Cytotoxicity and mitochondrial dysfunction caused by the dietary supplement l-norvaline.

In addition to the 20 protein amino acids that are encoded for protein synthesis, hundreds of other naturally occurring amino acids, known as non-proteinogenic amino acids (NPAAs) exist. It is well known that some NPAAs are toxic through their ability to mimic protein amino acids, either in protein synthesis or in other metabolic pathways, and this property is utilised by some plants to inhibit the growth of other plants or kill herbivores. L-norvaline is an NPAA readily available for purchase as a dietary supplement. In light of previous evidence of l-norvaline's antifungal, antimicrobial and herbicidal activity, we examined the toxicity of l-norvaline to mammalian cells in vitro and showed that l-norvaline decreased cell viability at concentrations as low as 125 µM, caused necrotic cell death and significant changes to mitochondrial morphology and function. Furthermore, toxicity was reduced in the presence of structurally similar 'protein' amino acids, suggesting l-norvaline's cytotoxicity could be attributed to protein amino acid mimicry.

Chemoembolization with Vascular Disrupting Agent CKD-516 Dissolved in Ethiodized Oil in Combination with Doxorubicin: A VX2 Tumor Model Study.

PURPOSE: To assess feasibility and efficacy of CKD-516, a vascular disrupting agent, in transarterial chemoembolization in a liver tumor model. MATERIALS AND METHODS: A VX2 carcinoma strain was implanted in rabbit liver (n = 40) and incubated for 2 weeks. After confirmation of tumor growth using computed tomography, transarterial chemoembolization was performed. CKD-516 was dissolved in ethiodized oil, and animals were allocated to 4 treatment groups (n = 10 in each): group A, ethiodized oil; group B, ethiodized oil/CKD-516; group C, ethiodized oil + doxorubicin; group D, ethiodized oil/CKD-516 + doxorubicin. To assess hepatic damage, serum aspartate transaminase and alanine transaminase levels were measured on day 1, 3, and 7 after delivery. To assess tumor necrosis, animals were euthanized on day 7, and explanted tumors were stained with hematoxylin and eosin and a terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay. Percentage areas of viable tumors were calculated using digitalized histopathologic specimen images. RESULTS: Tumor viability rates were 47.1% ± 11.4%, 27.5% ± 13.6%, 14.4% ± 12.5%, and 0.7% ± 1.0% in groups A, B, C, and D (P < .001). Liver enzyme levels were elevated after drug delivery but recovered during follow-up. Significant between-group differences were observed on days 1, 3, and 7 (aspartate transaminase and alanine transaminase: P = .0135 and P = .0134, P = .0390 and P = .0084, and P = .8260 and P = .0440). CONCLUSIONS: Treatment with a combination of CKD-516 and conventional transarterial chemoembolization showed therapeutic benefit in a liver tumor model.

Canadian valsartan study in patients with mild-to-moderate hypertension.

OBJECTIVE: This study was designed mainly to establish the rates of response to valsartan 80mg once daily (qd) and to valsartan 160mg qd given to non-responders to 80mg qd, as well as to determine the safety of valsartan and the blood pressure control achieved using valsartan over a period of 24 h or more, using ambulatory blood pressure monitoring (ABPM) devices. METHODS: This was a single-blind, single-arm, multicenter study involving 256 out-patients with mild-to-moderate essential hypertension. After previous antihypertensive treatments had been 'washed out', the patients were entered into a 2-week placebo run-in period to confirm the diagnosis of mild-to-moderate hypertension. Patients who, at the end of the placebo run-in period, had a mean sitting diastolic blood pressure of between 95 and 115mmHg inclusive received valsartan 80mg qd for 4 weeks. Non-responders (those not demonstrating a diastolic blood pressure of less than 90mmHg or a decrease in diastolic blood pressure of 10mmHg or more compared with baseline) received valsartan 160mg qd for another 4 weeks. In selected centers, patients who agreed also had their blood pressure monitored for 24 h, provided their blood pressure was shown to be controlled. Of these patients, half skipped one dose of valsartan and were monitored for an additional 24h period. RESULTS: The rate of response to valsartan 80mg was 45.4%, and of those not responding to this dose, 36.3% responded to valsartan 160mg. The response rate to one or other dose was 63.2%. The ambulatory blood pressure data support a consistent reduction of blood pressure with valsartan over a 24h period and for up to 32 h after dosing in those who missed a dose. The overall incidence of adverse experiences per person-year, treatment related or otherwise, was 6.3 and 10.6 for the valsartan and placebo study periods respectively. CONCLUSION: Antihypertensive treatment with valsartan for 8 weeks produced a significant decrease in diastolic blood pressure in hypertensive patients. In addition, the drug may be safely administered, and the results of 24 h/48 h ambulatory monitoring demonstrate that valsartan is a true once-a-day antihypertensive.