Toxic Cardiomyopathy Leading to Fatal Acute Cardiac Failure Related to Vandetanib: A Case Report With Histopathological Analysis.

Toxic Cardiomyopathy leading to fatal acute cardiac failure related to vandetanib: a case report with histopathological analysis.

Eur J Endocrinol. 2013 Mar 13;
Scheffel RS, Dora JM, Siqueira DR, Burttet LM, Cerski MR, Maia AL

CONTEXT: Medullary thyroid carcinoma (MTC) accounts for 3-4% of all malignant thyroid neoplasias. Vandetanib, a tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor 2 (VEGFR-2), epidermal growth factor receptor (EGFR), and RET, has been approved by the FDA for the treatment of locally advanced or metastatic MTC. The heart seems to be particularly susceptible to adverse effects associated with TKI therapy and virtually all TKIs have been associated with cardiovascular events. CLINICAL PRESENTATION: We report the case of a patient with metastatic MTC who was enrolled in the Phase III clinical study (NCT00410761) and presented a favorable response to vandetanib therapy, displaying marked decrease in the level of serologic tumor markers and shrinkage of metastatic lesions. After 14 months of therapy, the patient developed a fatal cardiac failure. Myocardial infarction was excluded by serial measurements of specific cardiac markers (serial troponin-T measurements varied from 0.037 to 0.042 ng/mL) and serologic tests for Chaga’s disease were negative. Postmortem examination of the heart revealed cardiomyocyte hypertrophy and marked myocyte degeneration in the subendocardial zones and papillary muscles of the myocardium. These pathological changes are similar to those observed in TKI-treated rats and are suggestive of drug-induced cardiotoxicity. CONCLUSION: This case illustrates a previously unreported serious vandetanib-related adverse effect and highlights the need to close monitoring of patients under TKI therapy in order to identify early signs of congestive heart failure or myocardium damage. HubMed – drug

Herpes Simplex Virus 2 expresses a novel form of ICP34.5, a major viral neurovirulence factor, through regulated alternative splicing.

J Virol. 2013 Mar 13;
Tang S, Guo N, Patel A, Krause PR

HSV-1 and HSV-2, two closely related neurotropic human herpesviruses, achieve neurotropism through ICP34.5, a major viral neurovirulence factor. In this report, in addition to the full-length 38 kD protein (ICP34.5?), we identified a 28 kD novel form of ICP34.5 (ICP34.5?) in HSV-2-infected cells. ICP34.5? is translated from unspliced ICP34.5 mRNA, with the retained intron introducing a premature stop codon. Thus, ICP34.5? lacks the C-terminal conserved GADD34 domain, but includes 19 additional amino acids encoded by the intron. While a fraction of both HSV-2 ICP34.5 proteins are detected in the nucleolus, ICP34.5? is predominantly located in cytoplasm and ICP34.5? is mainly detected more diffusely in the nucleus. ICP34.5? is unable to counteract PKR-mediated eIF2 phosphorylation, but does not interfere with ICP34.5?’s function in this process. Efficient expression of ICP34.5? in cell-culture assays is dependent on viral infection or expression of ICP27, a multifunctional immediate-early gene. The effect of ICP27 on the ICP34.5? protein level is attributed to its selective inhibition of ICP34.5 splicing, which results in increased expression of ICP34.5? but a reduced level of ICP34.5?. The C- terminal KH3 domain but not the RNA binding domain of ICP27 is required for its specific inhibition of ICP34.5 splicing and promotion of ICP34.5? expression. Our results suggest that expression of ICP34.5? and ICP34.5? is tightly regulated in HSV-2, and likely contributes to viral pathogenesis. HubMed – drug

Interaction between paliperidone extended release and TS-1(®), an oral anticancer drug containing a 5-fluorouracil derivative, in a schizophrenic patient.

Neuropsychiatr Dis Treat. 2013; 9: 317-9
Yasui-Furukori N, Hashimoto K, Kubo K, Tomita T

Until now there has been no information available on drug interaction between paliperidone and TS-1(®), an oral anticancer drug containing a 5-fluorouracil derivative. The patient in the case presented here was a 39-year-old man with a 15-year history of schizophrenia. The patient’s usual treatment of 2 mg/day of risperidone was changed to 3 mg/day of paliperidone extended release. He experienced worsening psychotic symptoms after switching from risperidone to paliperidone while he was also receiving TS-1. Retrospective analyses showed plasma concentration of paliperidone was consistently lower during the treatment with TS-1 than without TS-1. This case suggests there is drug interaction between paliperidone extended-release tablets and TS-1. HubMed – drug

Design, Synthesis and Biological Evaluation Studies of Novel Quinazoline Derivatives as Cytotoxic Agents.

Drug Res (Stuttg). 2013 Mar 13;
Zayed MF, Hassan MH

Some novel quinazoline derivatives 6a-h were designed, synthesized and evaluated for their in vitro cytotoxic activity against lymphoma cell line compared to etoposide as a reference drug. Compounds (S)-2-(6,8-diiodo-2-phenylquinazolin-4-ylamino)-3-phenylpropanoic acid (6 f), (S)-2-(6,8-diiodo-2-phenylquinazolin-4-ylamino)-3-(1H-imidazol-4-yl)propanoic acid (6 g) and (S)-2-(6,8-diiodo-2-phenylquinazolin-4-ylamino)-3-(1H-indol-3-yl) propanoic acid (6 h) had comparable higher cytotoxic activity than the reference drug. Compound 6 f, the most active compound, had IC50=13.2 µM. In an attempt to interpret such anti-cancer activity of these derivatives, their anti-inflammatory action was examined using the carrageenan induced rat paw edema method. The most active compounds showed moderate anti-inflammatory activity compared to the reference drug. In order to identify the most relevant physicochemical features important for high antitumor activity of the target compounds, specific 2D descriptors were calculated and correlated with the antileukemic activity. HubMed – drug