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BACKGROUND AND PURPOSE: Acute activation of κ opioid (KOP) receptors results in anticocaine-like effects, but adverse effects, such as dysphoria, aversion, sedation and depression, limit their clinical development. Salvinorin A, isolated from the plant Salvia divinorum, and its semi-synthetic analogues have been shown to have potent KOP receptor agonist activity and may induce a unique response with similar anticocaine addiction effects as the classic KOP receptor agonists, but with a different side effect profile. EXPERIMENTAL APPROACH: We evaluated the duration of effects of Mesyl Sal Bâ in vivo utilizing antinociception assays and screened for cocaine-prime induced cocaine-seeking behaviour in self-administering rats to predict anti-addiction effects. Cellular transporter uptake assays and in vitro voltammetry were used to assess modulation of dopamine transporter (DAT) function and to investigate transporter trafficking and kinase signalling pathways modulated by KOP receptor agonists. KEY RESULTS: Mesyl Sal B had a longer duration of action than SalA, had anti-addiction properties and increased DAT function in vitro in a KOP receptor-dependent and Pertussis toxin-sensitive manner. These effects on DAT function required ERK1/2 activation. We identified differences between Mesyl Sal B and SalA, with Mesyl Sal B increasing the Vmax of dopamine uptake without altering cell-surface expression of DAT. CONCLUSIONS AND IMPLICATIONS: SalA analogues, such as Mesyl Sal B, have potential for development as anticocaine agents. Further tests are warranted to elucidate the mechanisms by which the novel salvinorin-based neoclerodane diterpene KOP receptor ligands produce both anti-addiction and adverse side effects. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
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Trastornos Relacionados con Cocaína/tratamiento farmacológico , Diterpenos/farmacología , Diterpenos/uso terapéutico , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Mesilatos/farmacología , Mesilatos/uso terapéutico , Receptores Opioides kappa/agonistas , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Células COS , Línea Celular Tumoral , Chlorocebus aethiops , Cocaína/administración & dosificación , Trastornos Relacionados con Cocaína/metabolismo , Diterpenos de Tipo Clerodano , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Células HEK293 , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Dolor/tratamiento farmacológico , Dolor/metabolismo , Ratas Sprague-Dawley , Receptores Opioides kappa/metabolismo , AutoadministraciónRESUMEN
BACKGROUND: With current standard-dose chemotherapy ovarian cancer is a chemosensitive but not chemocurable disease in the majority of cases. The widely used first-line chemotherapy including a platinum analogue combined with cyclophosphamide results in response rates of 60-80%. However, only 10-20% of patients with advanced disease are alive 5 years after the diagnosis. The efficacy of high-dose chemotherapy supported by autologous stem cell transplantation (ASCT) is currently under intensive investigation. METHODS: We report here our initial experiences of the use of high-dose chemotherapy supported by ASCT for patients with high-risk ovarian cancer. Two patients were treated at Uppsala University Hospital in 1992 and four patients at Turku University Central Hospital in 1994. RESULTS: The first four patients treated either after heavy previous chemotherapy or recurrent disease relapsed within 5-10 months. Two patients received high-dose therapy as part of first-line treatment. One of them had a relapse 18 months after therapy, the other one has been disease free for 28 months. No toxic deaths occurred, but the patients had neutropenic febrile episodes and moderate to severe gastrointestinal toxicity. CONCLUSIONS: Coordinated efforts in Nordic countries are indicated to evaluate the usefulness of high-dose therapy supported by ASCT in the treatment of advanced ovarian cancer.
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Antineoplásicos Alquilantes/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trasplante de Médula Ósea , Ciclofosfamida/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Compuestos de Platino/administración & dosificación , Trasplante de Células Madre , Adulto , Relación Dosis-Respuesta a Droga , Femenino , Finlandia , Humanos , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Suecia , Trasplante AutólogoRESUMEN
Drugs in the tetracycline family can inhibit mammalian tissue collagenase both in vitro and in vivo by a mechanism that is independent of antibiotic action. The epiphyseal cartilages of rachitic rats contain extremely high levels of collagenase (CGase), and we have used this model to study further the phenomenon of tetracycline inhibition of tissue CGase. Rickets was induced in rats by phosphate/vitamin D deficiency and parameters of gross bone morphology, bone chemistry, and serum chemistry were evaluated in both rachitic and nonrachitic animals with and without treatment with oral tetracyclines (TETs). Minocycline (or doxycycline) partially suppressed the appearance of many of the expected changes in the rachitic animals, including gross bone hardness, growth plate widening, long bone length, suppression of weight gain, and decreased bone ash content. The effects were dose dependent and were associated with marked suppression of the enhanced CGase activity. Examination of collagen breakdown products by SDS-PAGE documented that the rachitic enzyme behaved like other mammalian collagenases including in vitro inhibition with minocycline 10-20 micrograms/ml and with a nonantibiotic tetracycline. No evidence of TET osseous toxicity was noted, and, in fact, administration of TET to nonrachitic animals had a mildly favorable effect on growth and development. TET suppression of CGase can be demonstrated in a well defined model system and this form of pharmacologic enzyme inhibition can be a useful probe for delineating the role of the enzyme in connective tissue pathology.
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Placa de Crecimiento/efectos de los fármacos , Colagenasa Microbiana/antagonistas & inhibidores , Raquitismo/enzimología , Tetraciclina/farmacología , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Doxiciclina/administración & dosificación , Doxiciclina/farmacología , Placa de Crecimiento/enzimología , Minociclina/administración & dosificación , Minociclina/farmacología , Ratas , Ratas Endogámicas , Raquitismo/fisiopatología , Tetraciclina/administración & dosificaciónRESUMEN
The effects of serum from patients with chronic lymphocytic leukaemia (CCL) on normal polymorphonuclear leucocyte migration (PMN) were examined by means of the leading front technique, using a modified Boyden chamber. 18 randomly selected patients were studied. 13 patients had a reduced chemokinetic activity. The defective migration was explained by the finding in serum from these patients of cell-directed inhibitory activity which was destroyed by heating (56 degrees C, 30 min). The B-lymphocytes as the origin of the inhibitory activity was suggested by the presence of a similar activity in supernatants from cultured tumour cells. 6 of the 18 patients had the combination of a defective chemokinetic activity and low levels of immunoglobulins. These 6 patients had an increased tendency towards infections.
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Aminopeptidasas , Factores Quimiotácticos/antagonistas & inhibidores , Leucemia Linfoide/sangre , Neutrófilos/inmunología , Anciano , Linfocitos B/inmunología , Inhibición de Migración Celular , Factores Quimiotácticos/inmunología , Femenino , Humanos , Inmunoglobulinas/análisis , Leucemia Linfoide/inmunología , Factores Inhibidores de la Migración de Leucocitos/inmunología , Masculino , Persona de Mediana EdadRESUMEN
The ability of lymphoid cells from immunized animals to regulate the response of naive B ceils to the immunizing hapten was studied. Mice were immunized with trinitrophenylated (TNP) bovine gamma globulin (BGG) in complete Freund's adjuvant, and their spleen cells were examined in vivo and in vitro for the presence of specific inhibitory activity. This activity was found to peak 1 wk after immunization, was active against TNP on both T-dependent (BGG) and T-independent (Ficoll and polyacrylamide beads) carriers, and was demonstrable both by mixed cell transfers and mixed cell culture experiments. In in vitro studies, it was shown that the inhibition of the response to TNP- polyacrylamide beads by immune spleen cells was mediated by a non-T cell, possibly a B cell, because the suppressor activity was enriched in a purified B cell preparation. A role for macrophages was not formally ruled out. A specific suppressor factor was produced in vitro by immune spleen cells cultured in the absence of antigen. The suppressor activity was modulated by T .cells because elimination of T cells from the normal spleen cell population decreased suppression; elimination of T cells from the immune spleen cell population did not effect suppression, but elimination of T cells from both the normal and immune spleen cell populations allowed the expression of marked specific suppression. Thus, T cells present in the normal spleen cell population augment the degree of suppression, whereas T cells present in the immune spleen cell population decrease the degree of suppression; that is, T cells present in the immune spleen cell population had the ability to specifically abrogate suppression ("abrosuppression") in a T-independent immune response. It is proposed that the response to a T- independent antigen is regulated by specific suppressor activity generated by a non-T cell and augmented by the interaction of this cell with a T cell. The suppressor activity can be blocked by a specific abrosuppressor T cell. It is suggested that, because suppressor activity appears dominant in the naive state of the immune system, the induction of specific abrosuppressor activity may be essential if an immune response is to take place.
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Comunicación Celular , Haptenos/inmunología , Terapia de Inmunosupresión , Linfocitos T/inmunología , Animales , Bovinos , Ficoll/inmunología , Adyuvante de Freund , Inmunidad Celular , Lisina/inmunología , Ratones , Ratones Endogámicos , Bazo/inmunología , Trinitrobencenos/inmunología , gammaglobulinas/inmunologíaRESUMEN
Early Proterozoic microfossils from the Sokoman Iron Formation, northeastern Canada, are indistinguishable from those of the Gunflint Formation in both morphology and inferred community structure. The contemporaneity of the Sokoman assemblage with the Bitter Springs-like cyanobacteria of the Belcher Supergroup indicates that differences between the two major types of early Proterozoic microbiotas are primarily ecological and not temporal (evolutionary) in nature. In arenaceous iron formations, microfossils are restricted to peloids and are absent from pore-filling silica interpreted as cement. Cemented arenaceous intraclasts indicate that some of the silica was penecontemporaneous, and the abundance of minus-cement porosity in arenaceous iron formations demonstrates that early (pre-compaction) cementation was common.