Subject(s)
Cancer Survivors , Neoplasms , Quality of Life , Humans , Cancer Survivors/psychology , Neoplasms/psychologyABSTRACT
In this short note we report on the shelf-life stability of pDERMATT (plasmid DNA encoding recombinant MART-1 and tetanus toxin fragment-c) 2mg lyophilized powder for reconstitution for intradermal administration, used in an in-house, investigator-initiated clinical phase I study. pDERMATT was stored at 25°C/60% relative humidity (6 months), 2-8°C (24 months), and -20°C (66 months) in the dark and analyzed at several timepoints during the conduct of the clinical study for appearance, identity, purity (plasmid topology), content and residual water content. pDERMATT appeared stable at all storage conditions for the periods tested which, although patient inclusion in the study was significantly delayed, ensured the clinical supply needs. This study shows that lyophilization is an useful tool to preserve the quality of the pDNA and can prevent the need for costly and time-consuming additional manufacture of drug product in case of study delays, not uncommon at the early stage of drug development. To our knowledge, this is the first study reporting shelf life stability of a pDNA formulation for more than 5 years.
Subject(s)
DNA/chemistry , MART-1 Antigen/genetics , Peptide Fragments/genetics , Plasmids , Tetanus Toxin/genetics , Cancer Vaccines , Drug Stability , Drug Storage , Freeze Drying , Humidity , TemperatureABSTRACT
Although it is well established that hallucinogens act as 5-HT(2A) and 5-HT(2C) receptor agonists, little is known about the relative contributions of 5-HT(2A) and 5-HT(2C) receptors to the acute behavioral effects of these drugs. The behavioral pattern monitor was used to characterize the effects of the hallucinogen 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on locomotor and investigatory behavior in mice. Studies were also conducted to assess the contributions of 5-HT(2A) and 5-HT(2C) receptors to the behavioral effects of DOI. DOI produced an inverted U-shaped dose-response function, with lower doses (0.625-5.0 mg/kg) increasing and higher doses (> or =10 mg/kg) decreasing locomotor activity. The increase in locomotor activity induced by 1.0 mg/kg DOI was absent in 5-HT(2A) receptor KO mice, suggesting the involvement of 5-HT(2A) receptors. The reduction in locomotor activity produced by 10 mg/kg DOI was potentiated in 5-HT(2A) KO mice and attenuated by pretreatment with the selective 5-HT(2C/2B) antagonist SER-082. These data indicate that the decrease in locomotor activity induced by 10 mg/kg DOI is mediated by 5-HT(2C) receptors, an interpretation that is supported by the finding that the selective 5-HT(2C) agonist WAY 161,503 produces reductions in the locomotor activity that are potentiated in 5HT(2A) KO mice. These results show for the first time that 5-HT(2A) and 5-HT(2C) receptors both contribute to the effects of DOI on locomotor activity in mice. Furthermore, these data also suggest that 5-HT(2A) and 5-HT(2C) receptors exert opposing effects on locomotor activity.
