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Pancreatic Ductal Adenocarcinoma (PDAC) has a five-year survival under 10%. Treatment is compromised due to a fibrotic-like stromal remodeling process, known as desmoplasia, which limits therapeutic perfusion, supports tumor progression, and establishes an immunosuppressive microenvironment. These processes are driven by cancer-associated fibroblasts (CAFs), functionally activated through transforming growth factor beta1 (TGFß1). CAFs produce a topographically aligned extracellular matrix (ECM) that correlates with reduced overall survival. Paradoxically, ablation of CAF populations results in a more aggressive disease, suggesting CAFs can also restrain PDAC progression. Thus, unraveling the mechanism(s) underlying CAF functions could lead to therapies that reinstate the tumor-suppressive features of the pancreatic stroma. CAF activation involves the f-actin organizing protein palladin. CAFs express two palladin isoforms (iso3 and iso4) which are up-regulated in response to TGFß1. However, the roles of iso3 and iso4 in CAF functions remain elusive. Using a CAF-derived ECM model, we uncovered that iso3/iso4 are required to sustain TGFß1-dependent CAF activation, secrete immunosuppressive cytokines, and produce a pro-tumoral ECM. Findings demonstrate a novel role for CAF palladin and suggest that iso3/iso4 regulate both redundant and specific tumor-supportive desmoplastic functions. This study highlights the therapeutic potential of targeting CAFs to restore fibroblastic anti-tumor activity in the pancreatic microenvironment.

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In this study, the effects of strain rate on the mechanical properties and the strain-induced austenite-to-martensite transformation in type 201 austenitic stainless steel (SS201) were investigated. This grade was selected as a low-cost stainless steel with good lightweighting potential for automotive applications. The material was tested in tension at a quasi-static rate (5×10-2 s-1), two low-intermediate rates (100 s-1 and 101 s-1), and a high rate (5×102 s-1). 3D digital image correlation was used to enable accurate strain measurements during mechanical testing. Magnetic induction and X-ray diffraction were used ex-situ of deformation to measure the volume fraction of martensite formed at each strain rate, for different plastic strain levels. The effects of strain rate on deformation-induced martensite formation and on the stress/strain behavior was determined in this study, and was compared to results reported in the literature for 300 series austenitic stainless steels. The results show a favourable response for the SS201, which exhibits a substantial increase in strength and energy absorption at high rates without compromising tensile ductility.

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Variation in moisture content of the capsule shells either due to the change of storage conditions or the moisture transfer between the capsule shell and its contents may lead to undesired physical properties, such as capsule brittleness and stickiness. DMP 504, a developmental bile-acid sequestrant, is a strongly basic anion-exchange polymer which contains randomly distributed primary, secondary, tertiary, and quaternary amine groups in their hydrochoride salt form. The alkylammonium groups which comprise this polymer form a random network containing a high level of branching and a low level of cross-linking. DMP 504 is very hygroscopic and has a tendency to gain or lose moisture with ease. The transfer of moisture from the capsule shell to DMP 504 powder contained in a hard gelatin capsule can be expected, and if a low water content of the capsule shell is achieved, the capsules become brittle and fracture easily. The sorption isotherm for DMP 504 was generated by storing the drug substance under various relative humidity conditions. After equilibrium, the moisture contents for the samples of individual isotherm points were measured by thermogravimetric analyses. This report applies the sorption-desorption moisture transfer (SDMT) model to predict the equilibrium relative humidity in a system containing DMP 504 in hard gelatin capsules and to establish target loss on drying values for DMP 504 and the capsule shell. Application of this SDMT model resulted in finding a solution to the brittleness problem. The moisture levels of capsule shells and contents for two formulations in a 12-month stability program are also reported here. Results of this study further demonstrate that the SDMT model can be used as a tool to guide the formulator to select optimal initial moisture contents for the empty capsule shell and the formulation to avoid the incidence of brittle capsule problems.

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The purpose of this study was to characterize the physicochemical properties of DMP 504 and lay the foundation for formulation development. Thermal properties were characterized by DSC and TGA and moisture sorption and desorption by TGA. The association rate and equilibrium binding capacity of the polymer for a prototype bile acid was evaluated using cholic acid, and solid state stability was examined at 25 degrees C, 40 degrees C (with and without 5% added water), 60 degrees C, and 600 foot candles/25 degrees C. The solid state excipient compatibility of binary mixtures of DMP 504 and several commonly used pharmaceutical excipients was also evaluated. Thermal analysis of the polymer showed a glass transition temperature at approximately 95 degrees C and no melting point, indicating a highly amorphous macromolecular structure with thermal stability up to 250 degrees C. Moisture sorption and desorption isotherms at controlled humidity ranging from 11% to 97% RH did not display hysteresis. Cholic acid associated with DMP 504 extremely rapidly so that binding was essentially complete within 5 min. Scatchard analysis of the equilibrium binding of cholic acid to DMP 504 was unconventional, and indicated that the system was exhibiting positive cooperative behavior. Modeling the binding curve for a system exhibiting cooperative behavior indicated a maximum binding capacity of DMP 504 for cholic acid in phosphate buffered saline (pH 7.0) of 4.9 mumol/mg, and a cooperativity value, P, of 2.2 implying that binding of one molecule promotes the binding of additional molecules. DMP 504, a hygroscopic, amorphous cross-linked polymer with a tendency to gain or lose moisture with ease, is stable in the solid state, either drug substance alone or in presence of excipients, at normal storage temperatures and light, and under controlled conditions of humidity.

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PURPOSE: The objective was to evaluate the degradation profile of the elastase inhibitor DMP 777 and lay the foundation for formulation development. METHODS: The pKa was determined by potentiometric titration in mixed-aqueous solvents. The degradation kinetics were studied as a function of pH, buffer concentration, ionic strength, methanol concentration and temperature using a stability-indicating HPLC assay. The degradation products were identified by LC-MS, NMR, and by comparison with authentic samples. RESULTS: The pKa for the protonated piperazine nitrogen was estimated to be 7.04. The pH-rate profile is described by specific acid-, water-, and specific base-catalyzed pathways. The pH of maximum stability is in the range of 4 to 4.5 where water is the principal catalyst in the reaction. Buffer catalysis, primary salt effects and medium effects were observed. The proposed mechanism for acid catalyzed degradation is the rarely observed AAL1 which involves alkyl-nitrogen heterolysis. The driving force for the reaction appears to lie in the stability of the benzylic carbocation. The proposed mechanism for base catalyzed degradation is BAC2 which involves beta-lactam ring opening. The beta-lactam ring of DMP 777, a monolactam, appears to be as reactive as that in benzylpenicillin in the KOH controlled region where a similar mechanism of hydrolysis should be operative. A contributing factor to this increased reactivity may lie in the reduced basicity of the beta-lactam nitrogen making it a good leaving group. CONCLUSIONS: The degradation profile indicates that development of a solution dosage form of DMP 777 with adequate shelf-life stability at room temperature is feasible.

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The purpose of this research was to enhance the aqueous solubility of DMP 840 by complexation with water-soluble and nontoxic agents, and to understand the nature of the interactions involved in complex formation using nuclear magnetic resonance (1H-NMR). The solubility of DMP 840 in water, saline, acetate buffers, and cosolvent mixtures was determined by high-performance liquid chromatography, and the effect of nicotinamide and pyridoxine concentrations on the solubility of DMP 840 was examined by the phase solubility method. 1H-NMR spectra were acquired in deuterated acetate buffer at 400 MHz on a Varian Unity-400 spectrometer. The aqueous solubility of DMP 840 was sensitive to the presence of chloride and acetate anions in solution, and did not improve in the presence of cosolvents. The use of the nontoxic and water-soluble complex-forming agents nicotinamide and pyridoxine, however, resulted in a linear increase in the aqueous solubility of DMP 840 with both ligands. The solubilization appears to be due to formation of 1:1 complexes between DMP 840 and the bioorganic ligands. The complexation constants were 15.57 M-1 for the DMP 840:nicotinamide complex and 13.36 M-1 for the DMP 840:pyridoxine complex. The NMR results indicate that the interaction is a result of vertical or plane-to-plane stacking and the complexation constants were in agreement with that obtained by phase solubility. The results suggest that the aqueous solubility of a poorly water soluble drug substance such as DMP 840 can be significantly enhanced by its complexation with water-soluble and nontoxic agents.

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A major challenge in intranasal delivery of peptides is to overcome the enzymatic barrier that limits their absorption. Aminopeptidase inhibitors may be useful for improving systemic delivery of peptide drugs administered nasally. A phosphinic acid dipeptide analogue, a transition-state analogue aminopeptidase inhibitor in which the phosphinate moiety exists in a tetrahedral state mimicking peptides during their enzymatic hydrolysis, was synthesized and tested nasally in situ in rats. This inhibitor was found to inhibit greatly the degradation of the model peptide leucine-enkephalin in the nasal perfusate at less than or equal to 2 microM concentrations. The nasal peptidase hydrolytic activity was reversible after exposure to the inhibitor. This inhibitor has the advantage of efficacy at very low concentrations and reversibility of effects.

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A total of 3622 physicians registered in the Association of Physicians of India were contacted through mail and requested to respond to a semistructured questionnaire pertaining to different aspects of medical ethics, with particular focus on informed consent. Six hundred twenty-nine physicians (17.4%) responded to the questionnaire; 86% of the respondents reported having had no formal training in medical ethics; 49% of the subjects who undertook research obtained oral consent only. Majority of the respondents noted the relevance of ethics in different medical situations, though in certain areas like community health and research using animals ethical issues were felt to be less important. Patients' inability to come for regular follow-up and illiteracy were opined to be the main constraints in obtaining consent. Opinion on the amount of information to be imported to research participants as part of informed consent was at variance with standard guidelines. Physicians who reported having had an orientation course in medical ethics and those with prior research experience were more aware of ethical issues. Majority of the professionals desired for inclusion of ethics in medical curriculum.

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This report describes the results of a multicentre collaborative study comparing the safety and efficacy of alprazolam with imipramine in patients suffering from major depressive disorder. Two hundred and eight patients diagnosed as major depression as per DSM-III criteria were randomly allocated to alprazolam (N= 105) or imipramine (N = 103) in a double-blind fashion. Detailed assessments were carried out for a period of six weeks. Results revealed that alprazolam was as effective as imipramine as an antidepressant. Side effects were less frequently reported with alprazolam.

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In a multicentre trial, intramuscular 15(S)15 methyl PGF2α (Prostin 15M, Up-john) was tried at 2-hourly and 3-hourly intervals for induction of second trimester abortion. The time schedule was assigned randomly. Eighty-eight patients for 2-hourly schedule and 89 patients for 3-hourly schedule were recruited. Of 2-hourly 83% and of 3-hourly schedule 88.8% of the patients aborted with the treatment. The induction abortion interval was 15.9 hours in 2-hourly and 17.2 hours in 3-hourly schedule. The dose of Prostin 15M was 2.2 mg and 1.7 mg respectively. The incidence of incomplete abortion was 21.9% in 2-hourly and 27.8% in the 3-hourly. The incidence of vomiting was less in the 3-hourly schedule, however, there was no difference in the incidence of diarrhoea.

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A multicentre study was undertaken to study intramuscular 15(S)15 methyl PGF2α (Prostin 15M, Upjohn) for induction of second trimester abortion. The patients were premedicated with Imodium and Perinorm to control the gastrointestinal side effects. The dose of Prostin 15M was 250 µg every two hours and the progress of the abortion was assessed before each injection. If there was no progress at the end of 10 injections the case was classified as a failure. Ninety-seven patients were recruited for the study, 39 were primigravidae and 58 multigravidae. Twenty-four out of 39 primigravidae and 52 out of 58 multigravidae aborted with the treatment. The mean induction abortion interval was 17.8 hours in the primigravidae and 14.5 hours in the multigravidae patients. The mean number of episodes of vomiting was 2.9 and diarrhoea 4.2 per patient per trial. The primigravidae had slightly higher incidence of gastrointestinal side effects. The overall incidence of incomplete abortion was 17.1%.

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In a multicentre trial the efficacy of 250 µg of intramuscular 15(S)15 methyl PGF2α (Prostin 15M, Upjohn) was tested in controlling the postpartum hemorrhage following delivery at term. All patients included in this study did not respond to the conventional therapy of intravenous oxytocin infusion and methergin. Forty-eight patients were included in this analysis. Forty patients responded to therapy. The blood loss following Prostin 15M injection was significantly (p<0.01) reduced from 666 ml to 341 ml. The mean blood replacement was 833 ml.

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Intramuscular 15(S)15 methyl PGF2α (Prostin 15M, Upjohn) was used for induction of labour in cases of missed abortion and intra-uterine fetal death. The patients received premedication to control the gastrointestinal side effects. Prostin 15M was given at a dose of 250 µg every three hours and escalated whenever required. The trial was interrupted in two out of 83 patients. Altogether 75 patients (92.6%) expelled the fetus with the treatment. The mean induction abortion interval was 14.7 hours. The primigravidae had a longer (18.2 hrs) interval than the multigravidae (13.8 hrs). The mean number of episodes of vomiting was 2.9 and of diarrhoea 3.5 per patient and treatment.

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A redox chemical delivery system based on the NADH in equilibrium NAD+ model was applied to an active metabolite (D) of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), i.e. CCNU-OH. The 1,4-dihydrotrigonelline ester of CCNU-OH, N-(2-chloro ethyl)-N'-[trans-4-(1,4-dihydro-1-methyl-3-pyridinecarbonyloxy)cyc lohexyl]- N-nitrosourea (D-CDS) was prepared by a direct hydride transfer reaction of the corresponding pyridinium precursor (D-Q+) with a highly reactive 1-benzyl-1,2-dihydroisonicotinamide. The in vitro kinetics in biological fluids indicated facile oxidative conversion of D-CDS to D-Q+. An in vivo study showed that one intravenous injection to rats of D-CDS resulted in rapid brain accumulation of D-Q+, followed by a sustained release of CCNU-OH, while D-Q+ was rapidly eliminated from systemic circulation. The ratio of brain/blood concentration of D-Q+ was found to increase progressively with time. At an equimolar dose of CCNU-OH, the ratio of brain/blood concentration for CCNU-OH was found to be close to unity.

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