Addiction Rehab: Tumor Resistance to HER2 Inhibitors: The Drug Sedimentation Concept.

Tumor resistance to HER2 inhibitors: the drug sedimentation concept.

Filed under: Addiction Rehab

Bull Cancer. 2012 May 22;
Campone M, Frenel JS, André F, Bachelot T, Juin P

Twenty years have passed between the discovery of oncogene HER2, the description of its implication in mammary carcinogenesis, and the development of specific targeted therapies. To date, trastuzumab and lapatinib are the two anti-HER2 targeted therapies commonly used, demonstrating therapeutic effects. Although their clinical efficacy seems to be exclusively related to the amplification of the HER2 gene or to the overexpression of the protein, these factors are not sufficient since tumors can develop resistance. Because of a better knowledge in those mechanisms of resistance, novel therapeutic agents could help to bypass them. How should these be used with respect to current anti-HER2 targeted therapies? Recent notions such as oncogene addiction, tumor cell dormancy and residual disease led us to propose a new entity that we named the “sedimentation strategy”, in which distinct targeted approaches are summed during the treatment of metastatic breast cancer patients.
HubMed – addiction


Blockade of the brain histamine H3 receptor by JNJ-39220675: preclinical PET studies with [(11)C]GSK189254 in anesthetized baboon.

Filed under: Addiction Rehab

Psychopharmacology (Berl). 2012 May 22;
Logan J, Carruthers NI, Letavic MA, Sands S, Jiang X, Shea C, Muench L, Xu Y, Carter P, King P, Fowler JS

RATIONALE: The preclinical characterization of a series of aryloxypyridine amides has identified JNJ-39220675 ((4-cyclobutyl-1,4-diazepan-1-yl)(6-(4-fluorophenoxy)pyridin-3-yl)methanone) as a high-affinity histamine H(3) receptor antagonist and a candidate for further drug development particularly in the treatment of alcohol-related behaviors. OBJECTIVE: This study measured brain histamine H(3) receptor blockade by JNJ-39220675 (1 mg/kg) in the female baboon. METHODS: Positron emission tomography imaging and [(11)C]GSK189254, a reversible high-affinity radiotracer with specificity for the histamine H(3) receptor, was used to measure histamine H(3) receptor availability at baseline and after i.v. and oral administration of JNJ-39220675 (1 mg/kg) in the anesthetized baboon. Histamine H(3) receptor availability was estimated as the total distribution volume (V (T)) in brain regions. The sensitivity of [(11)C]GSK189254 binding to injected mass and carryover effects was determined. RESULTS: JNJ-39220675 produces robust (ca. 90 %) blockade of [(11)C]GSK189254 binding after i.v. and oral administration. After oral administration of JNJ-39220675 (1 mg/kg), the fractional receptor occupancy was >0.9 at 90 min with a slight increase from 90 to 240 min. Similar to prior studies in humans, V (T) was highly sensitive to the mass of GSK189254 with ED(50) estimated to be 0.16 ?g/kg. CONCLUSIONS: The robust blockade of binding of [(11)C]GSK189254 by JNJ-39220675 demonstrates that this compound readily penetrates the blood-brain barrier and occupies the histamine H(3) receptor after oral administration at low plasma concentrations (?1 ng/cc) supporting further drug development for alcohol addiction and other disorders. This study corroborates prior reports of the high sensitivity of [(11)C]GSK189254 to injected mass at doses >0.1 ?g/kg.
HubMed – addiction


Pharmacological Differences Between Rat Frontal Cortex and Hippocampus in the Nicotinic Modulation of Noradrenaline Release Implicate Distinct Receptor Subtypes.

Filed under: Addiction Rehab

Nicotine Tob Res. 2012 May 21;
Kennett A, Heal DJ, Wonnacott S

INTRODUCTION: Noradrenergic mechanisms in frontal cortex and hippocampus are relevant to attentional and stress-related aspects of addiction, respectively. Nicotinic receptors (nAChRs) modulate the release of noradrenaline (NA) in these tissues. This study determined if similar subtypes of nAChR regulate NA release in rat frontal cortex and hippocampus. METHODS: The release of [(3)H]-NA from rat tissue prisms was characterized in a 96-well plate assay. In vivo microdialysis was used to monitor NA overflow from rat frontal cortex and hippocampus in conscious freely moving rats. RESULTS: [(3)H]-NA release from frontal cortex prisms was more sensitive to nicotinic agonists than release from hippocampal prisms. The ?2-selective agonist 5-iodo-A-85380 was 1000-fold more potent in frontal cortex compared with hippocampus. Agonist-evoked [(3)H]-NA release was inhibited by the ?2-selective antagonist dihydro-beta-erythroidine (DH?E) in frontal cortex, whereas in hippocampal tissue, DH?E had no effect. In vivo, 5-iodo-A-85380 (1, 100 ?M) applied locally via the dialysis probe, significantly increased NA overflow, compared with basal release, in frontal cortex but not in hippocampus.Conclusions:These data support the modulation of NA release by different nAChR subtypes in frontal cortex and hippocampus. The pharmacological profile for rat hippocampus is consistent with previous studies, implicating ?3?4* nAChRs in the modulation of NA release in this tissue. nAChRs having this function in frontal cortex are pharmacologically distinct and correspond to ?2-containing nAChRs.
HubMed – addiction



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5W Public Relations Named PR Agency of Record for Promises Treatment Center

Filed under: Addiction Rehab

Promises Treatment Centers in Malibu and West Los Angeles are the premier addiction treatment centers in southern California. Led by Dr. David Sack and some of the country's leading addiction specialists, Promises has built an international reputation …
Read more on PR Newswire (press release)


Indie Focus: A different take on addiction in 'Oslo, August 31st'

Filed under: Addiction Rehab

It's these classical themes I want to deal with more than a guy who gets out of rehab. People think they're going to see a lot of needles and street junkies. Those stories have been told. We wanted to break the stereotypical addict character and try to …
Read more on Los Angeles Times


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