Intranasal Rapamycin Rescues Mice From Staphylococcal Enterotoxin B-Induced Shock.

Intranasal rapamycin rescues mice from staphylococcal enterotoxin B-induced shock.

Filed under: Drug and Alcohol Rehabilitation

Toxins (Basel). 2012 Sep; 4(9): 718-28
Krakauer T, Buckley M

Staphylococcal enterotoxin B (SEB) and related exotoxins produced by Staphylococcus aureus are potent activators of the immune system and cause toxic shock in humans. Currently there is no effective treatment except for the use of intravenous immunoglobulins administered shortly after SEB exposure. Intranasal SEB induces long-lasting lung injury which requires prolonged drug treatment. We investigated the effects of rapamycin, an immunosuppressive drug used to prevent graft rejection, by intranasal administration in a lethal mouse model of SEB-induced shock. The results show that intranasal rapamycin alone delivered as late as 17 h after SEB protected 100% of mice from lethal shock. Additionally, rapamycin diminished the weight loss and temperature fluctuations elicited by SEB. Intranasal rapamycin attenuated lung MCP-1, IL-2, IL-6, and IFN? by 70%, 30%, 64%, and 68% respectively. Furthermore, short courses (three doses) of rapamycin were sufficient to block SEB-induced shock. Intranasal rapamycin represents a novel use of an immunosuppressant targeting directly to site of toxin exposure, reducing dosages needed and allowing a wider therapeutic window.
HubMed – drug

 

What’s Faith Got to Do with It? Religiosity Among Women Who Use Methamphetamine.

Filed under: Drug and Alcohol Rehabilitation

J Soc Work Pract Addict. 2012 Apr 1; 12(2): 189-204
Lutnick A, Lorvick J, Cheng H, Wenger L, Kral AH

Religiosity is not found to be consistently protective in mental health and substance use outcomes among illicit drug users. This study examines the association between religiosity, mental health and drug use among a community-recruited sample of women who use methamphetamine. The majority of the sample (74%) had high scores of religious faith. In multivariate analysis, those with high scores had higher odds of self-reporting a mental health diagnosis and of being psychologically dependent upon methamphetamine, and were less likely to report injection risk. Further examination of the role of religiosity in the lives of women who use methamphetamine is advised.
HubMed – drug

 

The prostamide-related glaucoma therapy, bimatoprost, offers a novel approach for treating scalp alopecias.

Filed under: Drug and Alcohol Rehabilitation

FASEB J. 2012 Oct 26;
Khidhir KG, Woodward DF, Farjo NP, Farjo BK, Tang ES, Wang JW, Picksley SM, Randall VA

Balding causes widespread psychological distress but is poorly controlled. The commonest treatment, minoxidil, was originally an antihypertensive drug that promoted unwanted hair. We hypothesized that another serendipitous discovery, increased eyelash growth side-effects of prostamide F(2?)-related eyedrops for glaucoma, may be relevant for scalp alopecias. Eyelash hairs and follicles are highly specialized and remain unaffected by androgens that inhibit scalp follicles and stimulate many others. Therefore, we investigated whether non-eyelash follicles could respond to bimatoprost, a prostamide F(2?) analog recently licensed for eyelash hypotrichosis. Bimatoprost, at pharmacologically selective concentrations, increased hair synthesis in scalp follicle organ culture and advanced mouse pelage hair regrowth in vivo compared to vehicle alone. A prostamide receptor antagonist blocked isolated follicle growth, confirming a direct, receptor-mediated mechanism within follicles; RT-PCR analysis identified 3 relevant receptor genes in scalp follicles in vivo. Receptors were located in the key follicle regulator, the dermal papilla, by analyzing individual follicular structures and immunohistochemistry. Thus, bimatoprost stimulates human scalp follicles in culture and rodent pelage follicles in vivo, mirroring eyelash behavior, and scalp follicles contain bimatoprost-sensitive prostamide receptors in vivo. This highlights a new follicular signaling system and confirms that bimatoprost offers a novel, low-risk therapeutic approach for scalp alopecias.-Khidhir, K. G., Woodward, D. F., Farjo, N. P., Farjo, B. K., Tang, E. S., Wang, J. W., Picksley, S. M., and Randall, V. A. The prostamide-related glaucoma therapy, bimatoprost, offers a novel approach for treating scalp alopecias.
HubMed – drug

 

Correctors of {Delta}F508 CFTR restore global conformational maturation without thermally stabilizing the mutant protein.

Filed under: Drug and Alcohol Rehabilitation

FASEB J. 2012 Oct 26;
He L, Kota P, Aleksandrov AA, Cui L, Jensen T, Dokholyan NV, Riordan JR

Most cystic fibrosis is caused by the deletion of a single amino acid (F508) from CFTR and the resulting misfolding and destabilization of the protein. Compounds identified by high-throughput screening to improve ?F508 CFTR maturation have already entered clinical trials, and it is important to understand their mechanisms of action to further improve their efficacy. Here, we showed that several of these compounds, including the investigational drug VX-809, caused a much greater increase (5- to 10-fold) in maturation at 27 than at 37°C (<2-fold), and the mature product remained short-lived (T(1/2)?4.5 h) and thermally unstable, even though its overall conformational state was similar to wild type, as judged by resistance to proteolysis and interdomain cross-linking. Consistent with its inability to restore thermodynamic stability, VX-809 stimulated maturation 2-5-fold beyond that caused by several different stabilizing modifications of NBD1 and the NBD1/CL4 interface. The compound also promoted maturation of several disease-associated processing mutants on the CL4 side of this interface. Although these effects may reflect an interaction of VX-809 with this interface, an interpretation supported by computational docking, it also rescued maturation of mutants in other cytoplasmic loops, either by allosteric effects or via additional sites of action. In addition to revealing the capabilities and some of the limitations of this important investigational drug, these findings clearly demonstrate that ?F508 CFTR can be completely assembled and evade cellular quality control systems, while remaining thermodynamically unstable. He, L., Kota, P., Aleksandrov, A. A., Cui, L., Jensen, T., Dokholyan, N. V., Riordan, J. R. Correctors of ?F508 CFTR restore global conformational maturation without thermally stabilizing the mutant protein. HubMed – drug

 

Academic investigator-initiated trials and the challenge of sponsor responsibility: the Cologne Sponsor Model.

Filed under: Drug and Alcohol Rehabilitation

Clin Trials. 2012 Oct 25;
Georgias C, Grunow A, Olderog M, May A, Paulus U

BACKGROUND: With the amendment to the German Drug Law in 2004, the conduct of clinical trials changed by at least two main aspects: (1) The principles of Good Clinical Practice (GCP) were implemented in the national legislation, and (2) for the first time, the function of the sponsor of a clinical trial and the clinical trial itself have become legally binding definitions. By that, legal differences between industrial and academic clinical trials no longer exist. Clinical trials initiated by investigators have to fulfil the same requirements while the entire sponsor responsibility has to be carried out by the Coordinating Investigator or his institution including implementation of a quality management system according to the GCP. PURPOSE: The Cologne Sponsor Model is an effective approach with settings, structures, basic features, action, and reporting lines, as well as funding for clinical trials initiated in an academic environment. RESULTS: The University of Cologne assumes the sponsor responsibility for clinical trials organised by the university researchers according to law. Sponsor’s duties are delegated to a central operational unit of the sponsor – the Clinical Trials Center Cologne – which further delegates duties to the Coordinating Investigator. Clinical Trials Center Cologne was established in 2002 to support the performance of clinical trials at the university by offering comprehensive advisory and practical services covering all aspects of study planning and conduct. Furthermore, a specialised division of its quality management department acts as an independent sponsor’s Quality Assurance Unit. The Clinical Trials Center Cologne has established a quality management system consisting of different components (1) to enable a reasoned decision to subsequent delegation, (2) for risk-based surveillance of trial conduct (audits, monitoring-checks, and reports), and (3) support and training of the Coordinating Investigator. LIMITATIONS: Double functions of persons and departments in the university environment sometimes make it difficult to define roles in such a model. Therefore, it is necessary to establish clear reporting lines and moreover to monitor regularly and carefully the roles and responsibilities. CONCLUSIONS: With the combination of central management and support, control and independence of the researchers, our model represents a ‘risk-based’ system that offers a sensible option that fulfils the requirements of legal regulations and GCP for trials organised within the university environment. Clinical Trials 2012; 0: 1-7 http://ctj.sagepub.com.
HubMed – drug

 


 

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