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ematical task by increasing dopamine in the human brain. Am 17. Woody GE, Gallop R, Luborsky L, Blaine J, Frank A, Salloum IM, Gastfriend D, Crits-Christoph P: HIV risk reduction in the Na- 16. Rosenkranz JA, Grace AA: Dopamine attenuates prefrontal cor- tional Institute on Drug Abuse Cocaine Collaborative Treat- tical suppression of sensory inputs to the basolateral amygdala ment Study. J Acquir Immune Defic Syndr 2003; 33:82–87 A Comparison of Aripiprazole, Methylphenidate, Method: Individuals meeting DSM-IV criteria for intravenous amphetamine dependence (N=53) were randomly assigned toreceive aripiprazole (15 mg/day), slow-release methylphenidate (54 mg/day), or placebo for 20 weeks. The study was terminated prematurely due to unexpected results of interim analysis. An intention-to-treat analysis was used. The primary outcomemeasure was the proportion of amphetamine-positive urine Results: Patients allocated to aripiprazole had significantly more amphetamine-positive urine samples than patients in the placebo group (odds ratio=3.77, 95% CI=1.55–9.18), whereaspatients who received methylphenidate had significantly fewer Objective: Problems related to illegal amphetamine use have amphetamine-positive urine samples than patients who had re- become a major public health issue in many developed coun- ceived placebo (odds ratio=0.46, 95% CI=0.26–0.81).
tries. To date, evidence on the effectiveness of psychosocial Conclusions: Methylphenidate is an effective treatment for re- treatments has remained modest, and no pharmacotherapy ducing intravenous drug use in patients with severe amphet- has proven effective for amphetamine dependence.
Amphetamine and methamphetamine dependence mine agonists such as aripiprazole are considered to be has become a substantial social and public health issue in promising medications for addiction, since they are sup- the United Kingdom and Australia, and it has grown into a posed to balance and restore normal function of the me- major illicit drug problem throughout the United States solimbic dopamine system (5). Observational studies, (1). In Finland, amphetamine is currently the most com- nonrandomized trials, and one randomized study without mon illegal drug used intravenously, and the collateral a placebo arm have suggested that oral dextroamphet- problems associated with intravenous amphetamine use amine may be used to replace illicit intravenous amphet- (e.g., unemployment, violence, crime, mortality, and HIV amine use (4), which suggests that oral methylphenidate and other infections) have become a major national con- (dopamine reuptake inhibitor) might also be used to sub- cern. Although cognitive behavior interventions, manual- stitute for intravenous amphetamine use. On the basis of ized treatment with cognitive behavior therapy, family ed- this information, we aimed to compare the effectiveness ucation, support, and counseling may give some benefit of aripiprazole, methylphenidate, and placebo in the (2), there has been no evidence from randomized con- treatment of amphetamine dependence using urinalysis trolled trials using an intention-to-treat approach on the as an objective measure of primary outcome.
efficacy of any psychosocial treatment in decreasing intra-venous amphetamine use.
While methadone and buprenorphine have proven It was estimated that a group size of 70 individuals was suffi- highly effective substitute medications for opioid depen- cient to detect an effect of medium magnitude (alpha=0.05, dence (3), no pharmacological treatment has been found beta=0.80). Therefore, we aimed to randomly assign 70 subjects thus far for amphetamine dependence (4). Partial dopa- to each group, resulting in a total number of 210 subjects. How- TABLE 1. Demographic and Clinical Characteristics of Amphetamine-Dependent Subjects Randomly Assigned to Treat- ment With Aripiprazole, Methylphenidate, or PlaceboCharacteristic a Significant difference (p<0.02) among groups.
ever, after obtaining unexpected results from interim analysis of amine-negative samples. The mean proportion of the first 53 patients (one active medication arm being signifi- amphetamine-positive urine samples was 90.7% in the cantly worse than placebo arm) and contacting the local ethical aripiprazole group, 67.3% in the methylphenidate group, committee and the National Agency of Medicines, the enroll-ment was discontinued.
and 82.0% in the placebo group in observed cases (miss- All study subjects gave written informed consent. The inclu- ing samples ignored). These values were 99.1% (aripipra- sion criteria were amphetamine (or methamphetamine) depen- zole), 93.5% (methylphenidate), and 97.2% (placebo) dence (per DSM-IV), age between 18 and 65, recent and accus- when all missing urine samples (considered as positive) tomed intravenous amphetamine/methamphetamine use,confirmed by urinalysis. The study protocol was approved by the were included in the intention-to-treat analysis (number local ethical committee. Details of the subject progression of samples for each patient: 40). During the second half of through the trial are included in the supplement that accompa- the follow-up period, i.e., during the last 10 weeks, the nies the online version of this article. The study was registered by mean proportion of amphetamine-positive urine samples Current Controlled Trials Ltd (http://www.controlled-trials.com).
was 100% in the aripiprazole arm, 46.3% in the meth- The eligibility of the potential study subjects was assessed dur- ing a 2-week screening period, after which subjects included in the ylphenidate arm, and 79.1% in the placebo arm in the ob- study started to receive oral regimens of aripiprazole (15 mg/day), served samples analysis, and 100% in the aripiprazole methylphenidate (18 mg/day for the first week, 36 mg/day for the arm, 91.5% in the methylphenidate arm, and 97.4% in the second week, and 54 mg/day thereafter) or placebo in identical placebo arm in the intention-to-treat analysis.
gelatin capsules for 20 weeks. The medication was given daily un-der staff supervision (the patient had to swallow the capsule and Two patients in the aripiprazole group were removed then drink a sufficient amount of water). The urine samples were from the trial because of a worsening in their physical con- obtained twice a week under supervision. All patients received un- dition: one patient developed a transient increase of liver structured psychosocial treatment with elements of cognitivetherapy and psycho-education, counseling, and support.
enzymes, attributed to recently started HIV medication, The primary outcome measure was the proportion of amphet- and the other incident was a transient ischemic attack that amine-positive urine samples during pharmacological treatment.
was attributed to continued amphetamine use. All other An intention-to-treat analysis was used, and all missing samples recorded adverse events were mild and did not lead to pre- were considered to be amphetamine positive. The data were ana- mature discontinuation of the medication. The frequency lyzed by a logistic regression model. Change in amphetamine use(proportion of positive urine samples) as a function of time in of reported side effects did not differ between the treat- each treatment group was tested with cumulative sums method.
Cumulative sums method tests existence of any change as a func- In the intention-to-treat analysis, patients allocated to tion of time in proportion of positive urine samples, and if change aripiprazole had a higher proportion of amphetamine- is observed, detects the change point (6). The retention in treat-ment was analyzed with Cox’s proportional hazard regression positive urine samples than patients who had received pla- analysis. All data analyses were carried out using R software (7).
cebo (odds ratio=3.09, 95% CI=1.29–7.40; z=2.53, p=0.01).
The patients allocated to methylphenidate had fewer posi- tive urine samples than patients in the placebo group The study groups differed concerning their mean age, (odds ratio=0.42, 95% CI=0.24–0.72; z=–3.14, p=0.002).
but not in baseline severity of dependence or other clini- Since the treatment groups differed in mean age, the age- cal or demographic characteristics (Table 1). None of the adjusted odds ratios were also calculated. Adjusted odds subjects were found to be using methamphetamine. No ratios were 3.77 (95% CI=1.55–9.18; z=2.92, p=0.003) for significant difference among the three treatment arms aripiprazole and 0.46 (95% CI=0.26–0.81; z=–2.67, p=0.008) was observed in study retention (p=0.32, age-adjusted p= for methylphenidate. The fluctuation in the proportion of 0.47). Fourteen patients gave at least one amphetamine- amphetamine-positive samples (only the analyzed sam- negative urine sample. No significant differences were ob- ples included) showed that the significant reduction in am- served in the baseline characteristics between these pa- phetamine use was observed after 18 weeks in the meth- tients versus those 39 patients who gave no amphet- ylphenidate arm (p value for change from the baseline was 0.01 for methylphenidate, 0.71 for aripiprazole, and 0.79 reduction attributable to methylphenidate treatment measured with urinalysis in a real-life setting might be be-tween 6 and 33 percentage units, and that the figures for the decrease in actual drug use would be probably evengreater. An effect of this magnitude should result in a sig- Our results indicate that methylphenidate treatment is nificant reduction of the collateral medical and social associated with a statistically significant reduction in in- problems related to intravenous amphetamine use.
travenous amphetamine use when compared with pla-cebo, providing the first controlled evidence of an effective Received Jan. 12, 2006; revisions received Feb. 28 and April 19, pharmacological treatment for amphetamine depen- 2006; accepted May 11, 2006. From the Department of Forensic Psy- dence. On the contrary, aripiprazole treatment was associ- chiatry, University of Kuopio; the Department of Psychiatry, Instituteof Clinical Medicine, University of Helsinki Faculty of Medicine, Hel- ated with a higher proportion of amphetamine-positive sinki; the Department of Mental Health and Alcohol Research, Na- tional Public Health Institute, Helsinki; Substance Abuse Welfare Work While aripiprazole (in amphetamine dependence) and and Mental Health Care, Helsinki Deaconess Institute, Helsinki; andthe Department of Psychiatry, Helsinki University Hospital, Helsinki.
naltrexone (in opioid dependence) may be good treat- Address correspondence and reprint requests to Dr. Tiihonen, Depart- ments in theory, it seems that effective pharmacological ment of Forensic Psychiatry, University of Kuopio, Niuvanniemi Hospi- maintenance treatments for intravenous drug depen- tal, FI-70240 Kuopio, Finland; jari.tiihonen@niuva.fi (e-mail).
All authors report no competing interests.
dence are substances that induce at least some euphoria, No support was provided by any pharmaceutical company. The such as methadone and buprenorphine in opioid depen- study was supported by Helsinki Deaconess Institute; National Public dence (3), or methylphenidate in amphetamine depen- Institute, Helsinki; Helsinki University Hospital; University of Helsinki; dence. Slow-release methylphenidate may be superior to and Annual EVO Financing (special government subsidies) from Niu-vanniemi Hospital, Kuopio, Finland.
usual short-acting formulation, since the patient may start The authors thank Erkki Vuori, Ulla Knuuti, Anna-Maarit Penttilä, experiencing cravings for amphetamine as soon as the ef- Petteri Sokero, Hannele Kanerva, Heikki Katila, Aarno Palotie, Sinikka fect of the substitute drug disappears. It is likely that meth- Lassila, Riitta Päivärinta, Sirpa Tamminen, Salli Lesonen, Tuuli Ber-nard, Pia Vironen, Anna Salo, Markku Nyman, Jouko Mattila, Aija ylphenidate should be dispensed mostly on a daily basis Räsänen, and Tarja Koskela for their collaboration.
under supervision because of its abuse potential. Ari- Current Controlled Trials Ltd. number: 1SRCTN54619615 piprazole (15 mg/day) was not effective in this trial (an ab- stinence facilitation trial), but we cannot draw any conclu-sions on its potential efficacy in a relapse prevention studyamong detoxified patients.
These results show that amphetamine use began to de- 1. Office of National Drug Control Policy: Drug facts: metham- crease substantially as a function of time after 10 weeks of phetamine. (http://www.whitehousedrugpolicy.gov/drugfact/ methylphenidate treatment reaching statistical signifi- cance at 18 weeks, which indicates that it may take an 2. Rawson RA, Marinelli-Casey P, Anglin MD, Dickow A, Frazier Y, Gallagher C, Galloway GP, Herrell J, Huber A, McCann MJ, Obert J, even longer period of time than 20 weeks to achieve full Pennell S, Reiber C, Vandersloot D, Zweben J, and the Metham- benefit from this treatment. The exclusion criteria in the phetamine Treatment Project Corporate Authors: A multi-site present study were mainly due to safety issues, and the pa- comparison of psychosocial approaches for the treatment of tient population included in the study, having a severe de- methamphetamine dependence. Addiction 2004; 99:708–717 pendence and long history of intravenous drug use, was 3. Mattick RP, Kimber J, Breen C, Davoli M: Buprenorphine main- tenance versus placebo or methadone maintenance for opioid practically similar to that found in real-life clinical prac- tice. Therefore, this trial was more of an effectiveness 4. Grabowski J, Shearer J, Merrill J, Negus S: Agonist-like, replace- study, rather than an efficacy study, and these results can ment pharmacotherapy for stimulant abuse and dependence.
be generalized to real-life settings.
Urinalysis may underestimate the decrease in drug in- 5. Lile JA, Stoops WW, Vansickel AR, Glaser PE, Hays LR, Rush CR: take, since decline in drug use from several times a day to Aripiprazole attenuates the discriminative-stimulus and sub-ject-rated effects of D-amphetamine in humans. Neuropsy- once a day would indicate no change (8). In this study, the difference between methylphenidate and placebo in the 6. Brown RL, Durbin J, Evans JM: Techniques for testing constancy proportions of amphetamine-positive urine samples was of regression relationships over time. J Royal Statistical Society 6 percentage units in the intention-to-treat analysis and 33 percentage units in observed samples analysis during 7. R Development Core Team: R: A Language and Environment the second half of the follow-up phase. It is likely that a for Statistical Computing. Vienna, R Foundation for Statistical large proportion of those patients who were removed from the trial because they stopped visiting the clinic for a time 8. Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, Big- elow GE: A comparison of levomethadyl acetate, buprenor- period longer than 7 days would continue to be treated in phine, and methadone for opioid dependence. N Engl J Med usual practice. Thus, it can be estimated that absolute risk

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