Direct-acting antiviral-associated dermatitis during chronic hepatitis C virus treatment.

Telaprevir and boceprevir are novel protease inhibitors recently approved for treatment of chronic hepatitis C virus infection, and have gained widespread use. Skin rash has been reported frequently in patients treated with telaprevir, but less commonly with boceprevir. Despite a high incidence in clinical trials, the telaprevir-related eruption has not been fully described in the literature. We describe six patients treated with telaprevir and three treated with boceprevir who developed skin rash related to the antiviral medication. Four patients treated with telaprevir developed laboratory abnormalities and/or systemic symptoms and five required discontinuation of their antiviral medication because of these adverse effects, including two patients who fit criteria for drug reaction with eosinophilia and systemic symptoms (DRESS). Patients with boceprevir-related rash had a milder course and none required discontinuation of the medication. This report confirms that cutaneous adverse effects from telaprevir and boceprevir are common. Patients treated with telaprevir may have a more severe course and more frequently require discontinuation of their antiviral therapy due to extensive rash or laboratory abnormalities. Dermatologists must be aware of these cutaneous adverse effects, as early intervention with topical corticosteroids and antihistamines may minimize the severity of the eruption and allow patients to complete antiviral therapy.

Cutaneous inoculation of nontuberculous mycobacteria during professional tattooing: a case series and epidemiologic study.

BACKGROUND: The increase in popularity of tattoos has coincided with an increase in reports of cutaneous inoculation of nontuberculous (atypical) mycobacteria (NTM) during the tattooing process. We report 3 NTM infections in otherwise healthy persons who received tattoos, which prompted a multiagency epidemiologic investigation. METHODS: Tattoo artists involved were contacted and interviewed regarding practices, ink procurement and use, and other symptomatic clients. Additional patients were identified from their client lists with an Internet survey. RESULTS: Thirty-one cases of suspected or confirmed NTM inoculation from professional tattooing were uncovered, including 5 confirmed and 26 suspected cases. Clinical biopsy specimens from 3 confirmed infections grew Mycobacterium abscessus strains that were indistinguishable by pulsed-field gel electrophoresis testing. Another 2 skin specimens grew Mycobacterium chelonae, which also grew from a bottle of graywash ink obtained from the tattoo artist. CONCLUSIONS: The pathogenicity and antibiotic resistance patterns of certain NTM isolates highlight the importance of correct diagnosis and potential difficulty in treating infections. Enforcement of new standards for the regulation and use of tattoo inks should be considered.

Actin microfilament aggregation induced by withaferin A is mediated by annexin II.

The actin cytoskeleton supports diverse cellular processes such as endocytosis, oriented growth, adhesion and migration. The dynamic nature of the cytoskeleton, however, has made it difficult to define the roles of the many accessory molecules that modulate actin organization, especially the multifunctional adapter protein annexin II. We now report that the compound withaferin A (1) can alter cytoskeletal architecture in a previously unknown manner by covalently binding annexin II and stimulating its basal F-actin cross-linking activity. Drug-mediated disruption of F-actin organization is dependent on annexin II expression by cells and markedly limits their migratory and invasive capabilities at subcytotoxic concentrations. Given the extensive ethnobotanical history of withaferin-containing plant preparations in the treatment of cancer and inflammatory and neurological disorders, we suggest that annexin II represents a feasible, previously unexploited target for therapeutic intervention by small-molecule drugs.

Time and dose-dependent radiosensitization of the glioblastoma multiforme U251 cells by the EGF receptor tyrosine kinase inhibitor ZD1839 ('Iressa').

Hyperactive epidermal growth factor receptor (EGFR) signaling, which promotes unregulated cell growth and inhibits apoptosis, is believed to contribute to clinical radiation resistance of glioblastoma multiforme (GBM). Blockage of the EGFR signalling pathways may offer an attractive therapeutic target to increase the cytotoxic effects of radiotherapy. We report the effects of ZD1839 ('Iressa'), a selective EGFR tyrosine kinase inhibitor on the radiation sensitivity of the U251 GBM cell line, which expresses high levels of EGFR. In radiation survival experiments, 5 microM of ZD1839 had a significant radiosensitizing effect and increased cell death was observed at doses of 5Gy in the presence of ZD1839. Dose and schedule of drug administration in combination with radiation appeared to be a crucial element to obtain radiosensitization of the cells. These studies suggest novel therapeutic strategies in the treatment of GBM.

The stress response: implications for the clinical development of hsp90 inhibitors.

In their role as molecular chaperones, heat shock proteins serve as central integrators of protein homeostasis within cells. As part of this function, they guide the folding, assembly, intracellular disposition and proteolytic turnover of many key regulators of cell growth, differentiation and survival. Not surprisingly then, heat shock proteins are over expressed in many types of cancer, and induction of the stress response may actually be required for cells to tolerate the genetic disarray characteristic of malignant transformation. Regulation of heat shock protein levels via the stress response is complex, but recent data indicate that the molecular chaperone Hsp90 plays a key role. Specifically, Hsp90 inhibitors alter the multi-chaperone complexes associated with Heat Shock Factor 1 (HSF1), the dominant transcription factor controlling induction of the stress response, and stimulate HSF1-activated heat shock gene expression. Induction of this heat shock response has now emerged as an important consideration in the further clinical development of Hsp90 inhibitors for several reasons. First, tumors in which the stress response is compromised appear particularly sensitive to Hsp90 inhibition. Second, induction of the stress response by Hsp90 inhibitors provides a sensitive pharmacodynamic endpoint with which to monitor drug action in individual patients. Third, Hsp90 inhibitors display important therapeutic interactions with both conventional DNA-targeted chemotherapeutics and newer molecularly targeted agents. These interactions are, at least in part, due to modulation of the stress response by these drugs. Lastly, stress response induction by Hsp90 inhibitors may have therapeutic benefits in non-neoplastic disorders such as heart disease, stroke and neurodegenerative diseases. These benefits are just beginning to be explored.