Naltrexone with or without fluoxetine for preventing relapse to heroin addiction in St. Petersburg, Russia

This randomized placebo-controlled trial tested the efficacy of oral naltrexone with or without fluoxetine for preventing relapse to heroin addiction and for reducing HIV risk, psychiatric symptoms, and outcome. All patients received drug counseling with parental or significant-other involvement to encourage adherence. Patients totaling 414 were approached, 343 gave informed consent, and 280 were randomized (mean age, 23.6 ± 0.4 years). At 6 months, two to three times as many naltrexone patients as naltrexone placebo patients remained in treatment and had not relapsed, odds ratio (OR) = 3.5 (1.96–6.12), p < .0001. Overall, adding fluoxetine did not improve outcomes, OR = 1.35 (0.68–2.66), p = .49; however, women receiving naltrexone and fluoxetine showed a trend toward a statistically significant advantage when compared to women receiving naltrexone and fluoxetine placebo, OR = 2.4 (0.88–6.59), p = .08. HIV risk, psychiatric symptoms, and overall adjustment were markedly improved among all patients who remained on treatment and did not relapse, regardless of group assignment. More widespread use of naltrexone could be an important addition to addiction treatment and HIV prevention in Russia.     

Naltrexone for heroin dependence treatment in St. Petersburg, Russia

Naltrexone may be more effective for treating opioid (heroin) dependence in Russia than in the U.S. because patients are mostly young and living with their parents, who can control medication compliance. In this pilot study we randomized 52 consenting patients who completed detoxification in St. Petersburg to a double blind, 6-month course of biweekly drug counseling and naltrexone, or counseling and placebo naltrexone. Significant differences in retention and relapse favoring naltrexone were seen beginning at 1 month and continuing throughout the study. At the end of 6 months, 12 of the 27 naltrexone patients (44.4%) remained in treatment and had not relapsed as compared to 4 of 25 placebo patients (16%; p<0.05). Since heroin dependence is the main way HIV is being spread in Russia, naltrexone is likely to improve treatment outcome and help reduce the spread of HIV if it can be made more widely available.     

Desipramine and contingency management for cocaine and opiate dependence in buprenorphine maintained patients

Co-dependence on opiates and cocaine occurs in about 60% of patients entering methadone treatment and has a poor prognosis. However, we recently found that desipramine (DMI) could be combined with buprenorphine to significantly reduce combined opiate and cocaine use among these dually dependent patients. Furthermore, contingency management (CM) has been quite potent in reducing cocaine abuse during methadone maintenance. To test the efficacy of combining CM with these medications we designed a 12-week, randomized, double blind, four cell trial evaluating DMI (150 mg/day) or placebo plus CM or a non-contingent voucher control in 160 cocaine abusers maintained on buprenorphine (median 16 mg daily). Cocaine-free and combined opiate and cocaine-free urines increased more rapidly over time in those treated with either DMI or CM, and those receiving both interventions had more drug-free urines (50%) than the other three treatment groups (25–29%). Self reported opiate and cocaine use and depressive and opioid withdrawal symptoms showed no differences among the groups and symptom levels did not correlate with urine toxicology results. Lower DMI plasma levels (average 125 ng/ml) were associated with greater cocaine-free urines. DMI and CM had independent and additive effects in facilitating cocaine-free urines in buprenorphine maintained patients. The antidepressant appeared to enhance responsiveness to CM reinforcement.     

The development of addiction to d-amphetamine in an animal model: same principles as for alcohol and opiate

We have established a rat model that reflects the course of development of alcohol and opiate addiction. The present study with d-amphetamine aimed to define general principles in the development of an addiction. Male rats had a continuous free choice between d-amphetamine solutions (100, 200 and 400 mg/l) and water for 47 weeks. An initial intake of high doses of d-amphetamine during the first weeks of drug choice was followed by an individually stable pattern of drug consumption of moderate drug doses. During this period of controlled consumption (from week 10 to week 40), the voluntary intake of d-amphetamine depended on individual factors (dominant rats: 0.37 ± 0.02 mg/kg per day, subordinate rats: 0.57 ± 0.05 mg/kg per day) and environmental variables (group housing: 0.21 ± 0.02 mg/kg per day, single housing: 0.41 ± 0.03 mg/kg per day). Beginning with week 41, voluntary d-amphetamine consumption progressively increased (1.9 ± 0.2 mg/kg per day in week 47), although the experimental conditions remained unchanged. Drug intake during a retest (free choice as before) after 6 months of drug deprivation revealed that the rats had persistently lost their control over drug intake and were no longer able to adjust drug taking to internal and external conditions. These addicted rats took very high drug doses, even when all d-amphetamine solutions but not water were adulterated with bitter tasting quinine (6.6 ± 0.6 mg/kg per day; age-matched controls: 0.37 ± 0.04 mg/kg per day). Forced intake of d-amphetamine for 47 weeks (7.1 ± 0.3 mg/kg per day) via the drinking fluid caused physical dependence (hyperreactivity during withdrawal) but did not lead to drug addiction (voluntary intake in the retest with adulteration: 0.42 ± 0.04 mg/kg per day). Both the temporal development and the prerequisites of psychostimulant addiction were in principle the same as for alcohol and opiates. Received: 3 April 1998/Final version: 26 August 1998     

No evidence for a protracted change in endogenous opioid activity following chronic opiate treatment in mice: parallel recovery of cross tolerance to stress and morphine antinociception

The involvement of central endogenous opioids in swim-induced antinociception in mice is well documented. The response is attenuated by central or systemic naloxone, displays two-way cross tolerance with morphine and is correlated with apparent occupation of central opiate receptors by endogenous ligands. Swim-induced antinociception was utilised as an in vivo model of endogenous opioid function to investigate a possible protracted functional change in endogenous opioid release or inactivation following chronic opiate treatment. Antinociceptive responses (tailflick latency) to morphine (4.4 mg/kg, SC) and swimming were determined at various times following chronic methadone (24 days treatment, 102 mg/kg day in drinking water for the last 20 days) and chronic morphine (1 g/kg sustained release) treatment. In both experiments, parallel recovery from cross tolerance was observed for morphine-and swim-induced antinociception. These results were consistent with the view that no protracted functional change in the release or inactivation of endogenous opioids had occurred following chronic opiate treatment.     

Phase I safety,pharmacokinetic and pharmacodynamic studies of 2-methoxyestradiol alone or in combination with docetaxel in patients with locally recurrent or metastatic breast cancer

Summary Purpose: We report the first phase I trials of 2-methoxyestradiol (2ME2, Panzem? Capsules, EntreMed, Rockville, MD), alone and in combination with docetaxel, in patients with metastatic breast cancer (MBC). Patients and methods: In Trial 001, 2ME2 monotherapy was administered orally once (200–1000 mg/d, cohorts 1–5) or twice daily (200–800 mg/q12h, cohorts 6–9) for 28 days followed by a 14-day observation period, continuously thereafter. In Trial 002, docetaxel 35 mg/m² was administered weekly for four of six weeks for a maximum six cycles; 2ME2 (200–1000 mg/d) was given orally once daily for 28 days followed by a 13-day observation period in cycle one, continuously thereafter. In both trials, responding or stable patients continued 2ME2 until progression. Results: Trial 001 enrolled 31 patients; there were no objective responses. Trial 002 enrolled 15 patients; ORR was 20% including one CR. There were no Grade IV toxicities; MTD was not reached in either study. When combined with docetaxel, three patients had significant transaminase elevations that returned to normal with continued treatment (in two of three patients). There was significant inter-patient variability and extensive metabolism to 2-methoxyestrone (2ME1). Steady-state AUC and trough concentrations of 2ME2 increased linearly up to 400–600 mg/d; doses above 400–600 mg/d did not increase 2ME2 levels. The target trough concentration (3–25 ng/mL) was not attained. Combined administration did not alter docetaxel or 2ME2 pharmacokinetics. Conclusion: 2ME2, alone or in combination with docetaxel, was well tolerated in patients with MBC but systemic exposure remained below the expected therapeutic range.     

A double-blind,randomized study evaluating losartan potassium monotherapy or in combination with hydrochlorothiazide versus placebo in obese patients with hypertension

ABSTRACT

Objectives: The objective of this study was to evaluate the effects of losartan ± hydrochlorothiazide (HCTZ) versus placebo in obese patients with systolic and diastolic hypertension.

Research design and methods: Randomized patients (n = 261) were non-diabetic with systolic blood pressure (SBP) ≥ 140 and ≤ 180?mmHg and diastolic BP (DBP) ≥ 95 and ≤ 115?mmHg, body mass index > 30?kg/m², and waist circumference > 40 (males)/> 35 (females)?inches. Patients were randomized to placebo or a forced titration of losartan 50?mg titrated at 4-week intervals to losartan 100?mg, losartan 100?mg/HCTZ 12.5?mg, and losartan 100?mg/HCTZ 25?mg. Primary efficacy measurements were change from baseline in SBP and DBP at 12 weeks. Secondary measurements were change from baseline in BPs at 8 and 16 weeks, percent responders at 12 and 16 weeks, and safety/tolerability. Post-hoc analyses were BP at 4 weeks and achieve­ment of controlled BP (SBP < 140 and/or DBP < 90?mmHg) at 12 and 16 weeks.

Results: Losartan 50?mg reduced BP from 151.6/99.2?mmHg at baseline to 140.1/89.8?mmHg at week 4 (post hoc), 139.5/89.6?mmHg with losartan 100?mg at week 8 (secondary), 134.3/85.9?mmHg with losartan 100?mg/HCTZ 12.5?mg at week 12 (primary), and 132.1/84.9?mmHg with losartan 100?mg/HCTZ50?mg at week 16 (secondary) (all p < 0.05). Rates of clinical adverse experi­ences were similar between treatment groups. A limitation of these analyses is the relatively rapid rate of study drug titration, which may not have allowed for the evaluation of the full treatment effect at each titration step.

Conclusions: We conclude that losartan alone or in combination with HCTZ was generally well tolerated and effective in the treatment of elevated systolic and diastolic BP in obese patients with hypertension.     

Treatment with alendronate plus calcium,alendronate alone,or calcium alone for postmenopausal low bone mineral density

ABSTRACT

Objective: Bisphosphonates such as alendronate are widely used for postmenopausal osteoporosis. Supplemental calcium is also generally recommended. This trial directly compares alendronate to supplemental calcium and examines the effect of calcium supplementa­tion on alendronate treatment.

Methods: This 2-year, randomized, double-blind, multicenter trial enrolled healthy, postmenopausal women with low bone mineral density (BMD). Patients with a dietary calcium intake ≥?800?mg/day received daily vitamin D 400?IU and alendronate 10?mg/calcium-placebo, alendronate 10?mg/elemental calcium 1000?mg, or alendronate-placebo/calcium 1000?mg (2:2:1). Endpoints included BMD, bone turnover markers (BTMs), and adverse events.

Results: Randomized patients (N = 701) were an average of 20.4 years postmenopausal. After 24 months, increases in lumbar spine BMD differed significantly between patients receiving calcium alone (0.8%) and either alendronate alone (5.6%) or alendronate + calcium (6.0%) (?p < 0.001). Significant differences were also seen at the trochanter and femoral neck (?p < 0.001). BTMs were significantly lower with alendronate-containing treatments than calcium alone (?p < 0.001). Addition of calcium supplementation to alendronate did not signif­icantly increase BMD compared to alendronate alone (?p = 0.29 to 0.97), but did result in a statistically significant, though small, additional reduction in urinary NTx. Adverse events were similar among treatment groups. Limitations include no assessment of vitamin D levels and a discontinuation rate of approximately 30%, although discontinuation rates were similar among treatment groups.

Conclusions: In postmenopausal women with a daily intake of ≥?800?mg calcium and 400?IU vitamin D, 24-month treatment with alendronate 10?mg daily with or without calcium 1000?mg resulted in significantly greater increases in BMD and reduction of bone turnover than supplemental calcium alone. Addition of supplemental calcium to alendronate treatment had no effect on BMD and resulted in a small, though statistically significant, additional reduction in NTx.     

Relationship between bone mass,invasive breast cancer incidence and raloxifene therapy in postmenopausal women with low bone mass or osteoporosis

ABSTRACT

Objective: To evaluate the relationship between bone mass and risk of breast cancer and to determine the effect of raloxifene therapy on breast cancer incidence in women categorized by bone mass into low bone mass and osteo­porosis subgroups.

Design: In this post hoc analysis, data were analyzed from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, enrolling postmenopausal women with low bone mass (N = 7705), and the Continuing Outcomes Relevant to Evista (CORE) trial, a follow-up to MORE enrolling 4011 MORE participants. Total follow-up was for up to 8 years. Women with a total hip bone mineral density (BMD) T-score <?–1 to >?–2.5 or T-score ≤?–2.5 (referent, NHANES III database) were classified as having low bone mass or osteoporosis, respectively. Women with a pre-existing vertebral fracture were considered as having osteoporosis irrespective of BMD T-score. Analyses were performed for invasive breast cancers and invasive estrogen-receptor (ER) positive breast cancers.

Results: Women with low bone mass (N = 3829) had a twofold higher incidence of invasive ER-positive breast cancer than those with osteoporosis (N = 3836) (HR 2.13, 95% CI 1.12–4.03). The incidence of all invasive breast cancers did not differ significantly between the bone mass groups. The incidences of invasive and invasive ER-positive breast cancers were 65–78% lower in women assigned raloxifene versus placebo in both the low bone mass and osteoporosis groups (?p < 0.05).

Conclusions: In this post hoc analysis of postmeno­pausal women participating in MORE and CORE, bone mass was a predictor of invasive ER-positive breast cancer. Raloxifene treatment reduced the risk of invasive and invasive ER-positive breast cancers in women with low bone mass and those with osteoporosis. Since participants were older postmenopausal women with low bone mass, whether these findings can be generalized to other postmenopausal women is unclear.     

HIV transmission from drug injectors to partners who do not inject,and beyond: Modelling the potential for a generalized heterosexual epidemic in St. Petersburg,Russia

Background

HIV infection is prevalent among drug injectors in St. Petersburg and their non-injecting heterosexual partners (PIDUs). There are fears that sexual transmission of HIV from IDUs to PIDUs may portend a self-sustaining, heterosexual epidemic in Russia.

Methods

Our model combines a network model of sexual partnerships of IDUs and non-IDUs to represent sexual transmission of HIV and a deterministic model for parenteral transmission among IDUs. Behavioural parameters were obtained from a survey of St. Petersburg IDUs and their sexual partners. We based our model fits on two scenarios for PIDU prevalence in 2006 (5.6% and 15.1%, calculated excluding and including HCV co-infected PIDUs respectively) and compared predictions for the general population HIV prevalence.

Results

Results indicate that sexual transmission could sustain a non-IDU HIV epidemic. The model indicates that general population prevalence may be greater than current estimates imply. Parenteral transmission drives the epidemic and the PIDU bridge population plays a crucial role transferring infection to non-IDUs. The model indicates that the high PIDU prevalence is improbable because of the high risk behaviour this implies; the lower prevalence is possible.

Conclusion

The model implies that transmission through PIDUs will sustain a heterosexual epidemic, if prevalence among IDUs and PIDUs is as high as survey data suggest. We postulate that current estimates of population prevalence underestimate the extent of the HIV epidemic because they are based on the number of registered cases only. Curtailing transmission among injectors and PIDUs will be vital in controlling heterosexual transmission.     

Patterns of alcohol use among men receiving treatment for heroin and/or cocaine use in England,Brazil and Spain. A cross-country analysis

Abstract

Introduction: Although alcohol is widely used concurrently with illicit drugs, the role of alcohol in recovery from and relapse to drug use is under-researched. This study investigates drinking patterns and factors associated with harmful drinking among men receiving community treatment for heroin and/or cocaine use.

Methods: Secondary analysis of 3 cross-sectional studies in England (n?=?153), Brazil (n?=?149) and Spain (n?=?131) was conducted. Sociodemographic, alcohol consumption (AUDIT), substance use, treatment characteristics, and physical health were assessed. Logistic regression determined factors associated with harmful drinking.

Results: 41% of men receiving heroin and/or cocaine treatment met criteria for harmful drinking. Of this, 28% were not receiving treatment for alcohol. Factors identified with harmful drinking among those who were not receiving treatment for alcohol use were as follows: homeless, unemployment/receiving benefits, poly drug use, history of injecting drug(s), hepatitis C seropositive, and receiving treatment for heroin use with/without treatment for cocaine use. Participants from England who met criteria for harmful drinking were more likely to report not receiving treatment for alcohol use than those from Brazil and Spain.

Discussion: Findings show that harmful drinking is common among men in treatment for drug use and remains neglected by the services.     

Population pharmacokinetics of nefopam in elderly,with or without renal impairment,and its link to treatment response

Aims

Nefopam is a nonmorphinic central analgesic, for which no recommendation exists concerning adaptation of regimen in aged patients with or without renal impairment. The objective was to describe the pharmacology of nefopam in aged patients to obtain guidelines for practical use.

Methods

Elderly patients (n = 48), 65–99 years old, with severe or moderate renal impairment or with normal renal function, were recruited. Nefopam (20 mg) was administered as a 30 min infusion postoperatively. Simultaneously, a 1 min intravenous infusion of iohexol was performed, in order to calculate the glomerular filtration rate. Blood samples were drawn to determine nefopam, desmethyl-nefopam and iohexol plasma concentrations. Nefopam and desmethyl-nefopam concentrations were analysed using a nonlinear mixed-effects modelling approach with Monolix version 4.1.3. The association between pharmacokinetic parameters and treatment response was assessed using logistic regression.

Results

A two-compartment open model was selected to describe the pharmacokinetics of nefopam. The typical population estimates (between-subject variability) for clearance, volume of distribution, intercompartmental clearance and peripheral volume were, respectively, 17.3 l h⁻¹ (53.2%), 114 l (121%), 80.7 l h⁻¹ (79%) and 208 l (63.6%). Morphine requirement was related to exposure of nefopam. Tachycardia and postoperative nausea and vomiting were best associated with maximal concentration and the rate of increase in nefopam plasma concentration.

Conclusions

We identified the nefopam pharmacokinetic predictors for morphine requirement and side-effects, such as tachycardia and postoperative nausea and vomiting. In order to maintain morphine sparing and decrease side-effects following a single dose of nefopam (20 mg), simulations suggest an infusion time of >45 min in elderly patients with or without renal impairment.     

Police sexual coercion and its association with risky sex work and substance use behaviors among female sex workers in St. Petersburg and Orenburg,Russia

BackgroundExtensive research documents that female sex workers (FSWs) in Russia are very vulnerable to abuses from police, including police sexual coercion. However, despite qualitative data suggesting abusive policing practices are more likely for FSWs contending with substance abuse issues and risky sex work contexts, there is a paucity of quantitative study evaluating these associations specifically in terms of police sexual coercion. Such research is needed to guide structural interventions to improve health and safety for FSWs in Russia and globally.ObjectiveThe purpose of this study is to assess the prevalence of police sexual coercion among FSWs from two Russian cities, St. Petersburg and Orenburg, and to determine whether riskier sex work behaviors and contexts and substance use behaviors, including both IDU and risky alcohol use, are associated with increased risk for sexual coercion from police.MethodFSWs in St. Petersburg and Orenburg were recruited via time-location and convenience sampling and completed structured surveys on demographics (age, education), sex work risks (e.g., violence during sex work) and substance use. Logistic regression analyses assessed associations of substance use and risky sex work with police sexual coercion, adjusting for demographics.ResultsParticipants (N = 896) were aged 15 and older (94% were 20+ years). Most (69%) reported past year binge alcohol use, and 48% reported IDU the day before. Half (56%) reported 4+ clients per day. Rape during sex work ever was reported by 64%. Police sexual coercion in the past 12 months was reported by 38%. In the multivariate model, both current IDU (AOR = 2.09, CI = 1.45–3.02) and past year binge alcohol use (AOR = 1.46, CI = 1.03–2.07) were associated with police sexual coercion, as was selling sex on the street (not in venues) (AOR = 7.81, CI = 4.53–13.48) and rape during sex work (AOR = 2.04, CI = 1.43–2.92).ConclusionCurrent findings document the substantial role police sexual violence plays in the lives of FSWs in Russia. These findings also highlight heightened vulnerability to such violence among self-managed and substance abusing FSWs in this context. Structural interventions addressing police violence against FSWs may be useful to improve the health and safety of this population.     

Disposition of d‐penicillamine,a promising drug for preventing alcohol‐relapse. Influence of dose,chronic alcohol consumption and age: studies in rats

Pharmacokinetic studies concerning d ‐penicillamine (an acetaldehyde sequestering agent) are scarce and have not evaluated the influence of chronic ethanol consumption and age on its disposition. Since recent preclinical studies propose d ‐penicillamine as a promising treatment for alcohol relapse, the main aim of the present work was to evaluate the influence of these two factors on d ‐penicillamine disposition in order to guide future clinical studies on the anti‐relapse efficacy of this drug in alcoholism. Additionally, the effect of the administered dose was also evaluated. To this end, three studies were carried out. Study 1 assessed the influence of dose on d ‐penicillamine disposition, whereas studies 2 and 3 evaluated, respectively, the influence of chronic alcohol consumption and age. Rapid intravenous administrations of 2, 10 and 30 mg/kg of d ‐penicillamine were performed using young or adult ethanol‐naïve rats or adult ethanol‐experienced (subjected to a long‐term ethanol self‐administration protocol) rats. Pharmacokinetic parameters were derived from the biexponential model. Statistical analysis of CL, normalized AUC₀^∞, V₁ and k₁₀ revealed that disposition, in the range plasma concentrations assayed, is non‐linear both in young ethanol‐naïve and in adult ethanol‐experienced rats. Notably, no significant changes in t_1/2 were detected. Chronic ethanol consumption significantly reduced CL values by 35% without affecting t_1/2. d ‐Penicillamine disposition was equivalent in young and adult animals. In conclusion, although DP pharmacokinetics is non‐linear, the lack of significant alterations of the t_1/2 would potentially simplify the clinical use of this drug. Chronic consumption of ethanol also alters d ‐penicillamine disposition but, again, does not modify t_1/2. Copyright © 2014 John Wiley & Sons, Ltd.     

Genes Expressed in Cell Types after Their Exposure to UV Stresses or Oxidative Stresses,e.g., Keratinocytes,Fibroblasts in the Skin,or Endothelial Cells,Neurones or Astrocytes in Age-Related Pathologies Where Oxidative Stresses have been Shown to Occur,such as Atherosclerosis,Parkinson's Disease,Alzheimer's Disease

Introduction: The IGF system controls growth, differentiation, and development at the cellular, organ and organismal levels. IGF1 receptor (IGF1R) signaling is dysregulated in many cancers. Numerous clinical trials are currently assessing therapies that inhibit either growth factor binding or IGF1R itself. Therapeutic benefit, often in the form of stable disease, has been reported for many different cancer types.

Areas covered: Canonical IGF signaling and non-canonical pathways involved in carcinogenesis. Three recent insights into IGF1R signaling, namely hybrid receptor formation with insulin receptor (INSR), insulin receptor substrate 1 nuclear translocation, and evidence for IGF1R/INSR as dependence receptors. Different approaches to targeting IGF1R and mechanisms of acquired resistance. Possible mechanisms by which IGF1R signaling supports carcinogenesis and specific examples in different human tumors.

Expert opinion: Pre-clinical data justifies IGF1R as a target and early clinical trials have shown modest efficacy in selected tumor types. Future work will focus upon assessing the usefulness or disadvantages of simultaneously targeting the IGF1R and INSR, biomarker development to identify potentially responsive patients, and the use of IGF1R inhibitors in combination therapies or as an adjunct to conventional chemotherapy.     

Dissociable deficits in the decision-making cognition of chronic amphetamine abusers, opiate abusers, patients with focal damage to prefrontal cortex, and tryptophan-depleted normal volunteers: evidence for monoaminergic mechanisms.

We used a novel computerized decision-making task to compare the decision-making behavior of chronic amphetamine abusers, chronic opiate abusers, and patients with focal lesions of orbital prefrontal cortex (PFC) or dorsolateral/medial PFC. We also assessed the effects of reducing central 5-hydroxytryptamine (5-HT) activity using a tryptophan-depleting amino acid drink in normal volunteers. Chronic amphetamine abusers showed suboptimal decisions (correlated with years of abuse), and deliberated for significantly longer before making their choices. The opiate abusers exhibited only the second of these behavioral changes. Importantly, both sub-optimal choices and increased deliberation times were evident in the patients with damage to orbitofrontal PFC but not other sectors of PFC. Qualitatively, the performance of the subjects with lowered plasma tryptophan was similar to that associated with amphetamine abuse, consistent with recent reports of depleted 5-HT in the orbital regions of PFC of methamphetamine abusers. Overall, these data suggest that chronic amphetamine abusers show similar decision-making deficits to those seen after focal damage to orbitofrontal PFC. These deficits may reflect altered neuromodulation of the orbitofrontal PFC and interconnected limbic-striatal systems by both the ascending 5-HT and mesocortical dopamine (DA) projections.     

Phase II trial of vinorelbine and trastuzumab in patients with HER2-positive metastatic breast cancer. A prospective, open label, non-controlled, multicenter phase II trial (to investigate efficacy and safety of this combination chemotherapy)

Summary  The purpose of this study was to evaluate the efficacy (progression free survival (PFS) and response rate) and safety of vinorelbine and trastuzumab combination chemotherapy in patients with HER2-overexpressing, metastatic breast cancer as a first line chemotherapy regimen. Patients with histologically confirmed, HER2-positive (immunohistochemistry (ICH) 3+, or 2+ and FISH+) metastatic breast cancer who had nor received prior vinorelbine or anti-HER2 therapy in the adjuvant setting, received at least eight weeks of vinorelbine i.v. (25 mg/g weekly) and trastuzumab (4 mg/kg on day 1 followed by 2 mg/kg weekly). Forty-one women from six participating centers were enrolled into the trial. The overall response rate, was 43.9% (18 of 41 patients), (CI 28–60.3%), 30% of patients were progression free after 1 year. Four patients reached complete remission, 14 partial remission and five had stable disease for at least 18 weeks. Six patients developed primary progression. 35 patients (85%) experienced progression after a median time of 235 days. Therapy was in general well-tolerated. There were two CTC grade 4 infusion syndromes and two patients experienced cardiotoxicity at least grade 2. This phase II trial of vinorelbine and trastuzumab demonstrated an effective and well-tolerated regimen with a favourable safety profile.     

Cytotoxicity,oxidative stress and expression of adhesion molecules in human umbilical vein endothelial cells exposed to dust from paints with or without nanoparticles

Abstract

Nanoparticles in primary form and nanoproducts might elicit different toxicological responses. We compared paint-related nanoparticles with respect to effects on endothelial oxidative stress, cytotoxicity and cell adhesion molecule expression. Primary human umbilical vein endothelial cells were exposed to primary nanoparticles (fine, photocatalytic or nanosized TiO₂, aluminium silicate, carbon black, nano-silicasol or axilate) and dust from sanding reference- or nanoparticle-containing paints. Most of the samples increased cell surface expressions of vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1), but paint sanding dust samples generally generated less response than primary particles of TiO₂ and carbon black. We found no relationship between the expression of adhesion molecules, cytotoxicity and production of reactive oxygen species. In conclusion, sanding dust from nanoparticle-containing paint did not generate more oxidative stress or expression of cell adhesion molecules than sanding dust from paint without nanoparticles, whereas the primary particles had the largest effect on mass basis.