RASopathic Skin Eruptions During Vemurafenib Therapy.

RASopathic Skin Eruptions during Vemurafenib Therapy.

PLoS One. 2013; 8(3): e58721
Rinderknecht JD, Goldinger SM, Rozati S, Kamarashev J, Kerl K, French LE, Dummer R, Belloni B

Vemurafenib is a potent inhibitor of V600 mutant BRAF with significant impact on progression-free and overall survival in advanced melanoma. Cutaneous side effects are frequent. This single-center observational study investigates clinical and histological features of these class-specific cutaneous adverse reactions.Patients were all treated with Vemurafenib 960 mg b.i.d. within local ethic committees approved clinical trials. All skin reactions were collected and documented prospectively. Cutaneous reactions were classified by reaction pattern as phototoxic and inflammatory, hair and nail changes, keratinocytic proliferations and melanocytic disorders.Vemurafenib was well tolerated, only in two patients the dose had to be reduced to 720 mg due to arthralgia. 26/28 patients (93%) experienced cutaneous side effects. Observed side effects included UVA dependent photosensitivity (n?=?16), maculopapular exanthema (n?=?14), pruritus (n?=?8), folliculitis (n?=?5), burning feet (n?=?3), hair thinning (mild alopecia) (n?=?8), curly hair (n?=?2) and nail changes (n?=?2). Keratosis pilaris and acanthopapilloma were common skin reactions (n?=?12/n?=?13), as well as plantar hyperkeratosis (n?=?4), keratoacanthoma (n?=?5) and invasive squamous cell carcinoma (n?=?4). One patient developed a second primary melanoma after more than 4 months of therapy (BRAF and RAS wild type).Vemurafenib has a broad and peculiar cutaneous side effect profile involving epidermis and adnexa overlapping with the cutaneous manifestations of genetic diseases characterized by activating germ line mutations of RAS (RASopathy). They must be distinguished from allergic drug reaction. Regular skin examination and management by experienced dermatologists as well as continuous prophylactic photo protection including an UVA optimized sun screen is mandatory. HubMed – drug


N-Substituted Benzyl Matrinic Acid Derivatives Inhibit Hepatitis C Virus (HCV) Replication through Down-Regulating Host Heat-Stress Cognate 70 (Hsc70) Expression.

PLoS One. 2013; 8(3): e58675
Du NN, Peng ZG, Bi CW, Tang S, Li YH, Li JR, Zhu YP, Zhang JP, Wang YX, Jiang JD, Song DQ

Heat-stress cognate 70 (Hsc70) is a host factor that helps hepatitis C virus (HCV) to complete its life cycle in infected hepatocytes. Using Hsc70 as a target for HCV inhibition, a series of novel N-substituted benzyl matrinic/sophoridinic acid derivatives was synthesized and evaluated for their anti-HCV activity in vitro. Among these analogues, compound 7c possessing N-p-methylbenzyl afforded an appealing ability to inhibit HCV replication with SI value over 53. Furthermore, it showed a good oral pharmacokinetic profile with area-under-curve (AUC) of 13.4 µM·h, and a considerably good safety in oral administration in mice (LD50>1000 mg/kg). As 7c suppresses HCV replication via an action mode distinctly different from that of the marketed anti-HCV drugs, it has been selected as a new mechanism anti-HCV candidate for further investigation, with an advantage of no or decreased chance to induce drug-resistant mutations. HubMed – drug


Aggressive regimens for multidrug-resistant tuberculosis decrease all-cause mortality.

PLoS One. 2013; 8(3): e58664
Mitnick CD, Franke MF, Rich ML, Alcantara Viru FA, Appleton SC, Atwood SS, Bayona JN, Bonilla CA, Chalco K, Fraser HS, Furin JJ, Guerra D, Hurtado RM, Joseph K, Llaro K, Mestanza L, Mukherjee JS, Muñoz M, Palacios E, Sanchez E, Seung KJ, Shin SS, Sloutsky A, Tolman AW, Becerra MC

A better understanding of the composition of optimal treatment regimens for multidrug-resistant tuberculosis (MDR-TB) is essential for expanding universal access to effective treatment and for developing new therapies for MDR-TB. Analysis of observational data may inform the definition of an optimized regimen.This study assessed the impact of an aggressive regimen-one containing at least five likely effective drugs, including a fluoroquinolone and injectable-on treatment outcomes in a large MDR-TB patient cohort.This was a retrospective cohort study of patients treated in a national outpatient program in Peru between 1999 and 2002. We examined the association between receiving an aggressive regimen and the rate of death.In total, 669 patients were treated with individualized regimens for laboratory-confirmed MDR-TB. Isolates were resistant to a mean of 5.4 (SD 1.7) drugs. Cure or completion was achieved in 66.1% (442) of patients; death occurred in 20.8% (139). Patients who received an aggressive regimen were less likely to die (crude hazard ratio [HR]: 0.62; 95% CI: 0.44,0.89), compared to those who did not receive such a regimen. This association held in analyses adjusted for comorbidities and indicators of severity (adjusted HR: 0.63; 95% CI: 0.43,0.93).The aggressive regimen is a robust predictor of MDR-TB treatment outcome. TB policy makers and program directors should consider this standard as they design and implement regimens for patients with drug-resistant disease. Furthermore, the aggressive regimen should be considered the standard background regimen when designing randomized trials of treatment for drug-resistant TB. HubMed – drug