Altretamine is a synthetic drug approved for treatment of ovarian cancer. The only drawback with its formulation is poor aqueous solubility and low oral bioavailability. In the present work an attempt has been made to prepare inclusion complex of altretamine with epichlorohydrin beta cyclodextrin. The complexes were prepared by kneading, co-evaporation and freeze-drying method and were confirmed by FTIR, XRD, DSC, drug content and dissolution study. Kneaded complex possess maximum solubilizing efficiency of 82.63 in 25mM Epi-β-CD solution. SLNs of pure altretamine and ALT complexed with Epi-β-CD were prepared by modified emulsification-ultrasonication method. The particle size and zeta potential was found to be 151.5nm and -21.3mV. The drug release pattern of SLNs was bi-phasic in nature; with an initial burst release followed by sustained drug release. Pharmacokinetic study showed that the average Cmaxwas found to be 0.94μg/ml, which was 2.47 times higher as compared to the pure drug. The AUCt for SLNs was 150minμgh/ml and 54minμgh/ml for pure ALT suspension which proved that the SLNs exhibited greater absorption compared to the pure drug. Thus, smaller particle size, higher entrapment efficiency and enhanced aqueous solubility led to improvement in oral bioavailability of ALT.

Genome-wide identification of the mechanism of action (MoA) of small-molecule compounds characterizing their targets, effectors, and activity modulators represents a highly relevant yet elusive goal, with critical implications for assessment of compound efficacy and toxicity. Current approaches are labor intensive and mostly limited to elucidating high-affinity binding target proteins. We introduce a regulatory network-based approach that elucidates genome-wide MoA proteins based on the assessment of the global dysregulation of their molecular interactions following compound perturbation. Analysis of cellular perturbation profiles identified established MoA proteins for 70% of the tested compounds and elucidated novel proteins that were experimentally validated. Finally, unknown-MoA compound analysis revealed altretamine, an anticancer drug, as an inhibitor of glutathione peroxidase 4 lipid repair activity, which was experimentally confirmed, thus revealing unexpected similarity to the activity of sulfasalazine. This suggests that regulatory network analysis can provide valuable mechanistic insight into the elucidation of small-molecule MoA and compound similarity.

The objective of the present study was to prepare solid lipid nanoparticles (SLNs) of altretamine (ALT) by the hot homogenization and ultrasonication method. The study was conducted using the Box-Behnken design (BBD), with a 3(3) design and a total of 17 experimental runs, performed in combination with response surface methodology (RSM). The SLNs were evaluated for mean particle size, entrapment efficiency, and drug-loading. The optimized formulation, with a desirability factor of 0.92, was selected and characterized. In vitro release studies showed a biphasic release pattern from the SLNs for up to 24 h. The results of % EE (93.21 ± 1.5), %DL (1.15 ± 0.6), and mean diameter of (100.6 ± 2.1) nm, were very close to the predicted values.

Liposomes incorporating sodium deoxycholate (NaDC) were prepared by the method of reverse phase evaporation and used for drug delivery by the oral route. Hexamethylmelamine (HMM), an anti-tumor agent, was chosen as a model drug and encapsulated into liposomes incorporating NaDC (NaDC-Lip). Several properties of NaDC-Lip containing HMM (HMM NaDC-Lip), such as particle size, entrapment efficiency, pinacyanol chloride (PIN) spectral characteristics with various molar ratio of NaDC/PC, as well as the vesicle stability measurements with calcein were evaluated. In vivo, the area under the plasma concentration-time curve obtained from the pharmacokinetics study of HMM NaDC-Lip was found to be approximately 9.76- and 1.21-fold higher than that of HMM solution and HMM Lip, respectively, indicating that NaDC-Lip can be used as a potential carrier for oral drug administration.

The aim of this study was to assess the efficacy of consolidation therapy with hexamethylmelamine (HMM) in patients with advanced epithelial ovarian cancer (EOC). Patients treated at our hospital between January 1997 and November 2006 and in documented clinical complete response from advanced ovarian cancer following front-line platinum-based therapy were retrospectively analyzed. The patients treated with HMM were compared to the patients of matched counterpart without consolidation therapy. Of 102 patients enrolled, 49 were treated with HMM and 53 received no consolidation treatment. For patients with HMM and observed patients, the mean age were 54.6 and 55.6 yr; the distribution of stage was similar (P=0.977); the optimal surgery was performed in 36 (73.5%) and 44 (83%) (P=0.336); the recurrence rate were 27 (55.1%) and 33 (62.3%) (P=0.463); and the median progression-free survival were 38 months and 21 months for patients with HMM and observed patients (P=0.235). No treatment-related adverse events were reported during the follow-up period. Although this study failed to show the significant survival benefit of consolidation therapy with HMM in patients with advanced EOC, we consider that our study can contribute data to investigate the effectiveness of consolidation therapy in epithelial ovarian cancer.

A novel method for the cyclotrimerization of dimethylcyanamide to form hexamethylmelamine has been developed using an aluminium amide catalyst; detailed DFT modelling of the catalytic cycle supports a triple insertion, nucleophilic ring closure, deinsertion mechanism.