RESUMEN
Phase II studies on tauro-urso-deoxycholic acid (TUDCA) raised the promise of safety and efficacy in patients with amyotrophic lateral sclerosis, a currently incurable and devastating disease. We review the available evidence on the efficacy and safety of TUDCA, administered alone or in combination, by analyzing and comparing published and ongoing studies on amyotrophic lateral sclerosis. Two independent phase II studies (using TUDCA solo or combined with sodium phenylbutyrate) showed similar efficacy in slowing disease progression measured by functional scales. One open-label follow-up TUDCA+sodium phenylbutyrate study suggested a benefit on survival. Two subsequent phase III studies with TUDCA (solo or combined with sodium phenylbutyrate) have been initiated and are currently ongoing. Their completion is expected by the end of 2023 and beginning of 2024. Evidence collected by phase II studies indicates that there are no safety concerns in patients with amyotrophic lateral sclerosis. The efficacy shown in phase II studies was considered sufficient to grant approval in some countries but not in others, owing to discrepant views on the strength of evidence. It will be necessary to wait for the results of ongoing phase III studies to attain a full appreciation of these data.
Asunto(s)
Esclerosis Amiotrófica Lateral , Humanos , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Fenilbutiratos , Ácido Tauroquenodesoxicólico/efectos adversosRESUMEN
BACKGROUND AND PURPOSE: Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is produced in the liver and used for treatment of chronic cholestatic liver diseases. Experimental studies suggest that TUDCA may have cytoprotective and anti-apoptotic action, with potential neuroprotective activity. A proof of principle approach was adopted to provide preliminary data regarding the efficacy and tolerability of TUDCA in a series of patients with amyotrophic lateral sclerosis (ALS). METHODS: As a proof of principle, using a double-blind placebo controlled design, 34 ALS patients under treatment with riluzole who were randomized to placebo or TUDCA (1 g twice daily for 54 weeks) were evaluated after a lead-in period of 3 months. The patients were examined every 6 weeks. The primary outcome was the proportion of responders [those subjects with improvement of at least 15% in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) slope during the treatment period compared to the lead-in phase]. Secondary outcomes included between-treatment comparison of ALSFRS-R at study end, comparison of the linear regression slopes for ALSFFRS-R mean scores and the occurrence of adverse events. RESULTS: Tauroursodeoxycholic acid was well tolerated; there were no between-group differences for adverse events. The proportion of responders was higher under TUDCA (87%) than under placebo (P = 0.021; 43%). At study end baseline-adjusted ALSFRS-R was significantly higher (P = 0.007) in TUDCA than in placebo groups. Comparison of the slopes of regression analysis showed slower progression in the TUDCA than in the placebo group (P < 0.01). CONCLUSIONS: This pilot study provides preliminary clinical data indicating that TUDCA is safe and may be effective in ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Evaluación de Resultado en la Atención de Salud , Riluzol/uso terapéutico , Ácido Tauroquenodesoxicólico/farmacología , Adulto , Anciano , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/efectos adversos , Proyectos Piloto , Ácido Tauroquenodesoxicólico/administración & dosificación , Ácido Tauroquenodesoxicólico/efectos adversosRESUMEN
We previously demonstrated that tauroursodeoxycholic acid (TUDCA) improved the developmental competence of mouse embryos by attenuating endoplasmic reticulum (ER) stress-induced apoptosis during preimplantation development. Here, we present a follow-up study examining whether TUDCA enhances the implantation and live-birth rate of mouse embryos. Mouse 2-cell embryos were collected by oviduct flushing and cultured in the presence or absence of 50 µM TUDCA. After culture (52 h), blastocysts were transferred to 2.5-day pseudopregnant foster mothers. It was found that the rates of pregnancy and implantation as well as the number of live pups per surrogate mouse were significantly higher in the TUDCA-treated group compared to the control group, but there was no significant difference in the mean weights of the pups or placentae. Thus, we report for the first time that TUDCA supplementation of the embryo culture medium increased the implantation and livebirth rates of transferred mouse embryos.
Asunto(s)
Blastómeros/efectos de los fármacos , Ectogénesis/efectos de los fármacos , Transferencia de Embrión , Fármacos para la Fertilidad Femenina/farmacología , Ácido Tauroquenodesoxicólico/farmacología , Animales , Peso al Nacer/efectos de los fármacos , Blastocisto/efectos de los fármacos , Cruzamientos Genéticos , Técnicas de Cultivo de Embriones , Femenino , Fármacos para la Fertilidad Femenina/efectos adversos , Tamaño de la Camada/efectos de los fármacos , Nacimiento Vivo , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Endogámicos ICR , Concentración Osmolar , Placentación/efectos de los fármacos , Embarazo , Técnicas Reproductivas Asistidas/instrumentación , Ácido Tauroquenodesoxicólico/efectos adversosRESUMEN
BACKGROUND/AIMS: We examined taurochenodeoxycholic acid-induced hepatotoxicity with reference to Ca2+ and calpain involvement, intracellular bile acid content, and zone specificity in isolated perfused rat liver. METHODOLOGY: Taurochenodeoxycholic acid or chenodeoxycholic acid was infused into the portal vein and lactate dehydrogenase release, a marker of hepatocyte injury, in the effluent and bile acid output were measured in the presence and absence of either nickel, a membranous Ca2+ channel blocker, or calpain inhibitor in isolated perfused rat liver. RESULTS: Taurochenodeoxycholic acid induced a significant and transient increase (first peak; 4 min) and subsequent time- and dose-dependent elevation in lactate dehydrogenase release which was proportional to accumulated bile acids in the liver. Although the first peak was significantly suppressed by pretreatment with nickel, the subsequent release was not reduced. Lactate dehydrogenase release at 15, 20, and 25 min was significantly suppressed by the calpain inhibitor. Numbers of damaged hepatocytes stained with trypan blue were significantly increased in the periportal region (zone 1) compared with the pericentral region (zone 3) and these cells were consistently stained with anti-calpain antibody. CONCLUSIONS: Taurochenodeoxycholic acid causes both transient damage and subsequent increasing hepatotoxicity which are respectively dependent on Ca2+ influx via membranous Ca2+ channels and calpain, with the periportal region being more susceptible.
Asunto(s)
Calcio/fisiología , Calpaína/fisiología , Hígado/efectos de los fármacos , Ácido Tauroquenodesoxicólico/efectos adversos , Animales , Ácidos y Sales Biliares/metabolismo , Hepatocitos/metabolismo , Inmunohistoquímica , Técnicas In Vitro , L-Lactato Deshidrogenasa/metabolismo , Masculino , Modelos Animales , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: The usefulness of ursodeoxycholic acid after liver transplantation is controversial. Tauroursodeoxycholic acid, the natural taurine-amidate, is a highly hydrophilic and cytoprotective bile salt currently under investigation. AIMS: To investigate the clinical usefulness of tauroursodeoxycholic acid after liver transplantation. PATIENTS: Thirty-three patients undergoing liver transplantation entered the study. METHODS: Sixteen patients were randomized to receive tauroursodeoxycholic acid (250 b.i.d. for 12 months) and 17 served as controls. Tauroursodeoxycholic acid was given from day 5 after transplantation for one year. RESULTS: Tauroursodeoxycholic acid treatment was safe and well tolerated. No drop outs occurred. Among the 29 patients undergoing long-term follow-up, five deaths occurred (3 of whom in the tauroursodeoxycholic acid group), none of which was related to treatment. The one-year actuarial survival was 78.6% in patients treated with tauroursodeoxycholic acid and 86.7% in controls (n.s.). No differences were observed with respect to early or late graft function and survival, nor to acute cellular rejection. Tauroursodeoxycholic acid therapy was associated with lower serum cholesterol levels (p < 0.02) during the early postoperative months; with milder cholestasis; with a drop in biliary cholates but no changes in endogenous hydrophobic bile salts. CONCLUSIONS: Long-term treatment with low dose tauroursodeoxycholic acid after liver transplantation is safe but does not affect graft function and survival.
Asunto(s)
Colagogos y Coleréticos/uso terapéutico , Inmunosupresores/uso terapéutico , Trasplante de Hígado , Cuidados Posoperatorios/métodos , Ácido Tauroquenodesoxicólico/uso terapéutico , Adulto , Bilis/química , Bilis/efectos de los fármacos , Quimioterapia Adyuvante , Colagogos y Coleréticos/efectos adversos , Colagogos y Coleréticos/farmacología , Femenino , Estudios de Seguimiento , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/farmacología , Isomerismo , Trasplante de Hígado/fisiología , Trasplante de Hígado/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Cuidados Posoperatorios/estadística & datos numéricos , Ácido Tauroquenodesoxicólico/efectos adversos , Ácido Tauroquenodesoxicólico/farmacología , Factores de TiempoRESUMEN
Taurochenodeoxycholate (TCDC) (or taurocholate, TC) excessively i.v. infused in rats causes an acute cholestasis accompanied by an excessive excretion of various proteins (lactate dehydrogenase, LDH, albumin, etc.) into the bile. This cholestasis was initially found to be effectively prevented by a simultaneous infusion of tauroursodeoxycholate (TUDC). Later this property was found to be shared by glycoursodeoxycholate (GUDC) and tauro (and glyco) alpha and beta-muricholate (MC) all known to be relatively hydrophilic. The extent of the preventative effect appears to be comparable for taurine and glycine conjugates of all three bile salts (UDC, alpha-MC and beta-MC). An albumin leakage into the bile enhanced by TCDC infusion appears to be mainly from albumin in the serum, since i.v. injected 125I-human serum albumin excretion into the bile paralled the rat albumin excretion. Despite very drastic biochemical abnormalities induced by TCDC infusion, morphological correlates in the liver are scarce both from light and electron microscopic examinations, the only correlate with biochemical parameters being a sporadic necrosis of hepatocytes, especially in the periportal areas. Although there is not sufficient morphological evidence, it appears that TCDC infusion causes a direct communication between serum and bile leading to a rapid leakage of large molecules such as albumin and even gamma-globulin. Conjugates of hydrophilic bile salts such as UDC, alpha-MC and beta-MC efficiently prevent such bile abnormalities but their hydrophilicity is not the sole determinant of this property since a more hydrophilic bile salt such as taurodehydrocholate does not possess this property. The underlying mechanism(s) for this protective property remains uncertain.
Asunto(s)
Ácidos y Sales Biliares/farmacología , Hígado/efectos de los fármacos , Ácido Tauroquenodesoxicólico/efectos adversos , Albúminas/metabolismo , Animales , Bilis/metabolismo , Ácidos y Sales Biliares/metabolismo , Colestasis/inducido químicamente , Colestasis/metabolismo , Colestasis/prevención & control , Ácidos Cólicos/farmacología , L-Lactato Deshidrogenasa/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Necrosis , Ratas , Ratas Wistar , Ácido Tauroquenodesoxicólico/farmacologíaRESUMEN
BACKGROUND/AIMS: The effectiveness of ursodeoxycholic acid in treating biliary liver diseases is limited by low bioavailability and moderate activity. A new analogue of ursodeoxycholic acid was synthesized with a fluorine atom in position 6 because this should have resulted in an analogue more hydrophilic than ursodeoxycholic acid but with similar detergency. METHODS: After synthesis, detergency, solubility, and lipophilicity of the 6-fluoro analogue in aqueous solution were determined and compared with those of natural analogues. Stability toward 7-dehydroxylation was assessed in human stools, pharmacokinetics and metabolism were evaluated in bile fistula rats and hamsters, accumulation in bile with long-term feeding was assessed in the hamsters, and the ability to prevent the hepatotoxic effects of taurochenodeoxycholic acid was evaluated in bile fistula rats after intraduodenal coinfusion. RESULTS: 6-Fluoro-ursodeoxycholic acid was more stable than its parent molecule toward 7-dehydroxylation, it was efficiently secreted in bile, and its total recovery was very high. With long-term administration of 6-fluoro-ursodeoxycholic acid, taurine and glycine amidates accounted for more than 60% of the total biliary bile acids (15% ursodeoxycholic acid). The 6-fluoro analogue prevented the hepatotoxic effects of taurochenodeoxycholic acid. CONCLUSIONS: The results suggest that 6-fluoro-ursodeoxycholic acid has considerable potential as a pharmaceutical agent in the treatment of cholestatic liver disease.
Asunto(s)
Hepatopatías/prevención & control , Ácido Tauroquenodesoxicólico/efectos adversos , Ácido Ursodesoxicólico/análogos & derivados , Albúminas/metabolismo , Animales , Bilis/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas , Cricetinae , Concentración de Iones de Hidrógeno , Hepatopatías/metabolismo , Masculino , Mesocricetus , Unión Proteica , Ratas , Ratas Sprague-Dawley , Solubilidad , Ácido Ursodesoxicólico/metabolismo , Ácido Ursodesoxicólico/farmacocinética , Ácido Ursodesoxicólico/farmacologíaRESUMEN
We investigated bile flow and biliary excretion of bile acids in the Eisai hyperbilirubinemic rat, a Sprague-Dawley mutant rat with conjugated hyperbilirubinemia, using both in vivo and in vitro models. In vivo bile flow was lower in Eisai hyperbilirubinemic rats than in the control rats before and after taurocholate was infused. After taurocholate was infused, bile acid output was similar in the Eisai hyperbilirubinemic rats and control rats. In the isolated perfused rat liver, biliary excretion of bile acids was higher in the Eisai hyperbilirubinemic rats than in the control rats after a high-dose infusion of taurocholate (0.33 mumol/min/gm liver). Infusion of taurochenodeoxycholate (0.22 mumol/min/gm liver) did not produce cholestasis and did not reduce the biliary excretion of bile acids in the Eisai hyperbilirubinemic rats. Taurochenodeoxycholate significantly increased the phospholipid/bile acid molar ratio and slightly reduced bile acid-induced alkaline phosphatase output into bile. The release of lactate dehydrogenase from the perfused liver 30 min after the start of the taurochenodeoxycholate infusion was 10 times lower in the Eisai hyperbilirubinemic rats than in the control rats (2.0 +/- 0.8 vs. 28.7 +/- 6.8 mU/min/gm liver). When the isolated perfused rat liver was infused with a 1-min pulse of horseradish peroxidase (25 mg), we observed an early and late peak of biliary excretion of horseradish peroxidase. The Eisai hyperbilirubinemic rats showed a significant increase in the late peak.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Ácidos y Sales Biliares/efectos adversos , Colestasis/inducido químicamente , Hiperbilirrubinemia/metabolismo , Hígado/efectos de los fármacos , Fosfatasa Alcalina/metabolismo , Animales , Bilis/efectos de los fármacos , Bilis/metabolismo , Bilis/fisiología , Ácidos y Sales Biliares/metabolismo , Peroxidasa de Rábano Silvestre , Técnicas In Vitro , L-Lactato Deshidrogenasa/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Fosfolípidos/metabolismo , Ratas , Ratas Mutantes , Ratas Sprague-Dawley , Ácido Tauroquenodesoxicólico/efectos adversos , Ácido Tauroquenodesoxicólico/metabolismo , Ácido Taurocólico/efectos adversos , Ácido Taurocólico/metabolismoRESUMEN
Ursodeoxycholate-induced bicarbonate-rich hypercholeresis was studied in isolated in situ forward- or backward-perfused rat livers. Both spontaneous bile flow and bile acid secretion were similar regardless of the direction of the perfusion. The choleretic effect of tauroursodeoxycholate infusion (400 nmol.min-1.100 g-1 body weight) was not significantly different in forward- or backward-perfused livers either. Ursodeoxycholate infusions at low rate (800 nmol.min-1.100 g-1 body weight) induced similar bile flow, bile acid output and bicarbonate output in both forward- and backward-perfused livers. Net ursodeoxycholate uptake, measured as [14C]ursodeoxycholate uptake over the bile acid infusion period (30 min), was not significantly different during forward- or backward-perfusion (4.8 and 5.1 mumol/g liver, respectively); i.e., approx. 67% of infused dose (approximately 7.5 mumol/g liver per 30 min). A 2-fold increase in the dose of ursodeoxycholate infusion (1600 nmol.min-1.100 g-1 b.wt.) induced additional enhancement in both bile flow and bicarbonate biliary secretion, but not in bile acid uptake or output, in forward-perfused livers. Moreover, infusion of the same dose of ursodeoxycholate to backward-perfused livers had a significantly lower choleretic effect (-29%, p less than 0.001) even though ursodeoxycholate uptake and biliary output were similar regardless of perfusion direction. Net ursodeoxycholate uptake, was only 2.4 mumol/g liver; i.e., approx. 16% of infused dose (approximately 15 mumol/g liver per 30 min). These findings indicate that a process related with the hepatic microanatomy may be involved in the hypercholeretic response to ursodeoxycholate.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Bilis/metabolismo , Hígado/metabolismo , Ácido Ursodesoxicólico/efectos adversos , Animales , Bicarbonatos/metabolismo , Hígado/efectos de los fármacos , Masculino , Perfusión/métodos , Ratas , Ratas Endogámicas , Ácido Tauroquenodesoxicólico/efectos adversosRESUMEN
Bile damage to gastric mucosa may be demonstrated by means of changes in the transmucosal movement of H+ and Na+ ions. In the present study pure 10 mM solutions of taurine and glycine conjugates of chenodeoxycholic acid were instilled into canine Heidenhain pouches. Solutions were prepared at pH 2, 4, and 8, as previous work had shown a greater damaging effect at low pH. The present study confirmed this pH effect, but only with respect to movement of Na+ ion for taurine conjugates. The magnitude of the changes in ionic movements was much greater with pure bile acid solutions than that seen previously with whole bile. These findings are discussed. The greater damage seen below the pKa of the bile acid conjugates suggests that its nonionized form is the more damaging.