RESUMEN
Major depressive disorder (MDD) is a debilitating disease affecting a wide cross section of people around the world. The current therapy for depression is less than adequate and there is a considerable unmet need for more efficacious treatment. Dopamine has been shown to play a significant role in depression including production of anhedonia which has been one of the untreated symptoms in MDD. It has been hypothesized that drugs acting at all three monoamine transporters including dopamine transporter should provide more efficacious antidepressants activity. This has led to the development of triple reuptake inhibitor D-473 which is a novel pyran based molecule and interacts with all three monoamine transporters. The monoamine uptake inhibition activity in the cloned human transporters expressed in HEK-293 cells (70.4, 9.18 and 39.7 for DAT, SERT and NET, respectively) indicates a serotonin preferring triple reuptake inhibition profile for this drug. The drug D-473 exhibited good brain penetration and produced efficacious activity in rat forced swim test under oral administration. The optimal efficacy dose did not produce any locomotor activation. Microdialysis experiment demonstrated that systemic administration of D-473 elevated extracellular level of the three monoamines DA, 5-HT, and NE efficaciously in the dorsal lateral striatum (DLS) and the medial prefrontal cortex (mPFC) area, indicating in vivo blockade of all three monoamine transporters by D-473. Thus, the current biological data from D-473 indicate potent antidepressant activity of the molecule.
Asunto(s)
Amino Azúcares/farmacología , Antidepresivos/farmacología , Bencilaminas/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Piranos/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Administración Oral , Amino Azúcares/síntesis química , Amino Azúcares/farmacocinética , Animales , Antidepresivos/síntesis química , Antidepresivos/farmacocinética , Conducta Animal/efectos de los fármacos , Bencilaminas/síntesis química , Bencilaminas/farmacocinética , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/fisiopatología , Dopamina/metabolismo , Inhibidores de Captación de Dopamina/síntesis química , Inhibidores de Captación de Dopamina/farmacocinética , Células HEK293 , Humanos , Masculino , Norepinefrina/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Piranos/síntesis química , Piranos/farmacocinética , Ratas , Ratas Sprague-Dawley , Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , NataciónRESUMEN
In this study,lactosaminated N-succinyl-chitosan (Lac-Suc) was investigated for its liver targeting ability in the early metastatic stage of liver cancer, and subsequently Lac-Suc-mitomycin C conjugate (Lac-Suc-MMC) and highly-succinylated N-succinyl-chitosan (Suc(II))-MMC conjugate (Suc(II)-MMC) were examined for efficacy against the liver metastasis. Mice into which M5076 cells were inoculated intravenously were used as liver metastatic models. Fluorescently labelled Lac-Suc (Lac-Suc-FTC) was intravenously administered at a daily dose of 0.2 mg/mouse for 4 days or at a single dose of 0.8 mg/mouse at 3 days post-inoculation. At a dose of 0.2 mg/mouse for 4 days, liver accumulation of Lac-Suc-FTC was increased after all except the fourth injection, indicating that the capacity of accumulation might be limited to around 110 microg per mouse with repeated daily administration at 0.2 mg/mouse. As to the efficacy of intravenous administration at 7 days post-inoculation, Lac-Suc-MMC was less effective at a dose of 1 mg kg(-1) for 4 days than a single dose of 4 mg kg(-1). This result was not in accordance with that expected from the biodistribution study. On the other hand, with intravenous administration at 3 days post-inoculation, Suc(II)-MMC was more effective on repeated administration, and it showed higher efficacy than Lac-Suc-MMC at both 1 mg kg(-1) for 4 days and 4 mg kg(-1) as a single dose. Further, with intravenous administration at 3 days post-inoculation, Suc(II)-MMC exhibited a much higher survival effect at a dose of 4 mg kg(-1) for 4 days.
Asunto(s)
Amino Azúcares/farmacocinética , Quitina/análogos & derivados , Quitina/farmacocinética , Quitosano , Neoplasias Hepáticas Experimentales/metabolismo , Mitomicina/farmacocinética , Metástasis de la Neoplasia/tratamiento farmacológico , Amino Azúcares/uso terapéutico , Animales , Área Bajo la Curva , Quitina/química , Quitina/uso terapéutico , Esquema de Medicación , Fluoresceína-5-Isotiocianato/metabolismo , Humanos , Inyecciones Intravenosas , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos C57BL , Mitomicina/química , Mitomicina/uso terapéutico , Distribución Tisular , Resultado del Tratamiento , Células Tumorales CultivadasRESUMEN
Lactosaminated N-succinyl-chitosan (Lac-Suc) was prepared by reductive amination of N-succinyl-chitosan (Suc) and lactose using sodium cyanoborohydride. Six-day reaction using lactose (12.8-fold (w/w)) yielded Lac-Suc with lactosamination degree of 30% (mol/sugar unit). Fluorescein thiocarbamyl-Lac-Suc (Lac-Suc-FTC) was prepared by labeling Lac-Suc with fluorescein isothiocyanate. Lac-Suc-FTC was injected intravenously at a dose of either 1 (high dose) or 0.2 (low dose) mg/mouse. At both doses, Lac-Suc-FTC initially underwent fast hepatic clearance, showed maximum liver localization at 8 h, and the amounts localized there were maintained even at 48 h post-injection. Very slow excretion into feces and urine was observed. The ratio of liver AUC(0--48 h) to plasma AUC(0--48 h) at low dose was three times higher than that at high dose. On the other hand, the Suc derivative, Gal-Suc, obtained by reductive amination of Suc/galactose showed very little distribution to the liver similarly to Suc itself. Further, since the liver uptake of Lac-Suc-FTC was inhibited by asialofetuin, it was suggested that the liver distribution of Lac-Suc should be concerned with asialoglycoprotein receptor. Thus, Lac-Suc was found available as a carrier exhibiting a high affinity to and long retention in the liver.
Asunto(s)
Quitina/análogos & derivados , Quitina/farmacocinética , Quitosano , Portadores de Fármacos , Hígado/metabolismo , Amino Azúcares/farmacocinética , Animales , Receptor de Asialoglicoproteína , Unión Competitiva , Fluoresceína-5-Isotiocianato/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores de Superficie Celular/metabolismo , Distribución TisularRESUMEN
Adenine arabinoside monophosphate (ara-AMP) is a potent antiviral agent against hepadnaviruses but its use in the treatment of chronic hepatitis B is hampered by severe neurotoxic side effects, which are dose dependent. In order to reduce these adverse reactions and to adopt the lysosomotropic approach to antiviral chemotherapy, ara-AMP was coupled to lactosaminated human serum albumin (L-HSA), a neoglycoprotein which specifically penetrates hepatocytes. In mice with Ectromelia virus hepatitis, ara-AMP coupled with L-HSA was selectively delivered to liver cells in which it was released in a pharmacologically active form. Moreover in woodchucks with WHV hepatitis and in patients with chronic HBV infection, coupled ara-AMP inhibited hepadnavirus replication at a dose (1.5 mg/kg/day) 3-6 times lower than the free drug. A clinical study using a 28-day period of treatment with conjugated ara-AMP at 1.5 mg/kg/day has now been started. In the first 6 patients the treatment has been completed. The conjugate inhibited virus growth without producing any side effects. L-HSA-ara-AMP conjugate must be given by intravenous infusion. New hepatotropic conjugates of ara-AMP have been recently prepared which could be administered by bolus intravenous injection or by intramuscular route. These complexes might assure a better compliance in patients with hepatitis B virus infection for a long lasting liver targeted antiviral treatment.
Asunto(s)
Amino Azúcares/administración & dosificación , Antivirales/administración & dosificación , Hígado/metabolismo , Polilisina/análogos & derivados , Fosfato de Vidarabina/análogos & derivados , Fosfato de Vidarabina/administración & dosificación , Amino Azúcares/farmacocinética , Animales , Antivirales/farmacocinética , Portadores de Fármacos , Hepatitis B/tratamiento farmacológico , Hepatitis B/virología , Humanos , Macaca fascicularis , Marmota , Ratones , Polilisina/administración & dosificación , Polilisina/farmacocinética , Conejos , Ratas , Albúmina Sérica/metabolismo , Fosfato de Vidarabina/farmacocinéticaRESUMEN
A conjugate of the antiviral agent adenine arabinoside monophosphate (ara-AMP) with a low molecular mass lactosaminated poly-L-lysine, administered to mice by i.m. route, selectively delivers the drug to the liver. In mice the conjugate is devoid of acute toxicity even at high dose (1.3 mg/g) and injected i.m. for 20 days does not induce antibodies. Moreover it is highly soluble in water; this means that a pharmacologically active dose may be administered in a small volume compatible with the i.m. route. Compared to the similar ara-AMP complex with lactosaminated albumin which must be injected intravenously, the present conjugate might assure a better compliance of patients with hepatitis B virus infection for a long lasting, liver targeted antiviral treatment.
Asunto(s)
Amino Azúcares/farmacocinética , Antivirales/administración & dosificación , Hígado/metabolismo , Polilisina/análogos & derivados , Polilisina/farmacocinética , Fosfato de Vidarabina/análogos & derivados , Fosfato de Vidarabina/farmacocinética , Animales , Radioisótopos de Carbono , Portadores de Fármacos , Femenino , Hepatitis B/tratamiento farmacológico , Ratones , Distribución Tisular , Tritio , Fosfato de Vidarabina/administración & dosificación , Fosfato de Vidarabina/químicaRESUMEN
Incorporation of a C-terminal pentahydroxy functionality led to potent, low molecular weight hydrophilic renin inhibitors lacking the P1' side chain. As these compounds are easy to synthesize and have sufficient water solubility, they were chosen for further study. Compound 33 was transported across rabbit intestinal brush border membrane vesicles and yielded a hypotensive effect in sodium-depleted rhesus monkeys which lasted for 90 min when dosed at 2 mg/kg id.