RESUMEN
BACKGROUND AND AIMS: In patients with chronic hepatitis B (CHB) infection, activation of toll-like receptor 8 may induce antiviral immunity and drive functional cure. Selgantolimod, a toll-like receptor 8 agonist, was evaluated in patients with CHB who were virally suppressed on oral antiviral treatment or viremic and not on oral antiviral treatment. APPROACH AND RESULTS: In this phase 1b study, patients were randomized 4:1 to receive either selgantolimod or placebo once weekly. Virally suppressed patients received either 1.5 mg (for 2 weeks) or 3 mg (for 2 weeks or 4 weeks). Viremic patients received 3 mg for 2 weeks. The primary endpoint was safety, as assessed by adverse events (AEs), laboratory abnormalities, and vital sign examination. Pharmacokinetic and pharmacodynamic parameters were assessed by plasma analysis. A total of 38 patients (28 virally suppressed, 10 viremic) were enrolled from six sites in Australia, New Zealand, and South Korea. Twenty patients (53%) experienced an AE and 32 (84%) had laboratory abnormalities, all of which were mild or moderate in severity. The most common AEs were headache (32%), nausea (24%), and dizziness (13%). With a half-life of 5 hours, no accumulation of selgantolimod was observed with multiple dosing. Selgantolimod induced transient dose-dependent increases in serum cytokines, including IL-12p40 and IL-1RA, which are important for the expansion and activity of multiple T- cell subsets and innate immunity. CONCLUSION: Selgantolimod was safe and well-tolerated in virally suppressed and viremic patients with CHB and elicited cytokine responses consistent with target engagement. Further studies with longer durations of selgantolimod treatment are required to evaluate efficacy.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Hexanoles/uso terapéutico , Pirimidinas/uso terapéutico , Receptor Toll-Like 8/agonistas , Adulto , Mareo/inducido químicamente , Relación Dosis-Respuesta a Droga , Femenino , Cefalea/inducido químicamente , Hepatitis B Crónica/sangre , Hexanoles/farmacología , Humanos , Proteína Antagonista del Receptor de Interleucina 1/sangre , Subunidad p40 de la Interleucina-12/sangre , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Pirimidinas/farmacología , Respuesta Virológica SostenidaRESUMEN
BACKGROUND AND AIMS: GS-9688 (selgantolimod) is an oral selective small molecule agonist of toll-like receptor 8 in clinical development for the treatment of chronic hepatitis B. In this study, we evaluated the antiviral efficacy of GS-9688 in woodchucks chronically infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to hepatitis B virus. APPROACH AND RESULTS: WHV-infected woodchucks received eight weekly oral doses of vehicle, 1 mg/kg GS-9688, or 3 mg/kg GS-9688. Vehicle and 1 mg/kg GS-9688 had no antiviral effect, whereas 3 mg/kg GS-9688 induced a >5 log10 reduction in serum viral load and reduced WHV surface antigen (WHsAg) levels to below the limit of detection in half of the treated woodchucks. In these animals, the antiviral response was maintained until the end of the study (>5 months after the end of treatment). GS-9688 treatment reduced intrahepatic WHV RNA and DNA levels by >95% in animals in which the antiviral response was sustained after treatment cessation, and these woodchucks also developed detectable anti-WHsAg antibodies. The antiviral efficacy of weekly oral dosing with 3 mg/kg GS-9688 was confirmed in a second woodchuck study. The antiviral response to GS-9688 did not correlate with systemic GS-9688 or cytokine levels but was associated with transient elevation of liver injury biomarkers and enhanced proliferative response of peripheral blood mononuclear cells to WHV peptides. Transcriptomic analysis of liver biopsies taken prior to treatment suggested that T follicular helper cells and various other immune cell subsets may play a role in the antiviral response to GS-9688. CONCLUSIONS: Finite, short-duration treatment with a clinically relevant dose of GS-9688 is well tolerated and can induce a sustained antiviral response in WHV-infected woodchucks; the identification of a baseline intrahepatic transcriptional signature associated with response to GS-9688 treatment provides insights into the immune mechanisms that mediate this antiviral effect.
Asunto(s)
Antivirales/uso terapéutico , Virus de la Hepatitis B de la Marmota/efectos de los fármacos , Virus de la Hepatitis B de la Marmota/genética , Hepatitis B Crónica/tratamiento farmacológico , Hexanoles/uso terapéutico , Pirimidinas/uso terapéutico , Receptor Toll-Like 8/agonistas , Animales , Antivirales/farmacología , ADN Viral/sangre , Modelos Animales de Enfermedad , Anticuerpos Antihepatitis/sangre , Antígenos de la Hepatitis/sangre , Virus de la Hepatitis B de la Marmota/inmunología , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/inmunología , Hexanoles/farmacología , Humanos , Marmota , Pirimidinas/farmacología , Replicación Viral/efectos de los fármacosRESUMEN
BACKGROUND AND AIMS: GS-9688 (selgantolimod) is a toll-like receptor 8 agonist in clinical development for the treatment of chronic hepatitis B (CHB). Antiviral activity of GS-9688 has previously been evaluated in vitro in HBV-infected hepatocytes and in vivo in the woodchuck model of CHB. Here we evaluated the potential of GS-9688 to boost responses contributing to viral control and to modulate regulatory mediators. APPROACH AND RESULTS: We characterized the effect of GS-9688 on immune cell subsets in vitro in peripheral blood mononuclear cells of healthy controls and patients with CHB. GS-9688 activated dendritic cells and mononuclear phagocytes to produce IL-12 and other immunomodulatory mediators, inducing a comparable cytokine profile in healthy controls and patients with CHB. GS-9688 increased the frequency of activated natural killer (NK) cells, mucosal-associated invariant T cells, CD4+ follicular helper T cells, and, in about 50% of patients, HBV-specific CD8+ T cells expressing interferon-γ. Moreover, in vitro stimulation with GS-9688 induced NK-cell expression of interferon-γ and TNF-α, and promoted hepatocyte lysis. We also assessed whether GS-9688 inhibited immunosuppressive cell subsets that might enhance antiviral efficacy. Stimulation with GS-9688 reduced the frequency of CD4+ regulatory T cells and monocytic myeloid-derived suppressor cells (MDSCs). Residual MDSCs expressed higher levels of negative immune regulators, galectin-9 and programmed death-ligand 1. Conversely, GS-9688 induced an expansion of immunoregulatory TNF-related apoptosis-inducing ligand+ NK cells and degranulation of arginase-I+ polymorphonuclear MDSCs. CONCLUSIONS: GS-9688 induces cytokines in human peripheral blood mononuclear cells that are able to activate antiviral effector function by multiple immune mediators (HBV-specific CD8+ T cells, CD4+ follicular helper T cells, NK cells, and mucosal-associated invariant T cells). Although reducing the frequency of some immunoregulatory subsets, it enhances the immunosuppressive potential of others, highlighting potential biomarkers and immunotherapeutic targets to optimize the antiviral efficacy of GS-9688.
Asunto(s)
Antivirales/farmacología , Hepatitis B Crónica/tratamiento farmacológico , Hexanoles/farmacología , Pirimidinas/farmacología , Receptor Toll-Like 8/antagonistas & inhibidores , Adulto , Anciano , Animales , Antivirales/uso terapéutico , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Estudios de Cohortes , Modelos Animales de Enfermedad , Femenino , Voluntarios Sanos , Células Hep G2 , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/virología , Hexanoles/uso terapéutico , Interacciones Huésped-Patógeno/efectos de los fármacos , Interacciones Huésped-Patógeno/inmunología , Humanos , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Leucocitos Mononucleares , Masculino , Marmota , Persona de Mediana Edad , Cultivo Primario de Células , Pirimidinas/uso terapéutico , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Receptor Toll-Like 8/metabolismo , Adulto JovenRESUMEN
Trimethylamine N-oxide (TMAO), a metabolite of gut microbiota, is involved in the regulation of lipid metabolism and inflammatory response; however, the role of TMAO in hyperlipidemia acute pancreatitis (HAP) is not clear. In this study, HAP mice were used as an animal model to explore the effects and possible mechanism of TMAO on HAP, which may provide new ideas for the treatment of HAP. Results found that the levels of triglycerides, total cholesterol, low-density lipoprotein cholesterol, nonestesterified fatty acid, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, α-amylase, TMAO, and flavin-containing monooxygenase 3 were significantly increased, the levels of high-density lipoprotein cholesterol and insulin were significantly decreased, and there was an obvious pancreatic injury and inflammatory response in the model group. The choline analogue 3,3-dimethyl-1-butanol (DMB) treatment reversed the changes of serum biochemical parameters, alleviated the pancreatic tissue injury, and reduced the levels of inflammatory cytokines. Further studies of toll-like receptor (TLR)/p-glycoprotein 65 (p65) pathway found that the expressions of TLR2, TLR4, and p-p65/p65 in the model group were significantly increased, which was more obvious after Escherichia coli (Migula) Castellani & Chalmers treatment, while activation of the TLR/p65 pathway was inhibited by DMB. The results indicated that TMAO promotes HAP by promoting inflammatory response through TLR/p65 signaling pathway, suggesting that TMAO may be a potential target of HAP.
Asunto(s)
Hiperlipidemias/etiología , Metilaminas/efectos adversos , Pancreatitis/etiología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Microbioma Gastrointestinal/fisiología , Hexanoles/farmacología , Hexanoles/uso terapéutico , Hiperlipidemias/tratamiento farmacológico , Hiperlipidemias/metabolismo , Inflamación , Mediadores de Inflamación/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Metilaminas/metabolismo , Ratones Endogámicos C57BL , Terapia Molecular Dirigida , Pancreatitis/tratamiento farmacológico , Pancreatitis/metabolismo , Transducción de Señal/efectos de los fármacos , Receptores Toll-Like/metabolismoRESUMEN
Identifying signaling pathways that induce B cell response can aid functional cure strategies for chronic hepatitis B infection (CHB). TLR8 activation with ssRNA was shown to enhance follicular helper T cell (TFH) function leading to improved B cell responses in vitro. We investigated whether this mechanism can rescue an exhausted immune response in CHB infection. Effect of TLR8 agonism on supporting cytokines and TFH and B cells were evaluated using ex vivo and in vitro assays. The ability of an oral TLR8 agonist to promote TFH and B cell response was tested in samples from phase 1b clinical trial. TLR8 agonism induced TFH polarizing cytokine IL-12 in monocytes. Treatment of peripheral blood mononuclear cells (PBMCs) from CHB patients with TLR8 agonists induced cytokine IL-21 by TFH cells with enhanced IL-21+BCL-6+ and ICOS+BCL-6+ co-expression. Mechanistically, incubation of isolated naïve CD4+ T cells with TLR8 triggered monocytes resulted in their differentiation into IL-21+ICOS+BCL-6+ TFH in an IL-12 dependent manner. Furthermore, co-culture of these IL-21 producing TFH with autologous naïve B cells led to enhanced memory (CD19+CD27+) and plasma B cell generation (CD19+CD27++CD38+) and IgG production. Importantly, in TFH from CHB patients treated with an oral TLR8 agonist, HBsAg-specific BCL-6, ICOS, IL-21 and CD40L expression and rescue of defective activation induced marker (AIM) response along with partial restoration of HBsAg-specific B cell ELISPOT response was evident. TLR8 agonism can thus enhance HBV-specific B cell responses in CHB patients by improving monocyte-mediated TFH function and may play a role in achieving HBV functional cure.
Asunto(s)
Antivirales/uso terapéutico , Linfocitos B/efectos de los fármacos , Antígenos de Superficie de la Hepatitis B/inmunología , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/tratamiento farmacológico , Hexanoles/uso terapéutico , Pirimidinas/uso terapéutico , Células T Auxiliares Foliculares/efectos de los fármacos , Receptor Toll-Like 8/agonistas , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos B/virología , Ligando de CD40/metabolismo , Estudios de Casos y Controles , Células Cultivadas , Ensayo de Immunospot Ligado a Enzimas , Virus de la Hepatitis B/patogenicidad , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/metabolismo , Hepatitis B Crónica/virología , Interacciones Huésped-Patógeno , Humanos , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , Interleucinas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Transducción de Señal , Células T Auxiliares Foliculares/inmunología , Células T Auxiliares Foliculares/metabolismo , Células T Auxiliares Foliculares/virología , Receptor Toll-Like 8/metabolismo , Resultado del TratamientoRESUMEN
Myocardial infarction (MI) is a common cause of chronic heart failure (HF). Increasing evidence has revealed that trimethylamine Noxide (TMAO), a gutmicrobiotaderived metabolite, contributes to the pathogenesis of cardiovascular disease by promoting inflammation. Elevated levels of circulating TMAO have been reported in patients following MI and were associated with unfavorable outcomes. The present study examined whether reductions in circulating TMAO could attenuate the progression of HF in rats following MI. SpragueDawley rats underwent coronary ligation to induce MI or a sham operation. Echocardiography confirmed MI and cardiac dysfunction one day following coronary ligation. MI and sham rats were then treated with either vehicle (tap water) or 1.0% 3,3dimethyl1butanol (DMB, a trimethylamine formation inhibitor) in tap water, for 8 weeks. At the end of the experiment, TMAO plasma levels were markedly elevated in vehicletreated MI rats compared with vehicletreated sham rats; however, TMAO plasma levels were reduced in DMBtreated MI rats compared with vehicletreated MI rats. Both MI groups exhibited cardiac hypertrophy, lung congestion, left ventricular remodeling and impaired cardiac function, according to the results of anatomical analysis, echocardiography and left ventricular hemodynamics; however, these manifestations of MIinduced HF were significantly improved in DMBtreated MI rats compared with vehicletreated MI rats. The plasma levels of the chemokine interleukin (IL)8, and cardiac expression of IL8 and its receptors were significantly increased in vehicletreated MI rats compared with vehicletreated sham rats; however, these were normalized in DMBtreated MI rats. In addition, elevated TMAO plasma level was positively correlated with increased IL8 plasma level in MI groups. Notably, DMB treatment of sham rats also reduced plasma TMAO, but did not alter other parameters. These results indicated that reducing circulating TMAO may ameliorate the development of chronic HF following MI in rats, potentially by inhibiting IL8 secretion. The results from the present study suggested that inhibition of TMAO synthesis may be considered as a novel therapeutic approach for the prevention and treatment of patients with chronic MIinduced HF.
Asunto(s)
Insuficiencia Cardíaca/tratamiento farmacológico , Hexanoles/uso terapéutico , Metilaminas/antagonistas & inhibidores , Infarto del Miocardio/tratamiento farmacológico , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/microbiología , Interleucina-8/sangre , Masculino , Metilaminas/sangre , Infarto del Miocardio/sangre , Infarto del Miocardio/complicaciones , Infarto del Miocardio/microbiología , Ratas , Ratas Sprague-DawleyRESUMEN
The 7-nitro-2,1,3-nitrobenzoxadiazole (NBD) derivatives are a series of compounds containing the NBD scaffold that are not glutathione (GSH) peptidomimetics, and result in a strong inhibition of glutathione S-transferases (GSTs). Growing evidences highlight their pivotal roles and outstanding anticancer activity in different tumor models. In particular, 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol (NBDHEX) is extensively studied, which is a very efficient inhibitor of GSTP1-1. It triggers apoptosis in several tumor cell lines and this cytotoxic activity is observed at micro and submicromolar concentrations. Importantly, studies have shown that NBDHEX acts as an anticancer drug by inhibiting GSTs catalytic activity, avoiding inconvenience of the inhibitor extrusion from the cell by specific pumps and disrupting the interaction between the GSTP1-1 and key signaling effectors. Additionally, some researchers also have discovered that NBDHEX can act as late-phase autophagy inhibitor, which opens new opportunities to fully exploit its therapeutic potential. In this review, we summarize the advantages, anticancer mechanisms, and analogs of this compound, which will establish the basis on the usage of NBDHEX in clinical applications in future.
Asunto(s)
Antineoplásicos/química , Gutatión-S-Transferasa pi/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Oxadiazoles/química , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Azoles/química , Azoles/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Gutatión-S-Transferasa pi/química , Hexanoles/química , Hexanoles/uso terapéutico , Humanos , Neoplasias/patología , Nitrobencenos/química , Nitrobencenos/uso terapéutico , Oxadiazoles/uso terapéuticoRESUMEN
In the present study, the effect of (Z)-3-hexenol, one of the main constituent of green odor, on the anxiety-related behavior of mouse and the content of 5-hydroxytryptamine (5-HT), dopamine and their metabolites in the brain were investigated. Evaluation of anxiety-related animal behavior was performed by measuring the percent of time spent on the open arms and the percent of open-arm entries as conventional anxiety indices. The number of times displaying risk-assessment from a closed arm was also measured as an ethological anxiety index. Diazepam, an anxiolytic agent, enhanced the percent of time spent on the open arms and the percent of open-arm entries. The number of times displaying risk-assessment was not affected by diazepam in the present study. The percent of time on the open arms were depressed, and the number of times displaying risk-assessment were stimulated by 1-(3-trifluoromethylphenyl)piperazine (TFMPP), indicating that TFMPP acts as an anxiogenic agent. (Z)-3-Hexenol revealed anxiolytic activity and increased the percent of time spent on the open arms and decreased the number of times displaying risk-assessment. In the neurochemical study, diazepam had no effect on the content of 5-HT and its metabolite in the brain cortex or hippocampus. On the other hand, TFMPP inhibited the 5-HT turnover rate accompanied by the elevation of the 5-HT content and reduction of the 5-HIAA content in the brain cortex and hippocampus. (Z)-3-Hexenol significantly increased the 5-HT content without affecting the 5-HIAA content or the 5-HT turnover rate in the brain cortex or hippocampus. Changes in serotonergic activity in the cortex and hippocampus were suggested to be involved in the anxiolytic effect of (Z)-3-hexenol observed in the elevated plus-maze test.
Asunto(s)
Ansiolíticos/farmacología , Aminas Biogénicas/metabolismo , Encéfalo/efectos de los fármacos , Hexanoles/farmacología , Aprendizaje por Laberinto/efectos de los fármacos , Animales , Ansiolíticos/uso terapéutico , Ansiedad/tratamiento farmacológico , Conducta Animal , Química Encefálica/efectos de los fármacos , Diazepam/uso terapéutico , Relación Dosis-Respuesta a Droga , Hexanoles/uso terapéutico , Masculino , Ratones , Piperazinas/uso terapéutico , Agonistas de Receptores de Serotonina/uso terapéutico , Factores de TiempoRESUMEN
OBJECTIVE: To investigate whether albumin can be substituted by mannitolum in cirrhotic patients with tense ascites treated by paracentesis. METHODS: Sixty-eight patients admitted to this therapeutic procedure were randomly assigned to receive intravenous albumin (36 patients) and mannitolum (32 patients) infusion. In repeated large-volume paracentesis (3-6 L/day), intravenous albumin 20 g or intravenous 20% mannitolum 250 ml were added. RESULTS: In 24 and 48 hours after paracentesis the mean value of electrolytes, liver and renal functions and various indicators of systemic circulation either in Group 1 or in Group 2 cases were found without changes (P > 0.05). As compared with that before paracentesis, the diameter of spleen vein was increased significantly (P < 0.05). The complications occurring after paracentesis were similar in both groups. CONCLUSIONS: It was suggested that paracentesis with intravenous infusion of mannitolum is an effective and safe method in treating cirrhotic patients with tense ascites.
Asunto(s)
Ascitis/terapia , Hexanoles/uso terapéutico , Cirrosis Hepática/terapia , Paracentesis , Sustitutos del Plasma/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Plasmodium falciparum, the major causative parasite for the disease, has acquired resistance to most of the antimalarial drugs used today, presenting an immediate need for new antimalarial drugs. Here, we report the in vitro and in vivo antimalarial activities of 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against P. falciparum and Plasmodium berghei parasites. The N-251 showed high antimalarial potencies both in the in vitro and the in vivo tests (EC(50) 2.3×10(-8) M; ED(50) 15 mg/kg (per oral)). The potencies were similar to that of artemisinin in vitro and greater than artemisinin's activity in vivo (p.o.). In addition, N-251 has little toxicity: a single oral administration at 2000 mg/kg to a rat gave no health problems to it. Administration of N-251 to mice bearing 1% of parasitemia (per oral 68 mg/kg, 3 times a day for 3 consecutive days) resulted in a dramatic decrease in the parasitemia: all the 5 mice given N-251 were cured without any recurrence, with no diarrhea or weight loss occurring in the 60 days of experiment. N-251 deserves more extensive clinical evaluation, desirably including future trials in the human.
Asunto(s)
Antimaláricos/farmacología , Artemisininas/farmacología , Compuestos Heterocíclicos con 2 Anillos/farmacología , Hexanoles/farmacología , Malaria Falciparum/tratamiento farmacológico , Plasmodium berghei/efectos de los fármacos , Plasmodium falciparum/efectos de los fármacos , Compuestos de Espiro/farmacología , Administración Oral , Animales , Antimaláricos/química , Antimaláricos/uso terapéutico , Artemisininas/uso terapéutico , Línea Celular Tumoral , Quimioterapia Combinada , Eritrocitos/efectos de los fármacos , Eritrocitos/parasitología , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/uso terapéutico , Hexanoles/química , Hexanoles/uso terapéutico , Humanos , Malaria/tratamiento farmacológico , Malaria/parasitología , Malaria Falciparum/parasitología , Ratones , Ratones Endogámicos ICR , Estructura Molecular , Parasitemia/tratamiento farmacológico , Pruebas de Sensibilidad Parasitaria , Ratas , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/uso terapéutico , Análisis de Supervivencia , TetraoxanosRESUMEN
Green odor (GO), a mixture of cis-3-hexenol and trans-2-hexenal, attenuates stress responses and anxiety to psychological stressors in rodents; however, it remains unknown whether GO affects behavioral and stress responses to risk-related olfactory stimuli and actual noxious stimuli. The present study investigated the effects of green odor on behavioral and plasma adrenocorticotropic hormone (ACTH) responses to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a component of fox feces, and electric footshock (FS) stress. When rats were simultaneously exposed to TMT and GO, they showed decreases in immobility and plasma ACTH levels compared with TMT alone. GO exposure after TMT increased immobility, but blocked the elevation of plasma ACTH levels compared with rats exposed to distilled water after TMT. This means that GO presentation during TMT attenuated the TMT-induced behavioral response and GO presentation during and after TMT inhibited TMT-induced elevation of plasma ACTH levels. Furthermore, electric FS-induced plasma ACTH elevations were attenuated by simultaneous GO and FS exposure. GO presentation after FS attenuated plasma ACTH elevations and fecal responses. These findings reveal that GO has alleviating effects on olfactory stimulus- and noxious stimulus-induced behavioral and endocrinal responses.
Asunto(s)
Hormona Adrenocorticotrópica/sangre , Aldehídos/farmacología , Ansiedad/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Hexanoles/farmacología , Estrés Psicológico/tratamiento farmacológico , Tiazoles/farmacología , Aldehídos/administración & dosificación , Aldehídos/uso terapéutico , Animales , Ansiolíticos/administración & dosificación , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Ansiedad/inducido químicamente , Ansiedad/complicaciones , Modelos Animales de Enfermedad , Quimioterapia Combinada , Estimulación Eléctrica/métodos , Conducta Excretoria Animal/efectos de los fármacos , Hexanoles/administración & dosificación , Hexanoles/uso terapéutico , Masculino , Percepción Olfatoria/efectos de los fármacos , Ratas , Ratas Wistar , Estrés Psicológico/inducido químicamente , Estrés Psicológico/complicacionesRESUMEN
Malaria is one of the world's deadliest diseases and is becoming an increasingly serious problem as malaria parasites develop resistance to most of the antimalarial drugs used today. We previously reported the in vitro and in vivo antimalarial potencies of 1,2,6,7-tetraoxaspiro[7.11]nonadecane (N-89) and 6-(1,2,6,7-tetraoxaspiro[7.11]nonadec-4-yl)hexan-1-ol (N-251) against Plasmodium falciparum and Plasmodium berghei parasites. To improve water-solubility for synthetic peroxides, a variety of cyclic peroxides having carboxyl functionality was prepared based on the antimalarial candidate, N-251, and their antimalarial activities were determined. The reactions of N-89 and its derivatives with Fe(II) demonstrated a highly efficient formation of the corresponding carbon radical which may be suspected as a key for the antiparasitic activity.