Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine‐maintained intravenous heroin abusers

Background Sublingual buprenorphine is an effective maintenance treatment for opioid dependence, yet intravenous buprenorphine misuse occurs. A buprenorphine/naloxone formulation was developed to mitigate this misuse risk. This randomized, double‐blind, cross‐over study was conducted to assess the intravenous abuse potential of buprenorphine/naloxone compared with buprenorphine in buprenorphine‐maintained injection drug users (IDUs). Methods Intravenous heroin users (n = 12) lived in the hospital for 8–9 weeks and were maintained on each of three different sublingual buprenorphine doses (2 mg, 8 mg, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intravenous placebo, naloxone, heroin and low and high doses of buprenorphine and buprenorphine/naloxone were examined. Every participant received each test dose under the three buprenorphine maintenance dose conditions. Results Intravenous buprenorphine/naloxone was self‐administered less frequently than buprenorphine or heroin (P < 0.0005). Participants were most likely to self‐administer drug intravenously when maintained on the lowest sublingual buprenorphine dose. Subjective ratings of ‘drug liking’ and ‘desire to take the drug again’ were lower for buprenorphine/naloxone than for buprenorphine or heroin (P = 0.0001). Participants reported that they would pay significantly less money for buprenorphine/naloxone than for buprenorphine or heroin (P < 0.05). Seven adverse events were reported; most were mild and transient. Conclusions These data suggest that although the buprenorphine/naloxone combination has intravenous abuse potential, that potential is lower than it is for buprenorphine alone, particularly when participants received higher maintenance doses and lower buprenorphine/naloxone challenge doses. Buprenorphine/naloxone may be a reasonable option for managing the risk for buprenorphine misuse during opioid dependence treatment.     

A model of resilience and meaning after military deployment: Personal resources in making sense of war and peacekeeping experiences

The aim of the present study was to examine whether the specific personal resources of self-esteem, optimism and perceived control, combined in the latent variable called ‘resilience’, were associated with cognitive processing of war-zone experiences. Data were collected by questionnaires from a sample of 1.561 veterans who had participated in various war or peacekeeping operations. Structural equation modelling was performed to assess the expected relationships between the observed and latent variables. The construct of resilience was well-defined and proved to be strongly associated with both construals of meaning, comprehensibility versus personal significance, after military deployment. According to our model, higher resilience predicted less distrust in others and the world, more personal growth and less intrusions and avoidance after military deployment.     

Gemcitabine, oxaliplatin and weekly high-dose 5-FU as 24-h infusion in chemonaive patients with advanced or metastatic pancreatic adenocarcinoma: a multicenter phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

BACKGROUND: Combinations of gemcitabine-oxaliplatin, gemcitabine-5-fluorouracil (5-FU) and 5-FU-oxaliplatin have synergistic activity and nonoverlapping adverse effect profiles. This trial assessed efficacy and safety of the triple combination gemcitabine-oxaliplatin and infusional 5-FU in patients with locally advanced (n=11) or metastatic (n=32) pancreatic adenocarcinoma. PATIENTS AND METHODS: A total of 43 eligible patients were treated with intravenous infusions of gemcitabine (900 mg/m2 over 30 min), followed by oxaliplatin (65 mg/m2 over 2 h) and 5-FU (1500 mg/m2 over 24 h) on days 1 and 8 of a 21-day cycle. RESULTS: Among all 43 patients, the tumor response rate was 19% [95% confidence interval 7% to 30%]. Nine patients were nonassessable for response because they did not complete the first two cycles of chemotherapy due to rapid disease progression, early death or treatment refusal. One patient was lost to follow-up. Median time to progression and overall survival were 5.7 and 7.5 months. Principal grade III/IV toxic effects were leucopenia in 11 (2%), thrombocytopenia in 13 (2%), nausea in 13 (0%), anorexia 16 (7%) and sensory neuropathy in 18 (0%) of patients. Unexpected cardiotoxicity was observed in this trial. CONCLUSION: Response rates and survival of the three-drug combination compare favorably with single-agent gemcitabine, but do not exceed results for doublets.     

Comparative studies on the ocular and dermal irritation potential of surfactants.

Comparative studies on the irritation potential of 18 surfactants were performed using the same stock solution of surfactant for each study. The ocular irritation potential of surfactants was studied using the red blood cell test (RBC), the hen's egg test-chorioallantoic membrane (HET-CAM) and the Skinethic ocular tissue model. The skin irritation potential was assessed based on data obtained from human studies using a 24h epicutaneous patch test (ECT) and a soap chamber test (SCT). The same pH and active substance (AS) content for all surfactants tested was used depending on the test conducted. In general, clusters of substances with varying irritation potential were identified similarly by most tests. These results show that when using standardized test conditions in which pH and % AS are the same for each surfactant tested, there is a good correlation between the in vitro ocular irritation assays themselves as well as between the dermal and ocular irritation assays. In particular the RBC test seems to be not only highly predictive for ocular irritation (H(50)/DI) but also for dermal irritation and changes in barrier function (DI) induced by surfactants.     

Investigations on the effects of alkyl polyglucosides on development and fertility.

Alkyl polyglucosides are non-ionic surfactants which are mainly used in laundry detergents, hard surface cleaners and personal care products. Two in vitro screening test systems were used to investigate the endocrine modulating potential of alkyl polyglucosides. No indications were observed for any estrogenic or anti-estrogenic effects in an MCF-7 E-Screen assay and a reporter gene assay using luciferase-transfected MCF-7 cells. Concentrations exceeding the effect concentration of estradiol by a factor of 1000 did not reveal any indication for an estrogenic activity. Furthermore, in a combination assay investigating the effects of estradiol in the presence of alkyl polyglucoside, no anti-estrogenic potential was observed. In an one-generation screening assay in rats no effects on the fertility were observed up to the highest dose of 1000 mg/kg bw/day alkyl glucoside. Potential embryo-/fetotoxicity and/or teratogenicity was investigated in a segment II study in rats. No effects were noted up to the limit dose of 1000 mg/kg bw/day. All parameters of the treatment groups were comparable with those of the control group. Skeletal and visceral investigations did not detect any treatment-related malformations. For the embryo/fetotoxicity, the teratogenicity and the maternal toxicity a NOAEL of 1000 mg/kg was deduced.     

Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure

OBJECTIVES: We sought to define the therapeutic dose range of levosimendan in patients with New York Heart Association class II-IV heart failure of ischemic origin. BACKGROUND: Levosimendan is a calcium sensitizer for treatment of acute decompensated heart failure. METHODS: A double-blind, placebo-controlled, randomized, multicenter, parallel-group study included 151 adult patients. Levosimendan was given as a 10-min intravenous bolus of 3, 6, 12, 24 or 36 microg/kg, followed by a 24-h infusion of 0.05, 0.1, 0.2, 0.4 or 0.6 microg/kg/min, respectively. Dobutamine, for comparative purposes, was given as an open-label infusion (6 microg/kg/min). The primary efficacy variable was the proportion of patients achieving in each treatment group at least one of the following: 1) a > or =15% increase in stroke volume (SV) at 23 h to 24 h; 2) a > or =25% decrease in pulmonary capillary wedge pressure (PCWP) (and > or =4 mm Hg) at 23 h to 24 h; 3) a > or =40% increase in cardiac output (CO) (with change in heart rate [HR] <20%); 4) a > or =50% decrease in PCWP during two consecutive measurements. RESULTS: The response rate to levosimendan ranged from 50% at the lowest dose to 88% at the highest dose (compared with placebo 14%, dobutamine 70%). A dose-response relationship was demonstrated for levosimendan on increases in CO and SV, and reductions in PCWP during the infusion (for all, p< or =0.001). Headache (9%), nausea (5%) and hypotension (5%) were the most frequently reported adverse events at higher dosages. CONCLUSIONS: Dosing of levosimendan with a 10-min bolus of 6 to 24 microg/kg followed by an infusion of 0.05 to 0.2 microg/kg/min is well tolerated and leads to favorable hemodynamic effects.