Investigation of N-hydroxythalidomide in vitro stability and comparison to other N-substituted derivatives.

The stability of N-substituted derivatives of thalidomide was studied and compared to that of thalidomide itself. Nitrogen atom included in glutarimide ring was successively substituted by a hydroxy group, a methyl acetate group, and an ethyl group. Lipophilicities of these compounds were determined using the method based on experimental determinations of partition coefficients developed by Hansch. Hydroxy group led to a decrease of lipophilicity. Substitution of the nitrogen atom by an ethyl group or a methyl acetate group allowed an increase of lipophilicity. Relative stabilities of each compound were determined under physiological conditions: pH (7.4) and temperature (37 degrees C) using high performance liquid chromatography procedure. The program Sigma Plot was used to fit experimental data in order to obtain the half-lifes of thalidomide and its analogs. In the case of substitution by an ethyl group, the increase of lipophilicity (Delta log P = 0.36) was in agreement with a higher stability in aqueous medium. In the case of methyl acetate group, hydrolysis of the cycle was chemically favoured despite a higher lipophilicity compared to those of thalidomide. In the case of N-hydroxy compound, the decrease in lipophilicity was not sufficient to affect the stability.

Prognostic factors of paraneoplastic pemphigus.

OBJECTIVE: To identify the prognostic factors of overall survival in a series of patients with paraneoplastic pemphigus (PNP). DESIGN: Multicenter retrospective cohort study. SETTING: Twenty-seven dermatology departments in France. PATIENTS: A total of 53 patients (31 men and 22 women; median age, 59 years; age range, 30-88 years) were diagnosed as having PNP between 1992 and 2010. MAIN OUTCOME MEASURES: Overall Kaplan-Meier survival rates were estimated, and features associated with survival were assessed using univariate (log-rank test) and multivariate (Cox regression) analyses. RESULTS: The study included 53 patients with PNP. Thirty-six patients (68%) died during the study. The 1-, 3-, and 5-year overall survival rates were 49%, 41%, and 38%, respectively. The main causes of death were infections (n=21) and evolution of neoplasia (n=6). In univariate analysis, the main detrimental prognostic factors identified were erythema multiforme­like skin lesions (P=.05) and histologic keratinocyte necrosis (P=.03). None of the 5 patients with Castleman disease died during the study. After adjustment for age and sex in multivariate analysis, erythema multiforme­like skin lesions remained predictive of fatal outcome, with a 2-fold increase in death rate (hazard ratio [HR], 2.3; 95% CI, 1.05-5.03; P=.04). The prognosis of patients with PNP was even poorer when erythema multiforme­like skin lesions were associated with severe skin or mucosal involvement at presentation (HR of death, 3.0; 95% CI, 1.01-8.92; P=.049). CONCLUSION: Patients with PNP with erythema multiforme­like skin lesions and histologic keratinocyte necrosis, especially when associated with extensive lesions at presentation, are likely to have a more severe and rapid fatal outcome and should be managed very carefully.