Phase I/II study of the novel proteasome inhibitor delanzomib (CEP-18770) for relapsed and refractory multiple myeloma.

Delanzomib (CEP-18770), a reversible P2 threonine boronic acid proteasome (ß5/ß1 subunits) inhibitor that showed promising anti-myeloma effects in preclinical studies, was investigated in a single-agent multicenter phase I/II study in patients with relapsed/refractory myeloma. Sixty-one patients (17 during dose escalation; 44 in the expansion cohort) received delanzomib on days 1, 8, and 15 in 28-d cycles; 47 received the maximum tolerated dose (MTD), 2.1 mg/m2. Dose-limiting toxicities (DLTs) at 2.4 mg/m2 were rash and thrombocytopenia. At the MTD, the most prominent adverse events were nausea, vomiting, anorexia, fatigue, and pyrexia; grade 3/4 thrombocytopenia and neutropenia occurred in 53 and 23% of patients, respectively. Peripheral neuropathy (21%) was limited to grades 1/2. At the MTD, 26 patients (55%) had stable disease and four (9%) had a partial response (PR). Median time to progression (TTP) was 2.5 months across the cohort. Based upon the efficacy results, development of delanzomib for myeloma was discontinued.

A first in human phase I study of the proteasome inhibitor CEP-18770 in patients with advanced solid tumours and multiple myeloma.

BACKGROUND: The safety, pharmacokinetics (PK) and pharmacodynamics of CEP-18770, a new peptide boronic acid proteasome inhibitor, have been investigated after intravenous administration on days 1, 4, 8 and 11 of every 21d cycle in patients with solid tumours and multiple myeloma (MM). PATIENTS AND METHODS: Thirty-eight patients were treated with CEP-18770 at escalating doses from 0.1 to 1.8mg/m(2) where 2 out of 5 patients showed dose limiting toxicities. The maximum tolerated/recommended dose (MTD/RD) of 1.5mg/m(2) was tested in 12 additional patients. Skin rash was dose-limiting and occurred in 53% of patients; other frequent toxicities were asthenia (29%), stomatitis (21%) and pyrexia (16%). No significant peripheral neuropathy was observed. PK in plasma was linear with a half-life of the elimination phase of 62.0±43.5h. Proteasome inhibition in peripheral blood mononuclear cells was dose related in MM patients; it was of 45.4±11.5% at the RD. CONCLUSIONS: CEP-18770 showed a favourable safety profile with lack of neurotoxicity and linear plasma PK. The definition of the optimal biological dose and schedule of treatment is actively pursued because of the high incidence of skin toxicity of the twice a week schedule.

Relações treonina: lisina digestíveis para suínos na fase inicial, alimentados com rações de baixa proteína, calculadas de acordo com o conceito de energia líquida / Digestible threonine: lysine ratios for starting pigs fed low protein diets, considering net energy concept

Foram realizados dois experimentos com o objetivo de estudar, no primeiro, o efeito de diferentes relações treonina:lisina digestíveis (TL) sobre a utilização do nitrogênio (N) em suínos na fase inicial, dos 15 aos 30kg de peso, e, no segundo, o efeito dessas relações sobre o desempenho dos animais. No primeiro experimento, foi avaliado o balanço de nitrogênio, utilizando-se 20 suínos machos castrados, híbridos comerciais de média a alta deposição de tecido magro, com peso inicial de 23,0±4,1kg. Os suínos foram distribuídos em um delineamento experimental inteiramente ao acaso. As rações continham baixo nível de proteína (17,3 por cento), e as relações TL foram: 0,574; 0,624; 0,673; 0,722 e 0,772. A proteína bruta total excretada (PBTE), a proteína bruta retida (PBR) e a utilização líquida da proteína (ULP) apresentaram efeito quadrático, e os melhores valores nas relações foram 0,648; 0,648 e 0,649, respectivamente. A melhor relação TL foi 0,649 (média da PBR e ULP). No segundo experimento, foi avaliado o efeito dessa relação sobre o desempenho dos suínos na fase inicial. Foram utilizados 60 animais (30 machos castrados e 30 fêmeas) com peso inicial de 15,5±1,5kg, de características semelhantes ao primeiro experimento, distribuídos em um delineamento experimental inteiramente ao acaso, em esquema fatorial 5x2 (cinco relações TL e dois sexos, com dois animais por baia). Foram utilizadas seis baias por tratamento, com três de machos e três de fêmeas cada. Não houve efeito da relação TL sobre o consumo diário de ração e o ganho diário de peso, e houve efeito quadrático, com ponto de mínimo, sobre a conversão alimentar com a relação TL de 0,691. Os resultados indicam que a relação TL de 0,649 maximiza a retenção de nitrogênio e a relação TL de 0,691 permite melhor conversão alimentar para leitões dos 15 aos 30kg de peso.

Two experiments were carried out to evaluate the effect of digestible threonine:lysine ratio (TL) on nitrogen (N) use and on growth performance of starting pigs (15-30kg). Experiment I evaluated nitrogen balance using twenty high-lean commercial crossbred barrows, with initial weight of 23.0±4.1kg. Pigs were allotted in a randomized design. Diets were formulated with low crude protein levels (17.3 percent) and TL ratios were: 0.574; 0.624; 0.673; 0.722; and 0.772. Excreted crude protein (CPEX), crude protein retention (CPR), and net protein utilization (NPU) showed quadratic effect and the best TL ratio values were achieved at 0.648, 0.648, and 0.649, respectively. The best TL ratio was 0.649 (CPR and NPU means). Experiment II was carried out to examine the same TL ratio effects on the performance of pigs. Sixty pigs (30 barrows and 30 gilts), averaging 15.5±1.5kg, used in experiment II, were allotted in a randomized design, following a factorial scheme (5x2), being five TL ratios (same as in experiment I) and two genders. Six pens per treatment (three barrows and three gilts) were used. There was no effect of TL ratio on daily feed intake and on average weight gain. However, the feed:gain ratio showed a quadratic effect and the best TL ratio was achieved at 0.691. The results pointed out that the 0.649 TL ratio maximized nitrogen retention and the 0.694 TL ratio allowed a better feed conversion for starting pigs averaging 15 to 30kg of b.w.

Níveis de treonina digestível para suínos machos castrados, de alto potencial genético para deposição de carne, na fase de terminação / Digestible threonine levels for high genetic potential lean deposition finishing barrows

Avaliou-se o efeito de níveis de treonina digestível em rações sobre o desempenho e características de cacaça de suínos machos castrados, selecionados geneticamente, para deposição de carne na carcaça, na fase de terminação. Foram utilizados 70 animais, com peso inicial de 59,00+1,25kg, distribuídos em delineamento experimental de blocos ao acaso, com cinco tratamentos, sete repetições e dois animais por unidade experimental, sendo que na distribuição dos animais, foi adotado como critério o peso inicial. Os tratamentos foram níveis de treonina na ração (0,480; 0,504; 0,528; 0,554 e 0,572 por cento de treonina digestível). Não houve efeito (P>0,05) dos tratamentos sobre o ganho de peso, consumo de ração e conversão alimentar. Os níveis de treonina digestível não influenciaram (P>0,05) a porcentagem de carne e a espessura de toucinho na carcaça. Conclui-se que o nível de 0,480 por cento de treonina digestível, correspondente a relação de treonina digestível:lisina digestível de 60 por cento, atendeu as exigências de suínos machos castrados de alto potencial para deposição de carne na carcaça dos 60 aos 95kg.

An experiment was carried out to determine the effects of digestible threonine levels in ration on the performance and carcass traits of hogs genetically selected for lean deposition at finishing. Seventy barrows averaging an initial weight of 59.00+1.25kg were distributed in a randomized experimental block design with five treatments and seven replicates, being two animals per experimental unit. Initial weight was adopted as a criterion for animal distribution in the treatments, which were the levels of digestible treonine in the diet (0.480; 0.504; 0.528; 0.554; and 0.572 percent). No effect (P>0.05) was observed among the treatments on daily weight gain, daily feed intake, and feed conversion. Digestible threonine levels did not influence (P>0.05) lean and backfat thickness percentage. It can be concluded that the level of 0.480 percent of digestible treonine, corresponding to the rate digestible treonine:lysine 60 percent, supplied the requirments of high potential lean deposition barows from 60 to 95kg.

Safety and tolerance of ester-C compared with regular ascorbic acid.

The goal of this randomized, double-blind crossover clinical trial in 50 healthy volunteers sensitive to acidic foods was to evaluate whether Ester-C calcium ascorbate causes fewer epigastric adverse effects than are produced by regular ascorbic acid (AA). Volunteers were randomly separated into 2 groups of 25. The study comprised an observation period of 9 days (phase 1 medication for 3 consecutive days, washout phase for 3 consecutive days, phase 2 medication for 3 consecutive days). Participants took 1000 mg vitamin C as Ester-C during phase 1 of the study followed by 1000 mg of vitamin C as AA during phase 2, or vice versa. During the course of the study, 3 examinations for the evaluation of epigastric adverse effects were performed (on days 0, 3, and 9). Participants used a diary to record epigastric adverse effects on a daily basis. In total, 28 (56%) of 50 participants reported 88 epigastric adverse effects of mild to moderate intensity. Of these 88 adverse effects, 33 (37.5%) occurred after intake of Ester-C and 55 (62.5%) were noted after intake of AA. The tolerability of Ester-C was rated "very good" by 72% of participants, whereas AA was rated "very good" by only 54%. This difference is statistically significant (P<.05). Investigators concluded that Ester-C compared with AA caused significantly fewer epigastric adverse effects in participants sensitive to acidic foods and that Ester-C is much better tolerated.

Threonine requirements of broiler chickens: an experimental validation of a model using growth responses and carcase analysis.

1. This paper describes the experimental testing of a model derived from an analysis of published data on the threonine requirements of broiler chickens. The model, published in a separate paper, showed that the age of the bird and dietary crude protein were highly significant determinants of threonine requirements. 2. We tested this model by measuring the threonine requirements of male broilers aged 7 to 21 d and 21 to 42 d fed on wheat-peanut meal diets containing graded concentrations of threonine. The growth of those birds given adequate threonine was compared with that of others fed a typical wheat-soyabean diet to measure the relative value of peanut meal as a protein concentrate. Finally, we measured the dry matter, nitrogen and fat concentrations in the carcase using near infrared reflectance spectroscopy (NIRS) to test the hypothesis that birds given diets deficient in an amino acid produce carcases with more fat. 3. Increasing the threonine concentration of the diet from 5.7 to 7.2 g/kg improved the growth and feed conversion ratio (FCR) of broilers. However, a further increase in dietary threonine to 7.7 g/kg had an adverse effect. The determined threonine requirement agreed with our prediction model. 4. From 7 to 21 d birds given the diet containing 7.2 g/kg threonine ate more, weighed more, had an improved FCR and, in absolute terms, had carcases with more dry matter, fat and protein than did birds given the wheat-soyabean diet. However, after correction for treatment differences in body mass there were no differences in the carcase parameters. Likewise, there were no differences in any measurements between birds given these two diets between 21 and 42 d.

Ethanol- and threonine-induced hypertension in rats: a common mechanism.

OBJECTIVE: To investigate the effects of oral L-threonine and ethanol, precursor of endogenous acetaldehyde, on systolic blood pressure, cystolic free calcium ([Ca2+]i) and vascular calcium uptake in Wistar-Kyoto (WKY) rats. METHODS: Twenty-four male WKY rats aged eight weeks were divided into four groups of six animals each. Animals were given either water or 5% ethanol, 8% L-threonine or 8% L-glycine in drinking water for 15 weeks, animals were sacrificed, aortic rings were incubated in physiological buffer containing 45Ca2+ and uptake was measured after 20 mins. ([Ca2+]i in platelets was measured with a fluorescence [Ca2+]i indicator, FURA-2. Tissues were processed for morphological investigation. RESULTS: After 15 weeks, systolic blood pressure, platelet [Ca2+]i and aortic calcium uptake were all significantly higher (P < 0.001) in rats given either threonine or ethanol than in control rats given water or glycine. Animals in threonine or ethanol group also showed smooth muscle cell hyperplasia, with some thickening of the wall and narrowing of the lumen in small arteries and arterioles of the kidney. Glycine treatment did not cause any of these changes in rats. CONCLUSION: These results suggest that acetaldehyde may be a common cause of both ethanol- and threonine-induced hypertension.