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Rats were fed diets containing the same composition of branched-chain amino acids as Livact at concentrations of 0, 2.5, 5.0 and 10.0% ad libitum. The results showed that 2.5% branched-chain amino acid supplementation group was most superior among other supplementation groups in respect of nutritional parameters eg, nitrogen balance, nitrogen balance efficiency, plasma total protein levels and plasma albumin levels, and exhibited an adequate correction of plasma Fischer ratio.
Rats were fed free access to diets supplemented with different branched-chain amino acids composition ratios as follows: L-isoleucine:L-leucine:L-valine composition ratio, I (2:1:1), II (1:2:1.2), and III (1:1:2). The results revealed that rats receiving the diet containing the same branched-chain amino acids composition (II) as Livact displayed better about nitrogen balance, plasma total protein levels and plasma albumin levels than the other composition ratio groups, and exhibited an adequate correction of plasma Fischer ratio.
Rats were fed ad libitum on diets supplemented with the same branched-chain amino acid composition as Livact or with a combination of essential amino acids comparable to Livact in terms of nitrogen and energy quantities. Greater nutritional effects were observed in the branched-chain amino acid diet group, compared with the essential amino acid diet group. In addition, suppression of thrombocytopenia and of decrease in liver weight was evident in the branched-chain amino acid diet group.
The effect of Livact was examined in rats with portocaval shunt as an animal model of hepatic encephalopathy. Plasma and brain amino acid concentrations and the brain monoamine level normalized in rats receiving the branched-chain amino acids as Livact, whereas a trend of aggravation rather than improvement was observed in rats administered a combination of essential amino acids equivalent in nitrogen quantity and amount of energy to Livact.
Clinical Studies: A 6-month open clinical trial performed in hypoalbuminemic patients with decompensated hepatic cirrhosis revealed resolution of hypoalbuminemia as indicated by increased serum albumin levels, improvement in nutritional parameters eg, serum total protein, transferrin and body weight, and improvement of malaise and fatigability during 2-weeks to 2-month period of the study treatment. Subsidence in ascites was noted at the fifth month. These improvements kept until the completion of the study. The usefulness rate of Livact, determined based on overall assessment of data regarding subjective symptom, objective symptom, nutriture, psychoneurological symptoms, quality of life, and safety, was 51.2% (104/203 patients). A subsequent survey on prognosis of these patients revealed a more favorable life prognosis in those showing improvement in nutriture after the study and in patients receiving long-term Livact therapy.
A 12-week double-blind placebo-controlled clinical study was conducted in hypoalbuminemic patients with decompensated hepatic cirrhosis. Treatment with Livact increased the serum albumin level, the primary endpoint, by 0.2 g/dL on average, and 31.5% of patients treated (17/54 patients) showed serum albumin levels increased by 0.4 g/dL or more, indicating a significantly greater improvement as compared with the placebo treatment. The total improvement rate, determined based on overall assessment of data regarding subjective and objective symptoms, nutriture, psychoneurological symptoms and quality of life, was 45.8% (38/83 patients) for the Livact-treated group and 17.3% (14/81 patients) for the placebo group. The usefulness rate, determined based on evaluation of safety in addition to the above variables, was 49.4% (42/85 patients) for the Livact-treated group and 18.1% (15/83 patients) for the placebo group.
An open-label follow-up clinical trial was performed for 2 years to investigate the relationship between serum albumin levels and clinical manifestations and prognosis for survival. The results revealed that changes in serum albumin levels over time were significantly correlated with status of ascites, oedema and performance status. As for the relationship to prognosis for survival, the risk of mortality (hazard ratio) per unit time based on no change group in serum albumin levels invariance was estimated to be 0.77 for subjects showing a serum albumin level increased by 0.2 g/dL, and to be 0.59 for those showing a serum albumin level increased by 0.4 g/dL in a year.
To evaluate the effect of Livact on the prognosis for survival, randomized controlled clinical trials were conducted for at least 2 years by comparison with dietary treatment in terms of study treatment time to discontinuation or dropout using significant events related to the prognosis for survival eg, exacerbation of hepatic insufficiency in patients with liver cirrhosis, as indicated by occurrence of ascites, oedema, hepatic encephalopathy and jaundice; rupture of oesophageal varices (rupture of gastric varices); development of hepatic cancer; and death, which were determined as serious complications occurring in association with advancing hepatic cirrhosis. The results showed that Livact significantly inhibited the development of the above serious complications of hepatic cirrhosis among 622 patients included in the analyses (308 and 314 patients in dietary-treated patients and Livact-treated patients, respectively). The hazard ratio for Livact-treated patients against dietary-treated patients was 0.67 with 95% confidence interval ranging from 0.49-0.93.
Pharmacokinetics: Absorption, Distribution, Metabolism and Excretion in Rats: The branched-chain amino acids administered to rats were rapidly absorbed, reaching a peak concentration in plasma and whole blood 4 hrs after dosing, followed by a slow decline. The branched-chain amino acids in plasma were promptly utilized for protein synthesis. The branched-chain amino acids absorbed were distributed extensively to the whole body, conspicuously in those tissues actively involved in protein synthesis. During a 168-hr period after dosing, the branched-chain amino acids administered was excreted in urine and feces, and in expired breath, 4% and 41%, respectively. It indicated that the branched-chain amino acids administered were utilized in part as a source of energy. It was also demonstrated that their absorption, distribution and excretion were not significantly affected in repeat-dose studies.
In hepatically impaired rats, absorption of the branched-chain amino acids administered proceeded slower than in normal rats, but their transition to plasma protein, distribution in tissues and excretion in urine and feces were essentially comparable with those seen in normal rats. It was thus indicated that the branched-chain amino acids administered were effectively utilized as substrates for protein synthesis in hepatically impaired rats as well. Compared with normal rats, the excretion in expired breath was greater in the hepatically impaired rats, in which the branched-chain amino acids administered were thus more efficiently utilized as a source of energy.
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