Role of pharmacoeconomics in formulary decision-making

Master'sMASTER OF SCIENCE (PHARMACY

Histidylated lipid-modified sendai viral envelopes mediate enhanced membrane fusion and potentiate targeted gene delivery

Recent studies have demonstrated that covalent grafting of a single histidine residue into a twin-chain aliphatic hydrocarbon compound enhances its endosome-disrupting properties and thereby generates an excellent DNA transfection system. Significant increase in gene delivery efficiencies has thus been obtained by using endosome-disrupting multiple histidine functionalities in the molecular architecture of various cationic polymers. To take advantage of this unique feature, we have incorporated L-histidine (N,N-di-n-hexadecylamine) ethylamide (L(H)) in the membrane of hepatocyte-specific Sendai virosomes containing only the fusion protein (F-virosomes (Process for Producing a Targeted Gene (Sarkar, D. P., Ramani, K., Bora, R. S., Kumar, M., and Tyagi, S. K. (November 4, 1997) U. S. Patent 5,683,866))). Such L(H)-modified virosomal envelopes were four times more (p <0.001) active in terms of fusion with its target cell membrane. On the other hand, the presence of L(H) in reconstituted influenza and vesicular stomatitis virus envelopes failed to enhance spike glycoprotein-induced membrane fusion with host cell membrane. Circular dichroism and limited proteolysis experiments with F-virosomes indicated that the presence of L(H) leads to conformational changes in the F protein. The molecular mechanism associated with the increased membrane fusion induced by L(H) has been addressed in the light of fusion-competent conformational change in F protein. Such enhancement of fusion resulted in a highly efficient gene delivery system specific for liver cells in culture and in whole animals

Conotoxin modulation of ion channels in pain pathways

Pain which is an unpleasant sensory and emotional experience incorporating substantial tissue damage, remains quite unexplored in terms of chronic pain treatment due to availability and over prescription of opioid analgesics. These opioid drugs modulate the inhibitory signaling through coupling with G protein-coupled receptors (GPCR) (-opioid receptor), modulating a variety of ion channels and thus, resulting in inhibition of neurotransmitter release at the primary afferent nerve terminals in the spinal cord producing anti-nociception. However, the desired outcomes cannot outweigh the resultant adverse effects such as tolerance and dependency, limiting opioids’ therapeutic effectiveness. Therefore, with the aim to discover an alternative drug effective in anti-nociception, my current approach is to investigate novel conopeptides derived from the venom of marine cone snails that modulate membrane receptors and ion channels in the pain pathways. I have primarily focused on -conotoxin Vc1.1 which was originally proposed to be anti-nociceptive through inhibition of neuronal nicotinic acetylcholine receptors (nAChRs). However, the disparity in its functional activity between human and rat 910 nAChR resulted in its withdrawal from phase II clinical trial (Metabolic Discontinues ACV1 Trial, 2007). Nevertheless, the extension of this study in α9α10 knockout mice producing effective analgesia elevated curiosity of the researchers to explore more thoroughly. Interestingly, this led to the discovery of Vc1.1 activity at the GABAB receptor (GABABR) that intensified the need for their preclinical development as an effective pharmacophore. Concurrently, development of a truncated version of full length -conotoxinVc1.1, with the aim to make the compound faster, serum stable and target specific, Vc1.1(1-8) from “loop” 1 was synthesized and shown analgesic for chronic visceral hypersensitivity (CVH)

Impact of co-morbid insomnia on health -related quality of life and patient preferences in the primary care setting.

It is estimated that almost one-thirds of the patients in primary care settings experience some form of insomnia. Co-morbid insomnia accounts for almost 75% of such cases and, is considered to be a symptom (rather than a stand-alone disorder) that remits with treatment of the underlying medical or psychiatric disorder. In Phase I, this study examined if there was any incremental impact of co-morbid insomnia (after controlling for confounding covariates) on health-related quality of life (as measured by the Medical Outcomes Study 36 Item Short-Form Health Survey, i.e., SF-36, and the EuroQoL 5D, i.e., EQ-5D) compared to similar patients without insomnia across five disease groups i.e., cardiovascular, diabetes, gastrointestinal, musculoskeletal, and obstructive airways diseases. The study also estimated ‘utilities’ (cardinal numbers reflecting health-related quality of life experienced) attached to various health states in insomnia (using the EQ-5D), by means of a self-administered mailed survey of patients visiting the Clark K. Sleeth Family Medicine Center, West Virginia University, Morgantown, WV. In Phase II, the study estimated the minimum quantum of improvements in sleep problems (as measured by the Insomnia Severity Index, i.e., ISI), sleep quality (as measured by the Pittsburgh Sleep Quality Index, i.e., PSQI), and HRQL (as measured by SF-36) considered ‘meaningful’ by patients suffering from insomnia, and examined stated preferences (in the form of willingness to pay) for various attributes of symptom relief offered by hypnotic drugs. Phase II employed, one-on-one discussions of patients, and filling of paper-and-pencil format discrete choice experiment questionnaire (DCE), in the presence of the researcher. As an extension arm of Phase II a mailed survey of the DCE questionnaire was also carried out. Phase I Results: Based on an overall response rate of 46.58% (N=1,020) it was seen that average scores (associated with insomnia) in HRQL domains compared with the no-insomnia group after controlling for socio-demographic characteristics, health habits, BMI, number of medical conditions, and the presence of depressive symptoms were significantly lower for all domains across the five disease groups. Analysis of EQ-5D scores after controlling for all relevant covariates, showed significantly lower utilities in the insomnia group when compared to the no-insomnia group in all disease groups. Phase II Results: Based on discussions of each of 45 patients (identified as having ‘insomnia’ from Phase I and invited to participate in discussions involving one-on-one interactions with three other patients) there seem to be certain quanta of changes on the ISI, PSQI, and SF-36 that insomnia patients consider ‘meaningful’. However, deterioration and improvements did not seem to be viewed in a similar manner. Again, willingness to pay (WTP) estimates obtained by means of a DCE administered to 45 patients, who were invited for discussions (and from another 82 patients through a mailed survey) revealed that patients have different preferences for different attributes of treatment-induced symptom relief in insomnia

A cross-sectional study to compare intraocular pressure measurement by sequential use of Goldman applanation tonometry, dynamic contour tonometry, ocular response analyzer, and Corvis ST

Objective: To study the correlation and effect of sequential measurement of intraocular pressure (IOP) with Goldmann applanation tonometer (GAT), ocular response analyzer (ORA), dynamic contour tonometer (DCT), and Corvis ST. Setting and Design: Observational cross-sectional series from the comprehensive clinic of a tertiary eye care center seen during December 2012. Methods: One hundred and twenty-five study eyes of 125 patients with normal IOP and biomechanical properties underwent IOP measurement on GAT, DCT, ORA, and Corvis ST; in four different sequences. Patients with high refractive errors, recent surgeries, glaucoma, and corneal disorders were excluded so as to rule out patients with evident altered corneal biomechanics. Statistical Analysis: Linear regression and Bland-Altman using MedCalc software. Results: Multivariate analysis of variance with repeated measures showed no influence of sequence of device use on IOP (P = 0.85). Linear regression r 2 between GAT and Corvis ST, Corvis ST and Goldmann-correlated IOP (IOPg), and DCT and Corvis ST were 0.37 (P = 0.675), 0.63 (P = 0.607), and 0.19 (P = 0.708), respectively. The Bland-Altman agreement of Corvis ST with GAT, corneal compensated IOP, and IOPg was 2 mmHg (−5.0 to + 10.3), −0.5 mmHg (−8.1 to 7.1), and 0.5 mmHg (−6.2 to 7.1), respectively. Intraclass correlation coefficient for repeatability ranged from 0.81 to 0.96. Conclusions: Correlation between Corvis ST and ORA was found to be good and not so with GAT. However, agreement between the devices was statistically insignificant, and no influence of sequence was observed

Site-specific microstructure, porosity and mechanical properties of LENSTM processed Ti-6Al-4V alloy

In the present study, pre-alloyed Ti-6Al-4V powder is deposited on CP-Titanium substrate by laser engineered net shaping (LENSTM) process using parameters optimized for best adhesion and densification. The optical montages from the three surfaces (front, side and top) show columnar beta grains growing along the building direction due to conductive heat transfer through the substrate. The as-deposited microstructure contains thin lamellar (alpha+beta)-colonies besides prior beta grain boundaries and basket-weave (alpha+beta)-structure inside prior beta grains. Narrow band-like structure forms between consecutive layers due to re-melting of previously deposited layers, thereby creating additional interfaces in the microstructure. In addition, tiny isolated pores appears in negligible fraction throughout the LENSTM-processed specimen due to gas entrapment, shrinkage during cooling and unmelted or partially melted powder particles. Both the number and volume of the pores increase along the building direction. Hardness on different surfaces (front, side and top) differs considerably due to the presence of different heating/cooling zones, residual stresses and variations in the thermal cycles and consequent change in the alpha'-martensite phase fraction. Larger variation in the hardness between these surfaces is observed in nanoindentation technique signifying for inhomogeneity in nano-scale structure. These microstructural variations also resulted in measurable changes in the coefficient in friction (COF) during scratch testing from the substrate along the building direction due to presence of different heating/cooling zones (diffused vs. reheating/re-melting zones). The variation in hardness and COF along different directions can ultimately lessen the in-service performance of the as-deposited parts