Pharmaceutical Profile Research Articles

Abstract 3261: Novel hemisynthetic derivatives of Amaryllidaceae alkaloids exert antitumor activity on xenograft melanoma models

Abstract Alkaloids pancratistatin and narciclasine, isolated from Amaryllidaceae, have been shown to present antitumor activity on preclinical models, including melanoma. Despite extensive investigations, pancratistatin or narciclasine analogues did not succeed to provide sufficient therapeutic benefit, [1] mostly hampered by poor water solubility and systemic toxicity [1]. To overcome those limitations, we developed a chemistry program aimed at improving both their physicochemical and pharmacological properties. A literature survey suggests that any structural modification of this highly oxigenated isocarbostiryl specific scaffold would lead to a loss of activity except on position 1, difficult to achieve but interesting to explore. A series of 40 novel 1-aminopancratistatin derivatives was synthesised starting from large quantities of narciclasine extracted from Narcissus bulbs. These novel compounds exhibit an improved pharmaceutical profile facing standard solubility, plasmatic and microsomal stability assays. Moreover, a subset of narciclasine derivatives demonstrated a significant enhancement of the antiproliferative effect with IC50 reaching the nM range, consistent with a major induction of pro-apoptotic signals, including mitochondrial depolarisation. To explore the mode of action of these alkaloids derivatives, we tested their capacity to inhibit protein synthesis, compared their pharmacological profile with 80 anticancer compounds on 16 tumor cell lines (oncoprofile.16) and explored their impact on major cellular functions such as cellular integrity, cell cycle, topoisomerases inhibition, DNA damage and synthesis. We demonstrated thus that inhibition of DNA synthesis is a key component of their mechanism of action. Based on the pharmacological properties, a structure-activity card can be built to select different categories of pancrastistatin derivatives depending on their ability to inhibit preferentially protein synthesis or/and DNA synthesis. Interestingly, the dimethylaminomethyl benzamide derivative F98604 exhibited a significant antiproliferative activity on the murine B16 and human A375 melanoma xenograft models associated with an increased therapeutic index as compared with the natural compound narciclasine. In conclusion, modulation of position 1 on the narciclasine pharmacophore overcomes the solubility issue and is a key position to modify their pharmacological profiles, this opening new perspectives as anticancer agents active against melanoma. 1. A. Kornienko, A. Evidente Chem. Rev. 2008, 108, 1982 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3261. doi:10.1158/1538-7445.AM2011-3261

Developing, Documenting, and Defending Your Hospice Care: An Advanced Curriculum (P5) (Advanced)

1.Describe the process to determine which patients with complex diagnoses are appropriate for hospice care and develop an interdisciplinary care plan based on best hospice practices.2.Revise patient pharmaceutical profiles and create appropriate pharmaceutical interventions.3.Produce documentation in a manner that lays the foundation for positive survey outcome and defend care in the current regulatory environment. As our field of medical care matures, the issues of how and when to offer appropriate end-of-life care become more complex; as disease-modifying treatments advance, the patients become more complicated. When a patient on a dobutamine or milrinone infusion or receiving active treatment with Tarceva or Atripla is referred to your hospice program are you comfortable making the decision to care for that patient? What process do you use and how do you determine what resources are needed are to make that decision? With the publication of the most recent Conditions of Participation and with the new physician requirements for certification of terminal illness there is an expectation of strong physician involvement in hospice care. What constitutes good hospice care and how can nurses and physicians work together to develop an appropriate plan of care? Does your team use best practices when reviewing a medication profile? Do you struggle with pharmacy and pharmaceutical issues in the elderly long-term care resident on 15 medications? Which are related versus unrelated and how do you determine which medications should be continued for good care and which ones should be discontinued? Is your documentation really telling the story of the care that your team is providing? How can you find your way through the alphabet soup of the new surveyor environment? Do you know what “ZPIC” and “RAC” mean? This interactive case-based presentation will answer these questions for you and prepare advanced hospice and palliative care providers to deliver high-quality hospice care while navigating through the current regulatory environment. Structure and Processes of Care

Spirodiketopiperazine-based CCR5 antagonist: discovery of an antiretroviral drug candidate.

Following the discovery that hydroxylated derivative 3 (Fig. 1) was one of the oxidative metabolites of the original lead 1, it was found that hydroxylated compound 4 possesses higher in vitro anti-HIV potency than the corresponding non-hydroxylated compound 2. Structural hybridation of 4 with the orally available analog 5 resulted in another orally-available spirodiketopiperazine CCR5 antagonist 6a that possesses more favorable pharmaceutical profile for use as a drug candidate.

ChemInform Abstract: Design and Synthesis of Fluorine‐Substituted 3‐Hydroxypyridin‐4‐ones.

AbstractSeveral 2‐ and 5‐fluoro‐containing 3‐hydroxpyridin‐4‐ones such as (I)‐(IV) are prepared as modified analogues of the known drug deferiprone (V) in order to get substances with improved pharmaceutical profile.

Design and synthesis of fluorine-substituted 3-hydroxypyridin-4-ones

The presence of fluorine in an organic molecule can dramatically alter its chemical and biological properties due to its unique characteristics. Several 2- and 5-fluorine-substituted 3-hydroxypyridin-4-ones have been synthesised with the intention of improving the pharmaceutical profile of deferiprone.

Chitosan: some pharmaceutical and biological aspects--an update.

Chitosan, a natural polysaccharide, is being widely used as a pharmaceutical excipient. It is obtained by the partial deacetylation of chitin, the second most abundant natural polymer. Chitosan comprises a series of polymers varying in their degree of deacetylation, molecular weight, viscosity, pKa etc. The presence of a number of amino groups permit chitosan to chemically react with anionic systems, thereby resulting in alteration of physicochemical characteristics of such combinations. Chitosan has found wide applicability in conventional pharmaceutical devices as a potential formulation excipient, some of which include binding, disintegrating and tablet coating properties. The polymer has also been investigated as a potential adjuvant for swellable controlled drug delivery systems. Use of chitosan in novel drug delivery as mucoadhesive, gene and peptide drug administration via the oral route as well as its absorption enhancing effects have been explored by a number of researchers. Chitosan exhibits myriad biological actions, namely hypocholesterolemic, antimicrobial and wound healing properties. Low toxicity coupled with wide applicability makes it a promising candidate not only for the purpose of drug delivery for a host of drug moieties (antiinflammatories, peptides etc.) but also as a biologically active agent. It is the endeavour of the present review to provide an insight into the biological and pharmaceutical profile of chitosan. Various investigations carried out recently are reported, although references to research performed on chitosan prior to the recent reviews have also been included, where appropriate.

Nimesulide: some pharmaceutical and pharmacological aspects--an update.

Nimesulide, a non-steroidal anti-inflammatory drug (NSAID), is administered orally or rectally twice daily for a variety of inflammation and pain states. This is a unique NSAID, not only because of its chemical structure but also because of its specific affinity to inhibit cyclooxygenase-2 (COX-2), thus exerting milder effects on the gastrointestinal mucosa. Current data on selective COX-2 inhibitors suggest that they may have an efficacy similar to that of standard NSAIDs. Initial general clinical experience with selective COX-2 inhibitors appears to show that they are particularly promising in individuals at risk because of renal diseases, hypertension or congestive heart failure. Various experimental models and clinical studies have demonstrated the anti-inflammatory efficacy of nimesulide. Nimesulide is superior, or at least comparable in efficacy, to other NSAIDs, but is better tolerated and has less potential for adverse reactions. Thus, selective COX-2 inhibitors should have anti-inflammatory effects devoid of side effects on the kidney and stomach. They may also demonstrate new important therapeutic benefits as anticancer agents as well as help prevention of premature labour and even retard the progression of Alzheimer's disease. No clinically significant drug interactions have been reported for nimesulide. Not much has been reported about the pharmaceutical aspects of nimesulide. Its poor aqueous solubility poses bioavailability problems in-vivo. This could be overcome by the formation of inclusion complexes with beta-cyclodextrin, as has been reported by various researchers. However, absence of any in-vivo data regarding the relative absorption of nimesulide from beta-cyclodextrin complex compared with that from conventional formulations of the drug makes the use of such fast-releasing complexes rather questionable. Only a limited number of assay procedures (HPLC, spectrophotometric, spectrofluorimetric) for the determination of nimesulide and its metabolite in plasma/urine samples or in dosage forms have been reported in the literature. The purpose of this review is to provide a concise overview of the pharmacological and pharmaceutical profile of nimesulide. Various investigations carried out recently are reported, although older references to research performed on nimesulide have also been included, where appropriate.

Pyrazole NNRTIs 4: Selection of UK-453,061 (lersivirine) as a Development Candidate

We prepared three discreet cohorts of potent non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) based on the recently reported 3-cyanophenoxypyrazole lead 3. Several of these compounds displayed very promising anti-HIV activity in vitro, safety, pharmacokinetic and pharmaceutical profiles. We describe our analysis and conclusions leading to the selection of alcohol 5 (UK-453,061, lersivirine) for clinical development.

Comparative analysis of pharmaceuticals versus industrial chemicals acute aquatic toxicity classification according to the United Nations classification system for chemicals. Assessment of the (Q)SAR predictability of pharmaceuticals acute aquatic toxicity and their predominant acute toxic mode-of-action

Pharmaceuticals have been reported to be ubiquitously present in surface waters prompting concerns of effects of these bioactive substances. Meanwhile, there is a general scarcity of publicly available ecotoxicological data concerning pharmaceuticals. The aim of this paper was to compile a comprehensive database based on OECD's standardized measured ecotoxicological data and to evaluate if there is generally cause of greater concern with regards to pharmaceutical aquatic toxicological profiles relative to industrial chemicals. Comparisons were based upon aquatic ecotoxicity classification under the United Nations Global Harmonized System for classification and labeling of chemicals (GHS). Moreover, we statistically explored whether the predominant mode-of-action (MOA) for pharmaceuticals is narcosis. We found 275 pharmaceuticals with 569 acute aquatic effect data; 23 pharmaceuticals had chronic data. Pharmaceuticals were found to be more frequent than industrial chemicals in GHS category III. Acute toxicity was predictable (>92%) using a generic (Q)SAR ((Quantitative) Structure Activity Relationship) suggesting a narcotic MOA. Analysis of model prediction error suggests that 68% of the pharmaceuticals have a non-specific MOA. Additionally, the acute-to-chronic ratio (ACR) for 70% of the analyzed pharmaceuticals was below 25 further suggesting a non-specific MOA. Sub-lethal receptor-mediated effects may however have a more specific MOA.

Chemiluminescence mechanisms of cerium-norfloxacin and its application in urine analysis

AbstractIn this article, novel chemiluminescence mechanisms between norfloxacin and cerium(IV) in an acidic medium were studied. Chemiluminescence spectra of the present system were recorded observing three maximum emissions at about 475 nm, 550 nm, and 620 nm, respectively. The results indicate that the chemiluminescence peaks located at 475 nm and 620 nm can be ascribed to the emission of a singlet oxygen, while the chemiluminescence emission at 550 nm occurred in course of the reaction between acidic cerium(IV) and the phenolic intermediate. Under optimum conditions, the chemiluminescence intensity was linear with the concentration of norfloxacin over the range of 2.0 × 10−8−1.0 × 10−5 g mL−1 and the detection limit of 1.0 × 10−8 g mL−1 (S/N = 3). The relative standard deviation was 1.94 % for a 4.0 × 10−7 g mL−1 norfloxacin solution considering eleven repeated measurements. The present chemiluminescence system was successfully applied in the determination of norfloxacin in pharmaceutical preparations and concentration-time profiles in urine.

Identification of Diarylsulfone Sulfonamides as Secreted Frizzled Related Protein-1 (sFRP-1) Inhibitors

Inhibitor of secreted frizzled related protein-1 (sFRP-1) would be a novel potential osteogenic agent, since loss of sFRP-1 affects osteoblast proliferation, differentiation, and activity, resulting in improved bone mineral density, quality, and strength. We have identified small molecule diarylsulfone sulfonamide derivatives as sFRP-1 inhibitors. Structure-activity relationship generated for various regions of the scaffold was utilized to improve the biochemical profile, resulting in the identification of potent selective analogues, such as 16 with desirable pharmaceutical profile.

Desirability-Based Methods of Multiobjective Optimization and Ranking for Global QSAR Studies. Filtering Safe and Potent Drug Candidates from Combinatorial Libraries

Up to now, very few applications of multiobjective optimization (MOOP) techniques to quantitative structure-activity relationship (QSAR) studies have been reported in the literature. However, none of them report the optimization of objectives related directly to the final pharmaceutical profile of a drug. In this paper, a MOOP method based on Derringer's desirability function that allows conducting global QSAR studies, simultaneously considering the potency, bioavailability, and safety of a set of drug candidates, is introduced. The results of the desirability-based MOOP (the levels of the predictor variables concurrently producing the best possible compromise between the properties determining an optimal drug candidate) are used for the implementation of a ranking method that is also based on the application of desirability functions. This method allows ranking drug candidates with unknown pharmaceutical properties from combinatorial libraries according to the degree of similarity with the previously determined optimal candidate. Application of this method will make it possible to filter the most promising drug candidates of a library (the best-ranked candidates), which should have the best pharmaceutical profile (the best compromise between potency, safety and bioavailability). In addition, a validation method of the ranking process, as well as a quantitative measure of the quality of a ranking, the ranking quality index (Psi), is proposed. The usefulness of the desirability-based methods of MOOP and ranking is demonstrated by its application to a library of 95 fluoroquinolones, reporting their gram-negative antibacterial activity and mammalian cell cytotoxicity. Finally, the combined use of the desirability-based methods of MOOP and ranking proposed here seems to be a valuable tool for rational drug discovery and development.

Desirability‐based multiobjective optimization for global QSAR studies: Application to the design of novel NSAIDs with improved analgesic, antiinflammatory, and ulcerogenic profiles

Up to now, very few reports have been published concerning the application of multiobjective optimization (MOOP) techniques to quantitative structure-activity relationship (QSAR) studies. However, none reports the optimization of objectives related directly to the desired pharmaceutical profile of the drug. In this work, for the first time, it is proposed a MOOP method based on Derringer's desirability function that allows conducting global QSAR studies considering simultaneously the pharmacological, pharmacokinetic and toxicological profile of a set of molecule candidates. The usefulness of the method is demonstrated by applying it to the simultaneous optimization of the analgesic, antiinflammatory, and ulcerogenic properties of a library of fifteen 3-(3-methylphenyl)-2-substituted amino-3H-quinazolin-4-one compounds. The levels of the predictor variables producing concurrently the best possible compromise between these properties is found and used to design a set of new optimized drug candidates. Our results also suggest the relevant role of the bulkiness of alkyl substituents on the C-2 position of the quinazoline ring over the ulcerogenic properties for this family of compounds. Finally, and most importantly, the desirability-based MOOP method proposed is a valuable tool and shall aid in the future rational design of novel successful drugs.

Celecoxib and ankylosing spondylitis

It is now over 100 years since the arrival of aspirin and, from the mid-20th Century onwards, we have seen numerous attempts at providing society with safer and more efficacious nonsteroidal drugs. Ironically, while aspirin went from strength to strength with an ever-increasing pharmaceutical profile, new nonsteroidal anti-inflammatory drugs arrived and disappeared with rapid succession. Finally, there appears to have been a breakthrough with the development of the coxibs but concern has recently developed because of potential toxic cardiovascular reactions. Although originally studied in rheumatoid arthritis and degenerative arthropathy, the coxibs have now been investigated in ankylosing spondylitis and efficacy appears to be favorable and, to date, there is little evidence of toxicity, although problems in the nonspondylarthropathic arena may spill over into the seronegative spondylarthritides.

KD5170, a novel mercaptoketone-based histone deacetylase inhibitor that exhibits broad spectrum antitumor activity in vitro and in vivo

Histone deacetylase (HDAC) inhibitors have garnered significant attention as cancer drugs. These therapeutic agents have recently been clinically validated with the market approval of vorinostat (SAHA, Zolinza) for treatment of cutaneous T-cell lymphoma. Like vorinostat, most of the small-molecule HDAC inhibitors in clinical development are hydroxamic acids, whose inhibitory activity stems from their ability to coordinate the catalytic Zn2+ in the active site of HDACs. We sought to identify novel, nonhydroxamate-based HDAC inhibitors with potentially distinct pharmaceutical properties via an ultra-high throughput small molecule biochemical screen against the HDAC activity in a HeLa cell nuclear extract. An alpha-mercaptoketone series was identified and chemically optimized. The lead compound, KD5170, exhibits HDAC inhibitory activity with an IC50 of 0.045 micromol/L in the screening biochemical assay and an EC50 of 0.025 micromol/L in HeLa cell-based assays that monitor histone H3 acetylation. KD5170 also exhibits broad spectrum classes I and II HDAC inhibition in assays using purified recombinant human isoforms. KD5170 shows significant antiproliferative activity against a variety of human tumor cell lines, including the NCI-60 panel. Significant tumor growth inhibition was observed after p.o. dosing in human HCT-116 (colorectal cancer), NCI-H460 (non-small cell lung carcinoma), and PC-3 (prostate cancer) s.c. xenografts in nude mice. In addition, a significant increase in antitumor activity and time to end-point occurred when KD5170 was combined with docetaxel in xenografts of the PC-3 prostate cancer cell line. The biological and pharmaceutical profile of KD5170 supports its continued preclinical and clinical development as a broad spectrum anticancer agent.

Dosage de l’activité toxine botulique : vers un nouveau dosage sur culture cellulaire ?

The actual gold standard of Botulin A toxin (BoTx A) batches qualification is the mouse lethality assay. With this assay it is nevertheless impossible to set a therapeutic value unit. The goal of this research was to study the effects of BoTx A increasing concentrations on glutamatergic rat neurons. We studied the glutamate release with increasing concentrations of BoTx A. We also studied the BoTx A target cleavage with a western blot technique. Our results proved that it is possible to establish a dose-response - like curve of BoTx A effects on glutamate release. Moreover the cleavage of the target protein was visible for the same toxin concentrations that inhibited the glutamate release. This technique could be the first step toward a new way of setting a better pharmaceutical profile for toxin batches.

Assessing drug-likeness – what are we missing?

The concept of drug-likeness helps to optimise pharmacokinetic and pharmaceutical properties, for example, solubility, chemical stability, bioavailability and distribution profile. A number of molecular descriptors have emerged as reasonably informative and predictive, for example, the Rule-of-Five. Here, we review some current approaches, then discuss their major shortcoming, namely the static nature of the structural features and physicochemical properties they encode. As we demonstrate, molecules are not 'frozen statues' but 'dancing ballerinas', and several of their computable physicochemical properties are conformation-dependent and lead to the concept of property spaces. Molecular sensitivity (namely, how much a given computable physicochemical property varies as a function of flexibility) appears as a promising descriptor to encode some of the information contained in molecular property spaces.

A Chemical Approach to the Pharmaceutical Optimization of an Anti-HIV Protein

Chemical protein synthesis is important for dissecting the molecular basis of protein function. Here we advance its scope by demonstrating the significant improvement of the multifaceted pharmaceutical profile of small proteins exclusively via a chemical-based approach. The focus of this work centered on CCL-5 (RANTES) derivatives with potent anti-HIV activity. The overall chemical strategy involved a combination of coded and noncoded amino acid mutagenesis, peptide backbone engineering, and site-specific polymer attachment. The ability to alter specific protein residues, as well as precise control of the position and type of polymer attachment, allows for the exploration of specific molecular designs and resulted in novel CCL-5 analogues with significant differences in their respective biochemical and pharmaceutical properties. Using this approach, the complex-interplay of variables contributing to the noncovalent self-association (aggregation) state, CCR-5 specificity, in vivo elimination half-life, and anti-HIV activity of CCL-5-based protein analogues could be empirically evaluated via total chemical synthesis. This work has led to the identification of potent (sub-nanomolar) anti-HIV proteins with significantly improved pharmaceutical profiles, and illustrates the increasing value of protein chemical synthesis in contemporary therapeutic discovery. These antiviral molecules provide a novel mechanism of action for the development of a new generation of anti-HIV therapeutics which are still desperately needed.

Abstracts for Oral Presentation

Abstracts for Oral Presentation

Determination of pharmaceuticals in environmental waters by liquid chromatography/electrospray ionization/tandem mass spectrometry

A high-performance liquid chromatography/electrospray ionization/tandem mass spectrometry (LC/MS-MS) method was developed, validated and used to characterize pharmaceutical inputs in the Grand River watershed, Ontario, Canada. Twenty-seven antibiotics and neutral pharmaceuticals were extracted from aqueous environmental samples in a single step using 13C6-labeled sulfamethazine phenyl as a method surrogate and analyzed by LC/MS-MS. Method detection limits were in the range of 20-1,400 ng/L for the compounds of interest with recoveries from 51 to 130%. Using this method, pharmaceutical profiles in tributaries flowing into the Grand River were investigated using samples collected from seven agricultural sites and one urban site. Quality control data collected during the 5-month field study period showed good method performance. Concentrations of pharmaceuticals in source water with heavy agricultural input and surface waters downstream with urban inputs were determined to examine the effect of agricultural and urban inputs to surface water quality. Only human prescription drugs were found from urban site samples taken at both high-flow (spring and fall) and low-flow (summer) events in 2003, indicating minimal agricultural input. We also found for the first time the presence of the ionophore monensin in the environment as well as the occurrence of the human prescription drug carbamazepine in surface waters receiving primarily agricultural inputs. Possible causes and analytical solutions for some poor recoveries are discussed with respect to extraction pH, total organic carbon and metal ions in the water samples. The ability to extract 27 pharmaceuticals in a single solid-phase extraction step from diverse environmental matrices such as agricultural tile drain, tributary and surface water samples, followed by a single LC/MS-MS analysis, enabled the effective delivery of quality data.