RESUMEN
BACKGROUND: Islatravir (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor in development for treatment and prevention of HIV-1. We present efficacy and safety data for islatravir and doravirine (DOR) through 96 weeks of the phase 2b trial (NCT03272347). METHODS: In this randomized, double-blind, dose-ranging trial, participants initially received islatravir (0.25, 0.75, or 2.25 mg) with doravirine (100 mg) and lamivudine (3TC, 300 mg) or a fixed-dose combination of doravirine, 3TC, and tenofovir disoproxil fumarate (DOR/3TC/TDF) daily. Beginning at week 24, participants receiving islatravir stopped 3TC if HIV-1 RNA from the prior visit was <50 copies per milliliter and continued taking the assigned islatravir dose (still blinded) with doravirine. All islatravir groups transitioned to open-label use of 0.75 mg between weeks 60 and 84. Efficacy end points at week 96 included the proportion of participants maintaining HIV-1 RNA of <50 copies per milliliter (FDA Snapshot). Safety was assessed by adverse event (AE) reporting. RESULTS: One hundred twenty-one treatment-naive participants received the study drugs and were included in the analyses. Through week 96, HIV-1 RNA<50 copies per milliliter was maintained in 86.2% (25/29), 90.0% (27/30), and 67.7% (21/31) of participants in the 0.25-, 0.75-, and 2.25-mg islatravir groups, respectively, 81.1% (73/90) of the combined islatravir group, and 80.6% (25/31) of the DOR/3TC/TDF group. One participant in the 2.25-mg islatravir group had Protocol-Defined Virologic Failure after week 48. Drug-related AE rates were higher for DOR/3TC/TDF participants (22.6%) compared with islatravir (combined 7.8%). Two participants (2.2%) receiving islatravir with doravirine and one (3.2%) receiving DOR/3TC/TDF discontinued because of an AE. CONCLUSIONS: Treatment regimens containing islatravir and doravirine maintained viral suppression through week 96 and were well tolerated regardless of dose.
Asunto(s)
Desoxiadenosinas , Infecciones por VIH , VIH-1 , Adulto , Fármacos Anti-VIH/uso terapéutico , Desoxiadenosinas/administración & dosificación , Desoxiadenosinas/efectos adversos , Combinación de Medicamentos , Infecciones por VIH/tratamiento farmacológico , Humanos , Lamivudine/uso terapéutico , Piridonas/uso terapéutico , ARN , Inhibidores de la Transcriptasa Inversa/efectos adversos , Tenofovir/uso terapéutico , TriazolesRESUMEN
Islatravir (MK-8591) is a highly potent type 1 human immunodeficiency virus (HIV-1) nucleoside reverse transcriptase translocation inhibitor with a long intracellular half-life that is in development for the prevention and treatment of HIV-1. We conducted a randomized, double-blind, placebo-controlled, phase 1 trial in adults without HIV-1 infection. Participants received islatravir or placebo subdermal implants for 12 weeks and were monitored throughout this period and after implant removal. The co-primary end points were safety and tolerability of the islatravir implant and pharmacokinetics, including concentration at day 85, of islatravir triphosphate in peripheral blood mononuclear cells (PBMCs). Secondary end points included additional pharmacokinetic parameters for islatravir triphosphate in PBMCs and the plasma pharmacokinetic profile of islatravir. Based on preclinical data, two doses were assessed: 54 mg (n = 8, two placebo) and 62 mg (n = 8, two placebo). The most frequently reported adverse events were mild-to-moderate implant-site reactions (induration, hematoma, pain). Throughout the 12-week trial, geometric mean islatravir triphosphate concentrations were above a pharmacokinetic threshold of 0.05 pmol per 106 PBMCs, which was estimated to provide therapeutic reverse transcriptase inhibition (concentration at day 85 (percentage of geometric coefficient of variation): 54 mg, 0.135 pmol per 106 cells (27.3); 62 mg, 0.272 pmol per 106 cells (45.2)). Islatravir implants at both doses were safe and resulted in mean concentrations above the pharmacokinetic threshold through 12 weeks, warranting further investigation of islatravir implants as a potential HIV prevention strategy.
Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Desoxiadenosinas/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Adulto , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/farmacocinética , Desoxiadenosinas/efectos adversos , Desoxiadenosinas/farmacocinética , Método Doble Ciego , Infecciones por VIH/genética , Infecciones por VIH/virología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , VIH-1/patogenicidad , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Masculino , Persona de Mediana Edad , Placebos , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/farmacocinética , Replicación Viral/efectos de los fármacosRESUMEN
Islatravir (MK-8591) is a nucleoside analogue in development for the treatment and prevention of HIV-1. Two phase 1 trials were conducted during initial evaluation of islatravir: rising single doses (Study 1) and rising multiple doses (Study 2) of oral islatravir in male and female participants without HIV (aged 18-60 years). Safety, tolerability, and pharmacokinetics of islatravir (plasma) and islatravir-triphosphate (peripheral blood mononuclear cells) were assessed. In Study 1, 24 participants, assigned to 1 of 3 panels, received alternating single doses of islatravir in a fasted state from 5 mg to 400 mg, or placebo, over 3 dosing periods; a 30 mg dose was additionally assessed following a high-fat meal. In Study 2, 8 participants per dose received 3 once-weekly doses of 10, 30, or 100 mg islatravir or placebo in a fasted state. For each panel in both trials, 6 participants received active drug and 2 received placebo. Islatravir was generally well-tolerated, with no serious adverse events or discontinuations due to adverse events. Islatravir was rapidly absorbed (median time to maximum plasma concentration 0.5 hours); plasma half-life was 49-61 h; intracellular islatravir-triphosphate half-life was 118-171 h. Plasma exposure increased in an approximately dose-proportional manner; there was no meaningful food effect. There was a modest degree of intracellular islatravir-triphosphate accumulation after multiple weekly dosing. After single oral doses of islatravir greater than or equal to 5 mg, intracellular islatravir-triphosphate levels were comparable to levels associated with efficacy in preclinical studies. These results warrant continued clinical investigation of islatravir.
Asunto(s)
Fármacos Anti-VIH/efectos adversos , Desoxiadenosinas/efectos adversos , Administración Oral , Adolescente , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Desoxiadenosinas/administración & dosificación , Desoxiadenosinas/farmacocinética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Semivida , Voluntarios Sanos , Humanos , Leucocitos Mononucleares , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVES: Islatravir (MK-8591) is a novel nucleoside analogue in development for the treatment and prevention of HIV-1 infection. Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1 infection. This study evaluated the pharmacokinetics, safety, and tolerability of islatravir and doravirine coadministration in a double-blind, placebo-controlled, randomized, fixed-sequence study. METHODS: Adult participants without HIV infection were administered oral doravirine 100 mg (n = 10) or placebo (n = 4) once daily (QD) for 5 days, immediately followed by oral islatravir 2.25 mg (n = 10) or placebo QD (n = 4) for 14 days; islatravir 2.25 mg and doravirine 100 mg QD, or placebo QD, were then coadministered for 5 days. Pharmacokinetic and safety data were collected. RESULTS: Doravirine geometric least-squares mean ratios (90% confidence intervals (CIs)) of (doravirine + islatravir)/doravirine for the area under the plasma drug concentration-time curve over 24 h (AUC0-24h), maximum plasma concentration (Cmax), and plasma concentration at 24 h post-dose (C24h) were not meaningfully impacted. Islatravir geometric least-squares mean ratios (90% CI) of (islatravir + doravirine)/islatravir for AUC0-24h and Cmax were both close to unity, 1.06 (1.01, 1.12) and 1.08 (0.91, 1.27), respectively. All study regimens were generally well tolerated. CONCLUSION: These results indicate that coadministration of islatravir and doravirine had no clinically meaningful effect on the pharmacokinetics of either drug, and support further clinical investigation of islatravir in combination with doravirine for the treatment of HIV-1 infection.
Asunto(s)
Desoxiadenosinas/administración & dosificación , Piridonas/administración & dosificación , Triazoles/administración & dosificación , Administración Oral , Adulto , Área Bajo la Curva , Desoxiadenosinas/efectos adversos , Desoxiadenosinas/sangre , Desoxiadenosinas/farmacocinética , Método Doble Ciego , Esquema de Medicación , Interacciones Farmacológicas , Femenino , Semivida , Humanos , Análisis de los Mínimos Cuadrados , Masculino , Persona de Mediana Edad , Efecto Placebo , Piridonas/efectos adversos , Piridonas/sangre , Piridonas/farmacocinética , Curva ROC , Somnolencia , Triazoles/efectos adversos , Triazoles/sangre , Triazoles/farmacocinética , Adulto JovenRESUMEN
Islatravir (ISL; 4'-ethynyl-2-fluoro-2'-deoxyadenosine or EFdA) is a novel reverse transcriptase translocation inhibitor and has a unique structure and high antiviral activity against wild-type and multidrug resistant HIV strains. In this study, we investigated whether islatravir (ISL) can cause kidney damage compared to tenofovir disoproxil fumarate (TDF) and tenofovir (TFV). We also investigated interactions of these drugs with organic anion transporters (OATs). There is a large gap in ISL concentration between the pharmacological dose to proximal tubular cells and the clinical dose. ISL is unlikely to be taken up via OAT1 or OAT3; therefore, OAT1 and OAT3 may not be involved in the injury to tubular cells. Present data strongly suggests that ISL is not toxic to proximal tubules because blood levels of ISL are not high enough to cause kidney damage in the clinical setting.
Asunto(s)
Desoxiadenosinas/efectos adversos , Desoxiadenosinas/metabolismo , Túbulos Renales Proximales/efectos de los fármacos , Transportadores de Anión Orgánico/metabolismo , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/metabolismo , Lesión Renal Aguda/etiología , Células Cultivadas , Desoxiadenosinas/sangre , Relación Dosis-Respuesta a Droga , HumanosRESUMEN
BACKGROUND: Islatravir (also known as ISL and MK-8591) is a unique nucleoside reverse transcriptase translocation inhibitor in clinical development for treatment of people with HIV-1 infection. In preclinical studies, intracellular islatravir-triphosphate exhibits a long half-life and prolonged virological effects. In this study, we aimed to assess islatravir safety, pharmacokinetics, and antiretroviral activity in treatment-naive adults with HIV-1 infection. METHODS: This open-label, consecutive-panel, phase 1b trial was done at Charité Research Organisation (Berlin, Germany) and included men and women (aged 18-60 years, inclusive) with HIV-1 infection who were ART naive. Participants were required to have plasma HIV-1 RNA counts of at least 10â000 copies per mL within 30 days before the trial treatment phase, without evidence of resistance to nucleoside reverse transcriptase inhibitors. Participants were enrolled in one of five consecutive dosing panels, receiving a single oral dose of islatravir (0·5-30 mg). The primary outcomes were safety and tolerability of islatravir and change from baseline in HIV-1 plasma RNA; secondary outcomes were islatravir plasma and islatravir-triphosphate intracellular pharmacokinetics. We obtained descriptive safety and pharmacokinetics statistics, and estimated efficacy results from a longitudinal data analysis model. This study is registered with ClinicalTrials.gov, NCT02217904, and EudraCT, 2014-002192-28. FINDINGS: Between Sept 17, 2015, and May 11, 2017, we enrolled 30 participants (six per panel). Islatravir was generally well tolerated. 27 (90%) participants had 60 adverse events after receipt of drug, of which 21 (35%) were deemed to be drug related. The most common (n>1) drug-related adverse events were headache (in nine [30%] participants) and diarrhoea (in two [7%]). No serious adverse events were reported, and no participants discontinued due to an adverse event. Plasma islatravir pharmacokinetics and intracellular islatravir-triphosphate pharmacokinetics were approximately dose proportional. The islatravir-triphosphate intracellular half-life was 78·5-128·0 h. Least-squares mean HIV-1 RNA at 7 days after dose decreased from 1·67 log10 copies per mL (95% CI 1·42-1·92) at 10 mg dose to 1·20 log10 copies per mL (0·95-1·46) at 0·5 mg dose. No genetic changes consistent with development of viral resistance were detected. INTERPRETATION: Single doses of islatravir as low as 0·5 mg significantly suppressed HIV-1 RNA by more than 1·0 log at day 7 in treatment-naive adults with HIV-1 infection and were generally well tolerated, supporting the further development of islatravir as a flexible-dose treatment for individuals with HIV-1 infection. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc, Kenilworth, NJ, USA.
Asunto(s)
Fármacos Anti-VIH/farmacocinética , Desoxiadenosinas/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Transcriptasa Inversa/farmacocinética , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Desoxiadenosinas/administración & dosificación , Desoxiadenosinas/efectos adversos , Femenino , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/enzimología , VIH-1/fisiología , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/efectos adversos , Adulto JovenAsunto(s)
Desoxiadenosinas/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Adulto , Desoxiadenosinas/efectos adversos , Femenino , Infecciones por VIH/prevención & control , Inhibidores de Integrasa VIH/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Masculino , Oxazinas , Piperazinas , Piridonas , Enfermedades Prevenibles por Vacunación/inmunologíaRESUMEN
BACKGROUND: The aim of the present study was to investigate whether cordycepin prevented adhesion formation in a rat model. METHODS: Rats were randomly assigned to 3 groups of 10 rats. CONTROL GROUP: The absence of adhesion was confirmed via laparotomy. Adhesion group: The cecum was removed from the abdomen and scraped with a dry gauze bandage until petechial hemorrhagic foci developed. Cordycepin group: The same surgical procedure was performed as in the adhesion group, and 10 mg/kg cordycepin was administered intraperitoneally. After 15 days, the rats were sacrificed humanely via cardiac blood withdrawal under anesthesia. The rats were then analyzed morphologically and histopathologically, and hydroxyproline (OH-p) and malondialdehyde (MDA) levels were measured. RESULTS: Macroscopic analysis revealed significantly less adhesion in the cordycepin group than in the adhesion group (p<0.01). Furthermore, significant histopathological improvement was also evident in the cordycepin group compared to the adhesion group (p<0.05). The levels of OH-p and MDA in blood and tissue were higher in the adhesion group than in the control group, and lower in the cordycepin group than the adhesion group. Interestingly, MDA level was significantly lower (blood: p<0.05; tissue: p<0.01) in the cordycepin group than in the adhesion group, whereas only tissue OH-p was significantly lower in the cordycepin group compared with the adhesion group (p<0.05). One rat in both adhesion group and cordycepin group died postoperatively. CONCLUSION: Results indicated that cordycepin effectively reduced adhesion in a rat abrasion model. Thus, this agent may be valuable to prevent postoperative adhesion.
Asunto(s)
Cavidad Abdominal/cirugía , Desoxiadenosinas , Adherencias Tisulares , Animales , Desoxiadenosinas/efectos adversos , Desoxiadenosinas/uso terapéutico , Distribución Aleatoria , Ratas , Adherencias Tisulares/tratamiento farmacológico , Adherencias Tisulares/prevención & controlRESUMEN
Cordyceps militaris is a mushroom traditionally used for diverse pharmaceutical purposes in East Asia, including China, and has been found to be effective for enhancing immunity through various types of animal testing. The aim of this study is to determine the efficacy of C. militaris for enhancing cell-mediated immunity and its safety in healthy male adults. Healthy male adults were divided into the experimental group (n = 39), given 1.5 g/day of ethanol treated C. militaris in capsules, and the control group (n = 40), given the same number of identical placebo capsules filled with microcrystalline cellulose and lactose for 4 weeks from February 13 to March 14, 2012; the natural killer (NK) cell activity, lymphocyte proliferation index (PI), and T-helper cell 1 (Th1) cytokine cluster (interferon [IFN]-γ, interleukin [IL]-12, IL-2, and tumor necrosis factor [TNF]-α) were measured, along with stability test, at weeks 0, 2, and 4. The C. militaris group showed a statistically significant greater increase in NK200 (P = .0010), lymphocyte PI (P ≤ .0001), IL-2 (P = .0096), and IFN-γ (P = .0126), compared with the basal level, than the placebo group. There was no statistically significant adverse reaction. C. militaris enhanced the NK cell activity and lymphocyte proliferation and partially increased Th1 cytokine secretion. Therefore, C. militaris is safe and effective for enhancing cell-mediated immunity of healthy male adults.
Asunto(s)
Cordyceps/química , Desoxiadenosinas/administración & dosificación , Inmunidad Celular/efectos de los fármacos , Adulto , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citocinas/sangre , Desoxiadenosinas/efectos adversos , Método Doble Ciego , Etanol , Humanos , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Leucemia Eritroblástica Aguda , Activación de Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Placebos , República de Corea , Células TH1/efectos de los fármacos , Células TH1/inmunología , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Cordyceps militaris has long been used in prescriptions of traditional Chinese medicine as a tonic for the treatment of metabolic syndrome. Cordycepin with proven immunomodulatory, antitumor, and hepatoprotective properties is the main active metabolite of C militaris. Diabetes mellitus is a group of metabolic diseases in which the body is unable to regulate blood sugar levels. Hence, we hypothesized that cordycepin can normalize blood sugar levels and improve the indicators of diabetes. The aim of this study was to investigate the possible effects of cordycepin from C militaris on diabetes in an alloxan-induced diabetic mouse model. Diabetic mice were intraperitoneally administered different doses of cordycepin (8, 24, and 72 mg/kg body weight) daily for 21 days. Acute toxicity test on normal mice was carried out by giving them maximum tolerance dose of cordycepin (3600 mg/kg) daily. A 47% reduction of the blood glucose level, 214% increase of hepatic glycogen content, and significant improvement of oral glucose tolerance were noticed after the effective dose of cordycepin was administered. Polyphagia and polydipsia, the typical symptoms of diabetes, were partly alleviated. Moreover, cordycepin offered protective effects against diabetes-related kidney and spleen injury. Maximum tolerance dose test indicated that cordycepin at the large dose of 3600 mg/kg did not show significant effect on body weight and major organ in normal mice after intraperitoneal administration for 14 days. The results showed that cordycepin from C militaris that elicited hypoglycemic activity contributes to the regulation of glucose metabolism in liver in alloxan-induced diabetic mice. Therefore, a cordycepin treatment during diabetes can improve some of the metabolic syndrome symptoms by regulation of glucose absorption in vivo. Cordycepin may serve as a therapeutic agent in the treatment of diabetes and its related complications.
Asunto(s)
Cordyceps/química , Desoxiadenosinas/uso terapéutico , Complicaciones de la Diabetes/prevención & control , Diabetes Mellitus Experimental/tratamiento farmacológico , Hiperglucemia/prevención & control , Hipoglucemiantes/uso terapéutico , Aloxano , Animales , Animales no Consanguíneos , Glucemia/análisis , Desoxiadenosinas/administración & dosificación , Desoxiadenosinas/efectos adversos , Desoxiadenosinas/aislamiento & purificación , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Relación Dosis-Respuesta a Droga , Etnofarmacología , Femenino , Hiperfagia/complicaciones , Hiperfagia/prevención & control , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/aislamiento & purificación , Inyecciones Intraperitoneales , Glucógeno Hepático/agonistas , Glucógeno Hepático/metabolismo , Medicina Tradicional China , Ratones , Polidipsia/complicaciones , Polidipsia/prevención & control , Distribución Aleatoria , Organismos Libres de Patógenos Específicos , Pruebas de Toxicidad AgudaRESUMEN
Cordycepin (Cor), which is a naturally occurring nucleoside derivative isolated from Cordyceps militaris, has been shown to exert excellent antiinflammatory activity in a murine model of acute lung injury. Thus, this study aimed to evaluate the antiasthmatic activity of Cor (10, 20, and 40 mg/kg) and to investigate the possible underlying molecular mechanisms. We found that Cor attenuated airway hyperresponsiveness, mucus hypersecretion, and ovalbumin (Ova)-specific immunoglobulin (Ig) E, and alleviated lung inflammation with decreased eosinophils and macrophages in the bronchoalveolar lavage (BAL) fluid. Notably, Cor reduced the upregulation of eotaxin, intercellular cell adhesion molecule-1 (ICAM-1), IL-4, IL-5, and IL-13 in the BAL fluid. Furthermore, Cor markedly blocked p38-MAPK and nuclear factor-kappaB (NF-κB) signalling pathway activation in the Ova-driven asthmatic mice. In conclusion, this study demonstrated that some of the antiasthmatic benefits of Cor attributable to diets and/or tonics may result from reductions in inflammatory processes and that these antiasthmatic properties involve the inhibition of Th2-type responses through the suppression of the p38-MAPK and NF-κB signalling pathways.
Asunto(s)
Antiinflamatorios/administración & dosificación , Asma/tratamiento farmacológico , Hiperreactividad Bronquial/tratamiento farmacológico , Cordyceps/inmunología , Desoxiadenosinas/administración & dosificación , Eosinófilos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Neumonía/tratamiento farmacológico , Animales , Antiinflamatorios/efectos adversos , Asma/inmunología , Hiperreactividad Bronquial/inmunología , Citocinas/metabolismo , Desoxiadenosinas/efectos adversos , Eosinófilos/inmunología , Humanos , Inmunoglobulina E/sangre , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Moco/metabolismo , FN-kappa B/metabolismo , Neumonía/inmunología , Transducción de Señal/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Cytotoxic nucleoside analogues were the first chemotherapeutic agents for cancer treatment. Cordycepin, an active ingredient of the insect fungus Cordyceps militaris, is a category of compounds that exhibit significant therapeutic potential. Cordycepin has many intracellular targets, including nucleic acid (DNA/RNA), apoptosis and cell cycle, etc. Investigations of the mechanism of anti-cancer drugs have yielded important information for the design of novel drug targets in order to enhance anti-tumor activity with less toxicity to patients. This extensive review covers various molecular aspects of cordycepin interactions with its recognized cellular targets and proposes the development of novel therapeutic strategies for cancer treatment.
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Antineoplásicos/farmacología , Desoxiadenosinas/farmacología , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/efectos adversos , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Cordyceps/química , Desoxiadenosinas/efectos adversos , Desoxiadenosinas/aislamiento & purificación , Diseño de Fármacos , Humanos , Terapia Molecular Dirigida , Neoplasias/patologíaRESUMEN
3'-Deoxyadenosine, so-called cordycepin, is a bioactive component of the fungus Cordyceps militaris. It has been known to exhibit multiple-biological effects including: modulation of immune response, inhibition of tumor growth, hypotensive and vasorelaxation activities, and promoting secretion of adrenal hormone. To investigate its lipid-lowering effect, hyperlipidemic hamsters and rats fed by high-fat diet were both administered orally with cordycepin extracted from Cordyceps militaris for four weeks. The levels of lipids in hamsters and rats were measured enzymatically before and after the administration of cordycepin (12.5, 25 and 50 mg x kg(-1)). The results suggested that levels of serum total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and very low density lipoprotein cholesterol (VLDL-C) increased markedly in the two animal models by feeding high-fat diet. Meanwhile, cordycepin reduced levels of serum TC, TG, LDL-C, VLDL-C as well as LDL-C/HDL-C (high density lipoprotein cholesterol) and TC/HDL-C ratios. In concert with these effects, an increase in lipoprotein lipase (LPL) and hepatic lipase (HL) activity afforded by cordycepin was considered to contribute to the regulation on lipid profiles. Furthermore, no toxicity of cordycepin was observed by intragastric administration at the maximal tolerant dose in ICR mice for 14 days. The exact lipid-lowering effect of cordycepin needs further investigation.
Asunto(s)
Cordyceps/química , Desoxiadenosinas/farmacología , Hiperlipidemias/sangre , Hipolipemiantes/farmacología , Lípidos/sangre , Animales , Colesterol/sangre , LDL-Colesterol/sangre , VLDL-Colesterol/sangre , Cricetinae , Desoxiadenosinas/efectos adversos , Desoxiadenosinas/aislamiento & purificación , Hipolipemiantes/aislamiento & purificación , Lipasa/sangre , Lipoproteína Lipasa/sangre , Masculino , Mesocricetus , Ratones , Ratones Endogámicos ICR , Ratas , Ratas Wistar , Triglicéridos/sangreRESUMEN
The aim of this study was to assess the outcome of treatment with 2-chlorodeoxyadenosine (2-CdA) in pediatric patients with Langerhans cell histiocytosis (LCH) in Japan. We retrospectively identified 17 pediatric LCH patients treated with 2-CdA. All patients were refractory or reactivated cases who had been initially treated according to the JLSG-02 protocol of the Japan LCH study group. At initiation of 2-CdA therapy, 4 patients had primary refractory multisystem (MS) disease with risk organ (RO) involvement (MS+), 9 patients had reactivated MS disease [5 MS+ and 4 without RO involvement (MS-)], and the remaining 4 patients had refractory/reactivated multifocal bone disease (MFB). Treatment with 2-CdA (4-9 mg/m(2)/day) was administered on 2-5 consecutive days and repeated every 3-4 weeks for a period that ranged from 2 to 12 months. Four primary refractory patients were treated with 2-CdA combined with high dose of cytarabine. In MS+ patients, response to treatment was observed in 5 of the 9 patients. In MS-/MFB patients, 5 of the 8 patients showed response to treatment. In the patients who were primary refractory or had reactivation during initial chemotherapy, 4 of 10 patients showed good response. On the other hand, in the patients having reactivation while off therapy, 6 of 7 patients showed good response. These findings suggest that 2-CdA is effective for reactivated LCH while off therapy.
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2-Cloroadenosina/análogos & derivados , Antimetabolitos Antineoplásicos/administración & dosificación , Recolección de Datos , Desoxiadenosinas/administración & dosificación , Histiocitosis de Células de Langerhans/tratamiento farmacológico , 2-Cloroadenosina/administración & dosificación , 2-Cloroadenosina/efectos adversos , Antimetabolitos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Preescolar , Citarabina/administración & dosificación , Citarabina/efectos adversos , Desoxiadenosinas/efectos adversos , Resistencia a Antineoplásicos , Femenino , Humanos , Lactante , Recién Nacido , Japón , Masculino , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
Rac is a protein involved in the various functions of macrophages (Mphi), including the production of reactive oxygen species (ROS), phagocytosis, chemotaxis and the secretion of cytokines (such as gamma-INF). This study tested the effects of nucleosides containing 8-oxoguanine(8-hydroxyguanine) such as 8-oxo-2'-guanosine (8-oxoG) or 8-oxo-2'-deoxyguanosine (8-oxodG), on Rac and the above-listed Rac-associated functions of Mphi using mouse peritoneal Mphi (MpMphi). It is reported that 8-oxodG was able to effectively inhibit Rac and the Rac-associated functions of MpMphi. Compared to 8-oxodG, 8-oxoG showed negligible effects. Furthermore, normal nucleosides such as deoxyguanosine (dG), guanosine (G) and adenosine (A) did not exert any effects. These results suggest that 8-oxodG could be used as a potential tool to modulate the functions of Mphi that are intimately related to various pathological processes.
Asunto(s)
Desoxiadenosinas/farmacología , Macrófagos/efectos de los fármacos , Proteínas de Unión al GTP rac/antagonistas & inhibidores , Proteínas de Unión al GTP rac/fisiología , Animales , Células Cultivadas , Quimiotaxis/efectos de los fármacos , Desoxiadenosinas/efectos adversos , Evaluación Preclínica de Medicamentos , Interferón gamma/metabolismo , Macrófagos/metabolismo , Macrófagos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , NADPH Oxidasas/metabolismo , Fagocitosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Proteínas de Unión al GTP rac/metabolismoRESUMEN
The nucleoside analogue cordycepin (3 '-deoxyadenosine, 3 '-dA), one of the components of Cordyceps militaris, has been shown to inhibit the growth of various tumor cells. However, the probable mechanism is still obscure. In this study, the inhibition of cell growth and changes in protein expression induced by cordycepin were investigated in BEL-7402 cells. Using the MTT assay and flow cytometry, we found that cordycepin inhibits cell viability and induces apoptosis in BEL-7402 cells. Additionally, the proteins were separated using two-dimensional polyacrylamide gel electrophoresis, and eight proteins were found to be significantly affected by cordycepin compared to untreated control; among them, two were downregulated and six were upregulated. Of the eight proteins, six were identified with peptide mass fingerprinting using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) after in-gel trypsin digestion. These proteins are involved in various aspects of cellular metabolism. It is suggested that the effect of cordycepin on the growth of tumor cells is significantly related to the metabolism-associated protein expression induced by cordycepin.
Asunto(s)
Antifúngicos/efectos adversos , Carcinoma Hepatocelular/genética , Desoxiadenosinas/efectos adversos , Expresión Génica/efectos de los fármacos , Proteómica/métodos , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Dermatoglifia del ADN , Electroforesis en Gel Bidimensional , Humanos , Espectrometría de Masas , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Tripsina/químicaRESUMEN
BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disorder characterized by clonal proliferation of immature and abnormal bone marrow derived langerhans cells. Treatment is usually multimodal. Potent anti-monocyte as well as immunomodulatory activity of 2-CDA and its proven efficacy in many lymphoproliferative disorders has made 2-CDA a rational choice in treatment of LCH. AIM: To evaluate the efficacy and toxicity profile of 2-CDA in children with relapsed or refractory LCH. SETTING AND DESIGN: This is a pilot study and we present the initial data of the first seven patients treated at our institution. MATERIALS AND METHODS: Seven patients of relapsed and refractory LCH were enrolled from July 2000 to June 2004. The cohort of seven patients included six males and one female with a median age at initiation of cladribine was 2.25 years (range, 1.67 to 7.0 years). Three patients had received one prior chemotherapy regimen while the rest were heavily pretreated. Cladribine was administered over two hours IV daily for five days and repeated every four weeks. RESULTS: After a median of six courses of cladribine (range, 2 to 9), two (33%) patients achieved PR and two (33%) patients have SD on imaging but are clinically better. None experienced grade 3 or 4 hematologic toxicity. At a median follow-up of 19 months (range, 8 to 52 months), five patients remain alive and one patient has died. CONCLUSION: Our study shows that single agent 2-CDA is active and well-tolerated in children with relapsed or refractory LCH.
Asunto(s)
2-Cloroadenosina/análogos & derivados , Antimetabolitos Antineoplásicos/uso terapéutico , Cladribina/uso terapéutico , Desoxiadenosinas/uso terapéutico , Histiocitosis de Células de Langerhans/tratamiento farmacológico , 2-Cloroadenosina/efectos adversos , 2-Cloroadenosina/inmunología , 2-Cloroadenosina/uso terapéutico , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/inmunología , Antineoplásicos/efectos adversos , Antineoplásicos/inmunología , Antineoplásicos/uso terapéutico , Preescolar , Cladribina/efectos adversos , Cladribina/inmunología , Desoxiadenosinas/efectos adversos , Desoxiadenosinas/inmunología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Histiocitosis de Células de Langerhans/inmunología , Histiocitosis de Células de Langerhans/fisiopatología , Humanos , Lactante , Masculino , Proyectos Piloto , Estudios Prospectivos , Factores de TiempoRESUMEN
Splenic Marginal Zone Lymphoma (SMZL) is a rare clinicopathological entity among marginal zone lymphomas. SMZL is an indolent lymphoma usually treated by splenectomy. A subset of patients is characterized by a more aggressive clinical course and poor prognosis. Treatment of these cases and second-line therapy for relapsed patients have not been yet identified. We report 10 cases treated with cladribrine (5 mg/m(2)/week) for six courses. Six patients (60%) achieved partial response, two patients (20%) achieved a complete response and the two remaining patients did not respond and died as a result of progression of the disease. The treatment was well tolerated. A total of 60% of the patients had an overall survival rate of 48 months and 24 months progression-free-survival was achieved by 37% with a median time of progression-free-survival of 17 months. Interestingly, in addition to a relevant percentage of hematological remission, some patients also experienced a molecular remission. We conclude that this treatment is safe and well tolerated and is able to induce a substantial number of responses. Our results suggest that this schedule is well tolerated and could be an useful alternative to splenectomy.
Asunto(s)
2-Cloroadenosina/análogos & derivados , 2-Cloroadenosina/uso terapéutico , Antimetabolitos Antineoplásicos/uso terapéutico , Desoxiadenosinas/uso terapéutico , Linfoma/tratamiento farmacológico , Neoplasias del Bazo/tratamiento farmacológico , 2-Cloroadenosina/efectos adversos , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/efectos adversos , Desoxiadenosinas/efectos adversos , Femenino , Humanos , Linfoma/mortalidad , Linfoma/cirugía , Persona de Mediana Edad , Esplenectomía , Neoplasias del Bazo/mortalidad , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
INTRODUCTION: Hairy cell leukaemia (HCL) is a rare lymphoproliferative disorder. Treatment options available are splenectomy, interferon, DCF and 2-CdA. 2-CdA is considered to have curative potential as proved by the other studies. METHODS: We gave 2-CdA in a dose of 0.09/kg/day as a continuous infusion in sixteen patients of hairy cell leukaemia. RESULTS: Three patients developed neutropenia post transfusion. At the end of three months all patients were in remission. Two patients relapsed at the median follow-up of 15 months. CONCLUSION: 2-CdA in HCL can achieve complete remission, prolonged survival and care as well.
Asunto(s)
2-Cloroadenosina/uso terapéutico , Antimetabolitos Antineoplásicos/uso terapéutico , Desoxiadenosinas/uso terapéutico , Leucemia de Células Pilosas/tratamiento farmacológico , Leucemia de Células Pilosas/mortalidad , 2-Cloroadenosina/efectos adversos , 2-Cloroadenosina/análogos & derivados , Adulto , Antimetabolitos Antineoplásicos/efectos adversos , Desoxiadenosinas/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Peliosis hepatis is an unusual disorder associated with a variety of diseases and treatments. This is the first report of peliosis hepatis associated with administration of 2-chloro-3'-deoxyadenosine. The literature is reviewed.