Evaluating Curriculum Differences in US PharmD Programs: A Peer Evaluation.

OBJECTIVE: To evaluate the differences in curriculum structure and content and observe commonalities across various Doctor of Pharmacy (PharmD) programs in the United States. METHODS: This research involves the collection of course content and credit hour data from the curricula and course descriptions, course catalogs, and student handbooks of all the PharmD programs available on their websites and categorization based on the content areas outlined in the Accreditation Council of Pharmacy Education. The core courses, elective offerings, and experiential education (eg, Introductory and Advanced Pharmacy Practice Experience) were evaluated using Excel® for credit hours, integration, non-integration, program duration (3-year vs 4-year), and online offerings. RESULTS: Of 142 accredited schools/colleges, 135 were included in the study, which met the inclusion criteria. In total, 85 of these schools have an integrated curriculum, 19 have a 3-year curriculum, and 15 offer a distance learning pathway for a PharmD degree. Fourteen of the 37 required content areas from the Accreditation Council of Pharmacy Education Appendix 1 were identified, with more than 50% of schools listing no credit hours allocated. Only 9 areas had 90% or more of pharmacy schools allocating credit hours. On average, biomedical, pharmaceutical, social/administrative/behavioral, clinical sciences, experiential education, and electives allocate 10.6, 25.3, 17.1, 40.5, 45.5, and 7.0 credit hours, respectively. CONCLUSION: Each school's curriculum has a significant variation in credit hours, and there is an opportunity to simplify the curricular structure and content by reducing redundancy and increasing flexibility based on health care needs.

The Status of Students, Faculty, and Leadership Diversities in US Pharmacy Schools/Colleges.

OBJECTIVE: The purpose of this research is to address knowledge gaps on diversity in the United States (US) population, pharmacy students, faculty, and school/college leadership. METHOD: The population data were collected from the US Census Bureau. The pharmacy student and faculty data were collected from the American Association of Colleges of Pharmacy enrollment and faculty profiles to compute Diversity Indices (DIs). To delve further into observed DI values, different ratios were calculated by dividing the total number of people in a racial/ethnic group of a particular category (eg, students) by the total number of people in the same racial/ethnic group in a different category (eg, faculty). Two factors (ratios among racial groups and changes in ratios over time) ANOVA without replication was conducted using Excel. RESULTS: The students are the most diverse category (average DI = 69%), followed by the US population (average DI = 58%), faculty diversity (average DI = 54%), assistant/associate dean (average DI = 42%) and dean (average DI = 31%). The ratio analyses among student, faculty, and leadership categories reveal a disproportionately high representation of White individuals in faculty and leadership roles when compared to other racial groups, resulting in low DI values in these categories. CONCLUSION: A significant ratio difference was found among various racial groups each year. However, there was no significant change observed in ratios over time. The academic community must develop hiring practices that increase the DI values among faculty and leadership categories to reduce the gap and promote student success.

On the prevalence of flow instabilities from high-fidelity computational fluid dynamics of intracranial bifurcation aneurysms.

High-fidelity computational fluid dynamics (HF-CFD) has revealed the potential for high-frequency flow instabilities (aka "turbulent-like" flow) in intracranial aneurysms, consistent with classic in vivo and in vitro reports of bruits and/or wall vibrations. However, HF-CFD has typically been performed on limited numbers of cases, often with unphysiological inflow conditions or focused on sidewall-type aneurysms where flow instabilities may be inherently less prevalent. Here we report HF-CFD of 50 bifurcation aneurysm cases from the open-source Aneurisk model repository. These were meshed using quadratic finite elements having an average effective spatial resolution of 0.065 mm, and solved under physiologically-pulsatile flow conditions using a well-validated, minimally-dissipative solver with 20,000 time-steps per cardiac cycle Flow instability was quantified using the recently introduced spectral power index (SPI), which quantifies, from 0 to 1, the power associated with velocity fluctuations above those of the driving inflow waveform. Of the 50 cases, nearly half showed regions within the sac having SPI up to 0.5, often with non-negligible power into the 100's of Hz, and roughly 1/3 had sac-averaged SPI > 0.1. High SPI did not significantly predict rupture status in this cohort. Proper orthogonal decomposition of cases with highest SPIavg revealed time-varying energetics consistent with transient turbulence. Our reported prevalence of high-frequency flow instabilities in HF-CFD modelling of aneurysms suggests that care must be taken to avoid routinely overlooking them if we are to understand the highly dynamic mechanical forces to which some aneurysm walls may be exposed, and their prevalence in vivo.

Non-Newtonian versus numerical rheology: Practical impact of shear-thinning on the prediction of stable and unstable flows in intracranial aneurysms.

Computational fluid dynamics (CFD) shows promise for informing treatment planning and rupture risk assessment for intracranial aneurysms. Much attention has been paid to the impact on predicted hemodynamics of various modelling assumptions and uncertainties, including the need for modelling the non-Newtonian, shear-thinning rheology of blood, with equivocal results. Our study clarifies this issue by contextualizing the impact of rheology model against the recently demonstrated impact of CFD solution strategy on the prediction of aneurysm flow instabilities. Three aneurysm cases were considered, spanning a range of stable to unstable flows. Simulations were performed using a high-resolution/accuracy solution strategy with Newtonian and modified-Cross rheology models and compared against results from a so-called normal-resolution strategy. Time-averaged and instantaneous wall shear stress (WSS) distributions, as well as frequency content of flow instabilities and dome-averaged WSS metrics, were minimally affected by the rheology model, whereas numerical solution strategy had a demonstrably more marked impact when the rheology model was fixed. We show that point-wise normalization of non-Newtonian by Newtonian WSS values tended to artificially amplify small differences in WSS of questionable physiological relevance in already-low WSS regions, which might help to explain the disparity of opinions in the aneurysm CFD literature regarding the impact of non-Newtonian rheology. Toward the goal of more patient-specific aneurysm CFD, we conclude that attention seems better spent on solution strategy and other likely "first-order" effects (eg, lumen segmentation and choice of flow rates), as opposed to "second-order" effects such as rheology.

Discovery of Antischistosomal Drug Leads Based on Tetraazamacrocyclic Derivatives and Their Metal Complexes.

Praziquantel (PZQ) is the only drug available for the treatment of schistosomiasis, and since its large-scale use might be associated with the onset of resistance, new antischistosomal drugs should be developed. A series of 26 synthetic tetraazamacrocyclic derivatives and their metal complexes were synthesized, characterized, and screened for antischistosomal activity by application of a phased screening program. The compounds were first screened against newly transformed schistosomula (NTS) of harvested Schistosoma mansoni cercariae, then against adult worms, and finally, in vivo using the mouse model of S. mansoni infection. At a concentration of 33 µM, incubation with a total of 12 compounds resulted in the mortality of NTS at the 62% to 100% level. Five of these showing 100% inhibition of viability of NTS at 10 µM were selected for further screening for determination of the 50 inhibitory concentrations (IC50s) against both NTS and adult worms. Against NTS, all 5 compounds showed IC50s comparable to the IC50 of the standard drug, PZQ (0.87 to 9.65 µM for the 5 compounds versus 2.20 µM for PZQ). Three of these, which are the bisquinoline derivative of cyclen and its Fe(2+) and Mn(2+) complexes, showed micromolar IC50s (1.62 µM, 1.34 µM, and 4.12 µM, respectively, versus 0.10 µM for PZQ) against adult worms. In vivo, the worm burden reductions were 12.3%, 88.4%, and 74.5%, respectively, at a single oral dose of 400 mg/kg of body weight. The Fe(2+) complex exhibited activity in vivo comparable to that of PZQ, pointing to the discovery of a novel drug lead for schistosomiasis.

Narrowing the Expertise Gap for Predicting Intracranial Aneurysm Hemodynamics: Impact of Solver Numerics versus Mesh and Time-Step Resolution.

BACKGROUND AND PURPOSE: Recent high-resolution computational fluid dynamics studies have uncovered the presence of laminar flow instabilities and possible transitional or turbulent flow in some intracranial aneurysms. The purpose of this study was to elucidate requirements for computational fluid dynamics to detect these complex flows, and, in particular, to discriminate the impact of solver numerics versus mesh and time-step resolution. MATERIALS AND METHODS: We focused on 3 MCA aneurysms, exemplifying highly unstable, mildly unstable, or stable flow phenotypes, respectively. For each, the number of mesh elements was varied by 320× and the number of time-steps by 25×. Computational fluid dynamics simulations were performed by using an optimized second-order, minimally dissipative solver, and a more typical first-order, stabilized solver. RESULTS: With the optimized solver and settings, qualitative differences in flow and wall shear stress patterns were negligible for models down to ∼800,000 tetrahedra and ∼5000 time-steps per cardiac cycle and could be solved within clinically acceptable timeframes. At the same model resolutions, however, the stabilized solver had poorer accuracy and completely suppressed flow instabilities for the 2 unstable flow cases. These findings were verified by using the popular commercial computational fluid dynamics solver, Fluent. CONCLUSIONS: Solver numerics must be considered at least as important as mesh and time-step resolution in determining the quality of aneurysm computational fluid dynamics simulations. Proper computational fluid dynamics verification studies, and not just superficial grid refinements, are therefore required to avoid overlooking potentially clinically and biologically relevant flow features.

Determination of log P values of new cyclen based antimalarial drug leads using RP-HPLC.

Lipophilicity, expressed by log P, is an important physicochemical property of drugs that affects many biological processes, including drug absorption and distribution. The main purpose of this study to determine the log P values of newly discovered drug leads using reversed-phase high-performance liquid chromatography (RP-HPLC). The reference standards, with varying polarity ranges, were dissolved in methanol and analyzed by RP-HPLC using a C18 column. The mobile phase consisted of a mixture of acetonitrile, methanol and water in a gradient elution mode. A calibration curve was plotted between the experimental log P values and obtained log k values of the reference standard compounds and a best fit line was obtained. The log k values of the new drug leads were determined in the same solvent system and were used to calculate the respective log P values by using the best fit equation. The log P vs. log k data gave a best fit linear curve that had an R2 of 0.9786 with Pvalues of the intercept and slope of 1.19 x 10(-6) and 1.56 x 10(-10), respectively, at 0.05 level of significance. Log P values of 15 new drug leads and related compounds, all of which are derivatives of macrocyclic polyamines and their metal complexes, were determined. The values obtained are closely related to the calculated log P (Clog P) values using ChemDraw Ultra 12.0. This experiment provided efficient, fast and reasonable estimates of log P values of the new drug leads by using RP-HPLC.

Synthesis and antimalarial activity of metal complexes of cross-bridged tetraazamacrocyclic ligands.

Using transition metals such as manganese(II), iron(II), cobalt(II), nickel(II), copper(II), and zinc(II), several new metal complexes of cross-bridged tetraazamacrocyclic chelators namely, cyclen- and cyclam-analogs with benzyl groups, were synthesized and screened for in vitro antimalarial activity against chloroquine-resistant (W2) and chloroquine-sensitive (D6) strains of Plasmodium falciparum. The metal-free chelators tested showed little or no antimalarial activity. All the metal complexes of the dibenzyl cross-bridged cyclam ligand exhibited potent antimalarial activity. The Mn(2+) complex of this ligand was the most potent with IC50s of 0.127 and 0.157µM against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) P. falciparum strains, respectively. In general, the dibenzyl hydrophobic ligands showed better anti-malarial activity compared to the activity of monobenzyl ligands, potentially because of their higher lipophilicity and thus better cell penetration ability. The higher antimalarial activity displayed by the manganese complex for the cyclam ligand in comparison to that of the cyclen, correlates with the larger pocket of cyclam compared to that of cyclen which produces a more stable complex with the Mn(2+). Few of the Cu(2+) and Fe(2+) complexes also showed improvement in activity but Ni(2+), Co(2+) and Zn(2+) complexes did not show any improvement in activity upon the metal-free ligands for anti-malarial development.

Medicinal chemistry and the pharmacy curriculum.

The origins and advancements of pharmacy, medicinal chemistry, and drug discovery are interwoven in nature. Medicinal chemistry provides pharmacy students with a thorough understanding of drug mechanisms of action, structure-activity relationships (SAR), acid-base and physicochemical properties, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles. A comprehensive understanding of the chemical basis of drug action equips pharmacy students with the ability to answer rationally the "why" and "how" questions related to drug action and it sets the pharmacist apart as the chemical expert among health care professionals. By imparting an exclusive knowledge base, medicinal chemistry plays a vital role in providing critical thinking and evidence-based problem-solving skills to pharmacy students, enabling them to make optimal patient-specific therapeutic decisions. This review highlights the parallel nature of the history of pharmacy and medicinal chemistry, as well as the key elements of medicinal chemistry and drug discovery that make it an indispensable component of the pharmacy curriculum.

Synthesis and antimalarial activities of cyclen 4-aminoquinoline analogs.

In an attempt to augment the efficacy of 7-chloro 4-aminoquinoline analogs and also to overcome resistance to antimalarial agents, we synthesized three cyclen (1,4,7,10-tetraazacyclododecane) analogs of chloroquine [a bisquinoline derivative, 7-chloro-4-(1,4,7,10-tetraaza-cyclododec-1-yl)-quinoline HBr, and a 7-chloro-4-(1,4,7,10-tetraaza-cyclododec-1-yl)-quinoline-Zn(2+) complex]. The bisquinoline displays the most potent in vitro and in vivo antimalarial activities. It displays 50% inhibitory concentrations (IC(50)s) of 7.5 nM against the D6 (chloroquine-sensitive) clone of Plasmodium falciparum and 19.2 nM against the W2 (chloroquine-resistant) clone, which are comparable to those of artemisinin (10.6 and 5.0 nM, respectively) and lower than those of chloroquine (10.7 and 87.2 nM, respectively), without any evidence of cytotoxicity to mammalian cells, indicating a high selectivity index (>1,333 against D6 clone and >521 against W2 clone). Potent antimalarial activities of the bisquinoline against chloroquine- and mefloquine-resistant strains of P. falciparum were also confirmed by in vitro [(3)H]hypoxanthine incorporation assay. The in vivo antimalarial activity of the bisquinoline, as determined in P. berghei-infected mice, is comparable to that of chloroquine (50% effective dose,

Synthesis of isoquinuclidine analogs of chloroquine: antimalarial and antileishmanial activity.

The isoquinuclidine (2-azabicyclo[2.2.2]octane) ring system may be viewed as a semi-rigid boat form of the piperidine ring and, when properly substituted, a scaffold for rigid analogs of biologically active ethanolamines and propanolamines. It is present in natural products (such as ibogaine and dioscorine) that display interesting pharmacological properties. In this study, we have expanded our continuing efforts to incorporate this ring system in numerous pharmacophores, by designing and synthesizing semirigid analogs of the antimalarial drug chloroquine. The analogs were tested in vitro against Plasmodium falciparum strains and Leishmania donovani promastigote cultures. Compounds 6 and 13 displayed potent antimalarial activity against both chloroquine-susceptible D6 and the -resistant W2 strains of P. falciparum. All analogs also demonstrated significant antileishmanial activity with compounds 6 and 13 again being the most potent. The fact that these compounds are active against both chloroquine-resistant and chloroquine-sensitive strains as well as leishmanial cells makes them promising candidates for drug development.

Analgesic activity of Enhydra fluctuans.

The methanol extract of Enhydra fluctuans, given orally at the dose of 250 and 500 mg/kg, was evaluated for its analgesic activity using the acetic acid induced writhing and the tail-flick methods. The extract showed promising activity in both tests.

Use of an additional hydrophobic binding site, the Z site, in the rational drug design of a new class of stronger trypanothione reductase inhibitor, quaternary alkylammonium phenothiazines.

Improved rationally designed lead drug structures against African trypanosomiasis, Chagas disease, and leishmaniasis were obtained against trypanothione reductase from Trypanosoma cruzi. Substituted-benzyl [3-(2-chloro-4a, 10a-dihydrophenothiazin-10-yl)propyl]dimethylammonium salts, synthesized by Menschutkin quaternization of the tertiary alkylamine omega-nitrogen atom of chlorpromazine, were linear, competitive inhibitors of recombinant trypanothione reductase from T. cruzi, with either trypanothione disulfide or N-benzyloxycarbonyl-L-cysteinylglycyl 3-dimethylaminopropylamide disulfide as substrate. The permanent positive charge on the distal nitrogen atom of the tricyclic side chain contribution to binding was estimated as >/=5.6 kcal.mol(-1) by comparison with the analogue with the cationic nitrogen atom of the quaternary replaced by an ether oxygen atom. A further major contribution to improving K(i) values and inhibition strength was the hydrophobic natures and structures of the N-benzyl substituents. The strongest inhibitor, the [3-(2-chloro-4a,10a-dihydrophenothiazin-10-yl)propyl](3, 4-dichlorobenzyl)dimethylammonium derivative (K(i) 0.12 microM), was approximately 2 orders of magnitude more inhibitory than the parent chlorpromazine. Several of these quaternary phenothiazines completely inhibited T. brucei parasite growth in vitro at <1 microM. Antiparasite activity was not solely determined by inhibition strength against trypanothione reductase, there being a strong contribution from hydrophobicity (for example, benzhydryl-quaternized chlorpromazime had ED(50) < 1 microM). Although active against Leishmania donovani, none of the analogues showed major improvement in this activity relative to chlorpromazine or other nonquaternized phenothiazines. The p-tert-butylbenzyl-quaternized analogue very strongly inhibited (ED(50) < 1 microM) growth of the amastigote stage of T. cruzi.

Ecthyma gangrenosum in patients with acquired immunodeficiency syndrome.

GOAL: To describe the reoccurrence of ecthyma gangrenosum (EG) in two patients with acquired immunodeficiency syndromes (AIDS). OBJECTIVES: 1. To describe the clinical characteristics of EG. 2. To discuss causative organism and risk factor for EG in patients with AIDS. 3. To identify rates of relapse/recurrence of EG in patients with AIDS.

Rational drug design using trypanothione reductase as a target for anti-trypanosomal and anti-leishmanial drug leads.

The parasite enzyme trypanothione reductase has been used as a target for rational drug design against trypanosomiasis and leishmaniasis in a number of laboratories. In this article the biochemical basis for its selection as a target is reviewed. The relevant structural aspects of the target are then compared with the homologous structure found in the mammalian hosts to indicate the molecular basis by which selective toxicity is likely to be achieved. An overview of known classes of inhibitors is provided, preparatory to a detailed coverage of approaches that have been taken to obtaining strong, selective inhibitors and the steps taken in the process of the initial discovery of tricyclic structures by interactive molecular graphics ligand design are outlined. Recent quantitative docking approaches which have been applied to this system are also described. Finally, the biological data of the activity against the various parasitic forms in vitro and in vivo are summarised.