 or MRP2cDNA, and 2008 ovarian carcinoma cells stably expressing MRP1 cDNA, we have investigated in this study the specificity of the reversal agents V-104 (a pipecolinate derivative), GF120918 (an acridone carboxamide derivative also known as GG918), and Pluronic L61 (a (poly)oxypropethylene and (poly)oxypropylene block copolymer). Transport experiments with cytotoxic drugs with polarized cell lines indicate that all three compounds efficiently inhibit MDR1 Pgp. Furthermore, V-104 partially inhibits daunorubicin transport by MRP1 but not vinblastine transport by MRP2. V-104 reverses etoposide resistance of 2008/MRP1 cells, whereas GF120918 does not reverse resistance due to MRP1. V-104 partially inhibits the export of the organic anion dinitrophenyl S-glutathione by MDCKII-MRP1 but not by MDCKII-MRP2 cells. Unexpectedly, export of the organic anion calcein by MDCKII-MRP1 and MDCKII-MRP2 cells is stimulated by Pluronic L61, probably because it relieves the block on entry of calcein AM into the cell by endogenous MDR1 Pgp.  (+info)

Discrimination of dimethylamphetamine and methamphetamine use: simultaneous determination of dimethylamphetamine-N-oxide and other metabolites in urine by high-performance liquid chromatography-electrospray ionization mass spectrometry. (43/1448)

A simple and sensitive method by high-performance liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) has been investigated for the simultaneous determination of dimethylamphetamine (DMA), its specific yet labile main metabolite dimethylamphetamine-N-oxide (DMAO), and other metabolites, methamphetamine (MA) and amphetamine (AP), in urine. A combination of Bond Elut SCX columns for the solid-phase extraction of urine and a semi-micro SCX column for LC separations provided satisfactory results. The use of acetonitrile/5mM ammonium acetate buffer adjusted to pH 4 (65:35, v/v) as the mobile phase at a flow rate of 0.2 mL/min was found to be the most effective. The detection limits were 5 ng/mL for DMAO, 10 ng/mL for DMA and MA, and 50 ng/mL for AP in the SIM mode.  (+info)

Effects of rolipram, a selective inhibitor of phosphodiesterase 4, on hyperlocomotion induced by several abused drugs in mice. (44/1448)

The effects of rolipram, a selective inhibitor of phosphodiesterase 4, on the hyperlocomotion induced by several abused drugs (methamphetamine, morphine and phencyclidine) and a dopamine D1-receptor agonist (SKF81297; (+/-)-6-chloro-7,8-dihydroxy-1-phenyl-2,3 ,4,5-tetrahydro-1H-3-benzazepin hydrobromide) in mice were investigated. Methamphetamine (0.5-2.0 mg/kg), morphine (5.0-20 mg/kg), phencyclidine (1.25-5.0 mg/kg) and SKF81297 (2.5-10 mg/kg) each induced dose-dependent hyperlocomotion. A low dose (1.0 mg/kg) or moderate dose (3.2 mg/kg) of rolipram suppressed methamphetamine (2.0 mg/kg)- and morphine (20 mg/kg)-induced hyperlocomotion, but not phencyclidine (5.0 mg/kg)-induced hyperlocomotion. These results suggest that cAMP in the brain is involved in methamphetamine- and morphine-induced hyperlocomotion, while the underlying mechanism(s) of phencyclidine-induced hyperlocomotion may be different from those of methamphetamine- and morphine-induced hyperlocomotion. It is well known that methamphetamine- and morphine-induced hyperlocomotion are mediated by the dopaminergic system and that interaction between postsynaptic D1- and D2-receptors may play an important role in the expression of various dopamine-mediated behaviors. In the present study, SKF81297 (10 mg/kg)-induced hyperlocomotion was significantly but not completely suppressed by the highest dose of rolipram (10 mg/kg). Therefore it is unlikely that postsynaptic D1-receptor-mediated functions are involved in the suppressive effects of rolipram on methamphetamine- and morphine-induced hyperlocomotion. These results suggest that rolipram may inhibit methamphetamine- and morphine-induced hyperlocomotion via increase cAMP levels at D2-receptors.  (+info)

The effects of high-dose methamphetamine in the aging rat: differential reinforcement of low-rate 72-s schedule behavior and neurochemistry. (45/1448)

High-dose methamphetamine (METH) causes damage to the dopamine and serotonin neurons in the brains of laboratory animals. The purpose of this report was to determine the long-term consequences of high-dose METH treatment on behavior and neurochemistry. Rats were trained on the differential reinforcement of low-rate 72-s (DRL 72-s) schedule of reinforcement. Twelve weeks after training began (age 23 weeks), they received one or three high-dose METH regimens. Each regimen consisted of four injections of 15 mg/kg, at 2-h intervals. Each regimen was separated by 7 weeks. A second group received METH treatment at age 23 weeks, but behavioral training was not initiated until the rats reached age 60 weeks. A third group received METH treatment without behavioral training. DRL behavior showed mild impairments 3 to 18 weeks after the onset of treatment; the impairments did not persist into middle age. At age 70 weeks, serotonin concentrations were decreased in somatosensory cortex, occipital cortex, and hippocampus but not in other subcortical structures. Serotonin tissue concentrations were enhanced in septum and striatum but only in rats receiving three regimens and behavioral training. Dopamine was not depleted at age 70 weeks. In three additional groups, one, two, or three METH regimens were administered, and tissue concentrations were measured 6 weeks after the last treatment (corresponding to the times of the behavioral test blocks in the DRL experiments). Serotonin depletions were noted in cortex, hippocampus, amygdala, and striatum but not in septum, hypothalamus, nucleus accumbens/olfactory tubercle, or ventral midbrain. Dopamine was decreased in striatum and septum but not in nucleus accumbens/olfactory tubercle, amygdala, hypothalamus, or ventral midbrain. DRL 72-s schedule impairments are attributed to serotonin depletions. Three METH regimens did not result in greater behavioral or neurochemical deficits than one regimen.  (+info)

Retrospective study of urinalysis for dl-amphetamine and dl-methamphetamine analysis under current Department of Defense guidelines. (46/1448)

Under current Department of Defense (DOD) directive, the laboratories certified to conduct urinalyis testing in support of the DOD Drug Deterrence Program are required to conduct dl-isomer analysis on all specimens that confirm at a concentration greater than 500 ng/mL methamphetamine (METH). Although the same cutoff concentration is required for amphetamine (AMP) reporting, there is no requirement for dl-isomer analysis of AMP-positive specimens. Of the 894,823 specimens screened by the Army Drug Testing Laboratory at Ft. Meade, MD during a 19-month period, 339 confirmed positive for METH. From this positive population, seven specimens failed to confirm at or above the DOD cutoff of > 20% d-isomer. One of the seven specimens contained 534 ng/mL l-AMP and was reported positive for AMP. Although 100% of the AMP was the l-isomer, under current DOD directive, this information was not passed along to the Medical Review Officers (MRO) to assist them during the interview process. Although this situation appears to be a rare event, consideration should be given to requiring dl-isomer analysis of AMP-positive specimens and forwarding this information to the MRO.  (+info)

A single dose of methamphetamine leads to a long term reversal of the blunted dopamine D1 receptor-mediated neocortical c-fos responses in mice deficient for D2 and D3 receptors. (47/1448)

Dopamine D(1) receptors play an essential role in the induction of expression of the immediate-early gene c-fos in response to pharmacological stimuli. In the forebrain of wild-type mice, administration of a D(1) receptor agonist leads to c-fos mRNA expression levels that are substantially higher than corresponding levels expressed after indirect stimulation of dopamine receptors with methamphetamine. In mice deficient for D(2) and D(3) receptors, c-fos mRNA levels expressed in response to D(1) agonist administration are significantly blunted. However, a single dose of methamphetamine (5 mg/kg) leads to a long lasting reversal of the blunted c-fos responses in these mutants. In the forebrain, this reversal is restricted to the neocortex. Moreover, methamphetamine also enhances c-fos expression levels in preadolescent wild-type mice that normally express low c-fos mRNA in response to D(1) agonist stimulation. Thus, a single dose of methamphetamine leads to a long term increase in D(1) receptor-dependent c-fos responses in brains with either low (preadolescent mice) or blunted (adult D(2) and D(3) mutant mice) c-fos expression levels. A similar long term reversal of the blunted c-fos responses is achieved with a single dose of a full D(1) agonist. These results indicate that the constitutive inactivation of D(2) and D(3) receptors leads to a decrease in agonist-promoted D(1) receptor activity that can be reversed by intermittent agonist stimulation.  (+info)

Effect of temperature on dopamine transporter function and intracellular accumulation of methamphetamine: implications for methamphetamine-induced dopaminergic neurotoxicity. (48/1448)

Hyperthermia exacerbates and hypothermia attenuates methamphetamine (METH)-induced dopamine (DA) neurotoxicity. The mechanisms underlying these temperature effects are unknown. Given the essential role of the DA transporter (DAT) in the expression of METH-induced DA neurotoxicity, we hypothesized that the effect of temperature on METH-induced DA neurotoxicity is mediated, at least in part, at the level of the DAT. To test this hypothesis, the effects of small, physiologically relevant temperature changes on DAT function were evaluated in two types of cultured neuronal cells: (1) a neuroblastoma cell line stably transfected with human DAT cDNA and (2) rat embryonic mesencephalic primary cells that naturally express the DAT. Temperatures for studies of DAT function were selected based on core temperature measurements in animals exposed to METH under usual ambient (22 degrees C) and hypothermic (6 degrees C) temperature conditions, where METH neurotoxicity was fully expressed and blocked, respectively. DAT function, determined by measuring accumulation of radiolabeled DA and 1-methyl-4-phenylpyridinium (MPP(+)), was found to directly correlate with temperature, with higher levels of substrate uptake at 40 degrees C, intermediate levels at 37 degrees C, and lower levels at 34 degrees C. DAT-mediated accumulation of METH also directly correlated with temperature, with greater accumulation at higher temperatures. These findings indicate that relatively small, physiologically relevant changes in temperature significantly alter DAT function and intracellular METH accumulation, and suggest that the effect of temperature on METH-induced DA neurotoxicity is mediated, at least in part, at the level of the DAT.  (+info)