Pharmaceutical Tools Research Articles

Poly (Glycerol Adipate): From a Functionalized Nanocarrier to a Polymeric-Prodrug Matrix to Create Amorphous Solid Dispersions

Amorphous solid dispersions are a promising strategy to overcome poor solubility and stability limitations, reducing the crystallinity of the drug through incorporation within a polymer matrix. However, to achieve an effective amorphous solid dispersion, the polymer and drug must be compatible, otherwise the drug can undergo recrystallization. In this work, we investigated the potential of the enzymatically synthesized poly(glycerol-adipate), as a pharmaceutical tool for producing a nanoamorphous formulation. A polymeric prodrug of poly(glycerol-adipate) was synthesized by coupling mefenamic acid as drug. The amorphicity of the polymeric prodrug was assessed combining differential scanning calorimetry and polarized optical microscopy. The prodrug was then formulated into nanoparticles and studied for stability and drug release in the presence of lipase. To realize the goal of combination drug therapies for overcoming drug resistance and improving treatment outcomes, the prodrug was screened as a solubility enhancer for a series of fenamic drugs and compared with commercially available polymers commonly used in solid dispersions. Screening was carried out by developing a high-throughput miniaturized screening assay using a 2D printer to dispense the polymer and drug combinations. Finally, the collected data showed that drug conjugation could improve drug-polymer compatibility, in addition to facilitating the release of drugs by 2 different mechanisms.

Identifying characteristics of drug-related problems in critically ill patients with decompensated liver cirrhosis.

Characteristics of drug-related problems and related patient harm has not been evaluated in critically ill patients with decompensated cirrhosis. Our objectives were to identify characteristics and incidence rate of drug-related problems and related preventable harm in critically ill patients with decompensated liver cirrhosis. A prospective observational study was conducted from February 2018 to January 2019 in 10-bed medical intensive care unit of a tertiary care hospital. Medication charts of 78 patients diagnosed with decompensated cirrhosis were reviewed by the clinical pharmacist. Pharmaceutical care-related standard tools were applied for classification of drug-related problems and their severity of outcomes. A total of 394 drug-related problems with an incidence rate of 298.48 per 1000 patient medical intensive care unit-day were identified. Most common drug-related problems were drug-drug interaction (48.7%) followed by guideline nonconformity (15.5%), inappropriate drug form (11.9%), and contraindication (9.6%). Approximately 27% of drug-related problems induced preventable harm, which included temporary harm (19.8%), permanent harm (5.8%), and death (0.8%). The incidence rate of preventable harm was found to be 78.78 per 1000 patient medical intensive care unit-day. Nonsteroidal anti-inflammatory drugs were the most common medications involved in drug-drug interaction, guideline nonconformity, and contraindication which led to gastrointestinal bleeding (24%) and worsening of renal function (11.5%). Drug-related problems occurred commonly in critically ill patients with decompensated liver cirrhosis and induced preventable harm which jeopardized the safety of these vulnerable patients. Clinical pharmacist's intervention is essential for identification of drug-related problems and related preventable harm among these patients.

Impact of Processing Parameters on the Quality of Pharmaceutical Solid Dosage Forms Produced by Fused Deposition Modeling (FDM).

Fused deposition modeling (FDM) three-dimensional (3D) printing is being increasingly explored as a direct manufacturing method to product pharmaceutical solid dosage forms. Despite its many advantages as a pharmaceutical formulation tool, it remains restricted to proof-of-concept formulations. The optimization of the printing process in order to achieve adequate precision and printing quality remains to be investigated. Demonstrating a thorough understanding of the process parameters of FDM and their impact on the quality of printed dosage forms is undoubtedly necessary should FDM advance from a proof-of-concept stage to an adapted pharmaceutical manufacturing tool. This article describes the findings of an investigation into a number of critical process parameters of FDM and their impact on quantifiable, pharmaceutically-relevant measures of quality. Polycaprolactone, one of the few polymers which is both suitable for FDM and is a GRAS (generally regarded as safe) material, was used to print internally-exposed grids, allowing examination of both their macroscopic and microstructural reproducibility of FDM. Of the measured quality parameters, dimensional authenticity of the grids was found to poorly match the target dimensions. Weights of the grids were found to significantly vary upon altering printing speed. Printing temperature showed little effect on weight. Weight uniformity per batch was found to lie within acceptable pharmaceutical quality limits. Furthermore, we report observing a microstructural distortion relating to printing temperature which we dub The First Layer Effect (FLE). Principal Component Analysis (PCA) was used to study factor interactions and revealed, among others, the existence of an interaction between weight/dosing accuracy and dimensional authenticity dictating a compromise between the two quality parameters. The Summed Standard Deviation (SSD) is proposed as a method to extract the optimum printing parameters given all the perceived quality parameters and the necessary compromises among them.

Targeted enhancement of the therapeutic window of L19-TNF by transient and selective inhibition of RIPK1-signaling cascade.

IntroductionCytokine-based products are gaining importance for cancer immunotherapy. L19-TNF is a clinical-stage antibody-cytokine fusion protein that selectively accumulates to tumors and displays potent anticancer activity in preclinical models. Here, we describe an innovative approach to transiently inhibit off-target toxicity of L19-TNF, while maintaining antitumor activity.MethodsGSK’963, a potent small molecule inhibitor of RIPK1, was tested in tumor-bearing mice for its ability to reduce acute toxicity associated with TNF signaling. The biological effects of L19-TNF on tumor cells, lymphocytes and tumor vessels were investigated with the aim to enable the administration of TNF doses, which would otherwise be lethal.ResultsTransient inhibition of RIPK1 allowed to increase the maximal tolerated dose of L19-TNF. The protective effect of GSK’963 did not affect the selective localization of the immunocytokine to tumors as evidenced by quantitative biodistribution analysis and allowed to reach high local TNF concentrations around tumor blood vessels, causing diffused vascular shutdown and hemorrhagic necrosis within the neoplastic mass.ConclusionsThe selective inhibition of RIPK1 with small molecule inhibitors can be used as a pharmaceutical tool to transiently mask TNF activity and improve the therapeutic window of TNF-based biopharmaceuticals. Similar approaches may be applicable to other pro-inflammatory cytokines.

Challenging contingency: Viruses and the nature of molecular life

Understandings of the nature or inherent workings of molecular life in the field of biopolitical security studies have today been characterized predominantly in terms of contingency. This article challenges this characterization. It does so by identifying a particular logic of operation that organizes political action and intervention at both the level of the population and the molecular in response to the threats of smallpox, Ebola and pandemic influenza. It argues that, in fact, rather than securing by instantiating a general economy of the contingent, governing practices rely upon the characterization of the nature of molecular life in terms of its constant biological dynamics. Governments around the world, and the US government in particular, have reacted to the increased likelihood of the emergence of disease through the stockpiling of new pharmaceuticals, including the antivirals ST-246, ZMapp and Tamiflu. Antivirals represent a pharmaceutical tool stockpiled by governments to ensure that they can respond to the emergence of novel biological threats. The characterization of the nature of molecular life in terms of its constant biological dynamics is so important, then, as it is this that underpins political programmes of preparedness that utilize antivirals in the prevention of disease.

Neutral Sphingomyelinase Modulation in the Protective/Preventive Role of rMnSOD from Radiation-Induced Damage in the Brain.

Studies on the relationship between reactive oxygen species (ROS)/manganese superoxide dismutase (MnSOD) and sphingomyelinase (SMase) are controversial. It has been demonstrated that SMase increases the intracellular ROS level and induces gene expression for MnSOD protein. On the other hand, some authors showed that ROS modulate the activation of SMase. The human recombinant manganese superoxide dismutase (rMnSOD) exerting a radioprotective effect on normal cells, qualifies as a possible pharmaceutical tool to prevent and/or cure damages derived from accidental exposure to ionizing radiation. This study aimed to identify neutral SMase (nSMase) as novel molecule connecting rMnSOD to its radiation protective effects. We used a new, and to this date, unique, experimental model to assess the effect of both radiation and rMnSOD in the brain of mice, within a collaborative project among Italian research groups and the Joint Institute for Nuclear Research, Dubna (Russia). Mice were exposed to a set of minor γ radiation and neutrons and a spectrum of neutrons, simulating the radiation levels to which cosmonauts will be exposed during deep-space, long-term missions. Groups of mice were treated or not-treated (controls) with daily subcutaneous injections of rMnSOD during a period of 10 days. An additional group of mice was also pretreated with rMnSOD for three days before irradiation, as a model for preventive measures. We demonstrate that rMnSOD significantly protects the midbrain cells from radiation-induced damage, inducing a strong upregulation of nSMase gene and protein expression. Pretreatment with rMnSOD before irradiation protects the brain with a value of very high nSMase activity, indicating that high levels of activity might be sufficient to exert the rMnSOD preventive role. In conclusion, the protective effect of rMnSOD from radiation-induced brain damage may require nSMase enzyme.

Identification and resolution of drug-related problems in a tertiary hospital respiratory unit in China

Background The prevalence of drug-related problems in patients hospitalized at respiratory care units is unknown in mainland China. Objective To identify and categorize drug-related problems in a respiratory care unit in China. Setting Respiratory care unit in a tertiary university hospital in China. Methods Clinical pharmacy services were introduced and documented during an 18-months study period. The problems were categorized using the Pharmaceutical Care Network Europe DRP classification tool V8.02. Main outcome measures Problems and causes of drug-related problems, interventions proposed, and outcome of pharmacy recommendations. Results A total of 474 patients were reviewed, 164 patients had DRPs (34.6%). Total 410 problems were identified, an average of 2.5 per patient. Treatment effectiveness was the major type of problem detected (219; 53.4%) followed by treatment safety (140; 34.1%). The most common causes of the problems were patient-related (25.8%), drug selection (24.0%), and drug use process (23.4%). Pharmacist made 773 interventions; average 1.9 per drug-related problem. A total of 96.2% of these interventions were accepted leading to solving 81.9% of the identified problems. Conclusion There is a high prevalence of drug-related problems in patients hospitalized at the respiratory unit of this clinic. Clinical pharmacists should focus on improving prescribing practice and patient counseling.

Human CAP cells represent a novel source for functional, miRNA-loaded exosome production.

Exosomes represent a promising delivery tool for nucleic acid-based pharmaceuticals. They are highly suitable for transporting therapeutic miRNAs to tumor cells, due to their natural membrane components. Further, exosomes are capable of effectively protecting nucleic acids against ribonucleases and enable the delivery of their content through cell membranes. However, no suitable production host for miRNA containing exosomes of non-tumorigenic origin has yet been identified. In this study we engineered an immortalised human amniocyte cell line (CAP® cells), whose exosomes were enriched and characterised. The cell line modifications not only enabled the production of GFP-labelled but also pro-apoptotic miRNA containing exosomes without negative influence on host cell growth. Furthermore, we demonstrated that pro-apoptotic miRNA containing CAP exosomes are taken up by ovarian cancer cells. Strikingly, delivery of functional exosomal miRNA led to downregulation of several reported target genes in the treated tumor cells. In summary, we revealed CAP cells of non-tumorigenic origin as a novel and efficient exosome production host with the potential to produce functional miRNA-loaded exosomes.

Impact of adding natural bioactive mixture composed of lemon, onion, and garlic juice at different levels on productive performance, egg quality, and some blood parameters of commercial laying hens

BackgroundThe World Health Organization (WHO) encourages using medicinal herbs and plants to substitute or minimize the use of chemicals through the global trend to go back to nature. Many studies mentioned that using medicinal herbs and plants as feed additives seems to be a recent trend depending on availability and their cost but using them with monogastric animals and birds, as pharmaceutical tool, is available. Their action was manifested in a reduced expanding range of pathogenic microorganisms in the digestive tract, which resulted in the improvement of growth performance, efficient digestion, immunity, and health of poultry.MethodsThe present work aimed to establish the influence of adding natural bioactive mixture composed of the juice of lemon, onion, and garlic (LOG) at portions 1.00, 1.00, and 0.125/l clean water, respectively, to laying hens’ diets on their performance, egg quality, and some blood constituents. Seventy-two 30-week-old commercial Bovan Brown layers were randomly divided into four dietary treatment groups. Each treatment included eighteen hens in 6 replicates (3 birds each). All tested diets were almost isocaloric and isonitrogenous.ResultsAdding LOG in laying hens’ diets significantly (P < 0.05) improved feed conversion throughout the second stage of egg collection in comparison with the control group. Inclusion of LOG in laying hen diets significantly (P < 0.05) improved the number of eggs/hen, percentage of egg production, and egg mass/hen throughout the second stage of egg collection comparing with the control (G1). Diet supplied by 1% LOG recorded the best value of yolk color (5.40) and yolk percentage (28.42%) compared with the other groups. Adding 2% or 3% LOG significantly (P < 0.05) decreased the total plasma cholesterol content compared to the control group. Inclusion of LOG at different levels significantly (P < 0.05) decreased blood plasma contents of GPT and GOT. However, insignificant decreases in blood plasma creatinine occurred comparing to control.ConclusionAdding the natural bioactive mixture composed of the juice of lemon, onion, and garlic can be safely used in improving the general health, egg weight, and feed conversion with decreasing the blood cholesterol of laying hens. Supplementation of LOG in the ration of hens improved the feed conversion and egg production.

Liver‐on‐a‐Chip: A Human Liver‐on‐a‐Chip Platform for Modeling Nonalcoholic Fatty Liver Disease (Adv. Biosys. 8/2019)

In article number 1900104, Junmin Lee, Ali Khademhosseini, and co-workers develop a bioengineered liver steatosis model based on the interactions between human hepatocytes and primary human endothelial cells by forming multicellular aggregates to investigate steatosis pathogenesis. The spheroids on a chip platform can be used for monitoring hepatocyte functionality and developing pharmaceutical tools to evaluate new potential drugs.

Development and validation of in-line near-infrared spectroscopy based analytical method for commercial production of a botanical drug product

Near-infrared (NIR) spectroscopy is one of the most successful pharmaceutical process analytical tools. For botanical drug products (BDPs), many studies have applied NIR spectroscopy for rapid analysis of botanical raw materials, extracts and formulations. However, the real-time process analysis reported for BDPs was still mainly conducted on lab- or pilot- scale equipment, where some essential conditions of the materials and process parameters can be easily controlled for NIR spectral measurement. Due to the chemical and physical characteristics of the commercial production of BDPs, it is challenging to develop in-line NIR methods with enough robustness for industrial-scale application. This is the first reported case study of the development and validation of the in-line NIR method for the commercial production of BDPs, taking Compound Danshen Dripping Pill (CDDP) as an example. An in-line NIR method was developed for simultaneous measurement of the three critical quality attributes, i.e. the relative density, the moisture content and the content of 3,4-dihydroxyphenyl lactic acid (danshensu, a key active compound), during the extract concentration process. The NIR spectra and sample collection lasted for three years (67 production batches) to cover the variability of raw materials and process conditions. NIR calibration models were established respectively, with determination coefficients (r2) of 0.9905, root mean square errors of prediction (RMSEP) of 0.004 for the relative density in the range of 1.042–1.184; r2 of 0.9870, RMSEP of 1.1% for the moisture content in the range of 50.8–83.0%; r2 of 0.9870, RMSEP of 0.461 mg/g for danshensu in the range of 2.563–8.869 mg/g. Then, all the method validation parameters (accuracy, precision, range, specificity, linearity, robustness, detection and quantitation limits) were discussed according to the characteristics of the commercial production of BDPs. The NIR method development and validation strategy proposed may also be applied in the future for the commercial production of other BDPs.

Carbazole Derivatives as Antiviral Agents: An Overview.

Viruses represent the most common cause of infectious diseases worldwide and those with rapid propagation and high infection rates cause human and animal pandemics. These fast-spreading diseases are generally treated with antiviral drugs but, often, drug resistance occurs because of the ability of the pathogens to mutate rapidly and become less susceptible to the treatments. Even though new antivirals have been approved, e.g., in HIV (human immunodeficiency virus) and HCV (hepatitis C virus) therapeutic areas, the need to dispose of new pharmaceutical tools for the management of infections that still have no treatment is of growing interest. In these areas, carbazole represents an important privileged scaffold in drug discovery. Many compounds with a carbazolic core have been developed and some of them have shown antiviral activity. This review provides an overview on some already known carbazole derivatives, pointing the attention on the running progresses in identifying new molecules with carbazolic structure, that have shown interesting and encouraging in vitro and in vivo properties. These drugs may be exploited as valid alternatives in antiviral therapy.

Polyphenols in the treatment of autoimmune diseases.

In addition to protecting body from infections and diseases, the immune system produces auto-antibodies that can cause complex autoimmune disorders, such as Type I diabetes, primary biliary cirrhosis, rheumatoid arthritis, and multiple sclerosis, to name a few. In such cases, the immune system fails to recognize between foreign agents and its own body cells. Different factors, such as genetic factors (CD25, STAT4), epigenetic factors (DNA methylation, histone modifications) and environmental factors (xenobiotics, drugs, hormones) trigger autoimmunity. Glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), immunosuppressive and biological agents are currently used to manage autoimmune diseases of different origins. However, complete cure remains elusive. Many dietary and natural products including polyphenols have been widely studied as possible alternative treatment strategies for the management of autoimmune disorders. Polyphenols possess a wide-range of pharmacological and therapeutic properties, including antioxidant and anti-inflammatory activities. As immunomodulatory agents, polyphenols are emerging pharmaceutical tools for management of various autoimmune disorders including vitiligo, ulcerative colitis and multiple sclerosis (MS). Polyphenols activate intracellular pathways such as arachidonic acid dependent pathway, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, mitogen-activated protein kinases (MAPKs) pathway, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway and epigenetic modulation, which regulate the host's immune response. This timely review discusses putative points of action of polyphenols in autoimmune diseases, characterizing their efficacy and safety as therapeutic agents in managing autoimmune disorders.

Emerging Therapeutic Targets in Oncologic Photodynamic Therapy.

Reactive oxygen species sustain tumorigenesis and cancer progression through deregulated redox signalling which also sensitizes cancer cells to therapy. Photodynamic therapy (PDT) is a promising anti-cancer therapy based on a provoked singlet oxygen burst, exhibiting a better toxicological profile than chemo- and radiotherapy. Important gaps in the knowledge on underlining molecular mechanisms impede on its translation towards clinical applications. The main objective of this review is to critically analyse the knowledge lately gained on therapeutic targets related to redox and inflammatory networks underlining PDT and its outcome in terms of cell death and resistance to therapy. Emerging therapeutic targets and pharmaceutical tools will be documented based on the identified molecular background of PDT. Cellular responses and molecular networks in cancer cells exposed to the PDT-triggered singlet oxygen burst and the associated stresses are analysed using a systems medicine approach, addressing both cell death and repair mechanisms. In the context of immunogenic cell death, therapeutic tools for boosting anti-tumor immunity will be outlined. Finally, the transcription factor NRF2, which is a major coordinator of cytoprotective responses, is presented as a promising pharmacologic target for developing co-therapies designed to increase PDT efficacy. There is an urgent need to perform in-depth molecular investigations in the field of PDT and to correlate them with clinical data through a systems medicine approach for highlighting the complex biological signature of PDT. This will definitely guide translation of PDT to clinic and the development of new therapeutic strategies aimed at improving PDT.

Drug-related problems in patients with rheumatoid arthritis.

BackgroundRheumatoid arthritis (RA) patients are at risk of acquiring drug-related problems (DRPs). However, there has been a lack of studies on DRPs in patients with RA up to now.MethodThis retrospective study was conducted in a tertiary hospital in Malaysia from January 2012 to December 2017 with the purpose of assessing DRPs in RA patients and factors associated with its occurrence. A total of 200 patients who had received pharmacological treatment for RA were enrolled in this study. Assessment of DRPs was based on the Pharmaceutical Network Care Europe tool version 5.01.ResultsA total of 289 DRPs with an average of 1.5±1.0 problems per patient were identified, in which 78.5% of the population had at least one DRP. The most common DRPs encountered were adverse reactions (38.8%), drug interactions (33.6%), and drug-choice problems (14.5%). Factors that had significant association with the occurrence of DRPs were polypharmacy (P=0.003), multiple comorbidities (P=0.001), hyperlipidemia (P=0.009), osteo (P=0.040), and renal impairment (P=0.044). These data indicated that the prevalence of DRPs was high among RA patients.ConclusionEarly identification of types of DRPs and associated factors may enhance the prevention and management of RA.

Nutritional impact of inclusion of garlic (Allium sativum) and/or onion (Allium cepa L.) powder in laying hens\u2019 diets on their performance, egg quality, and some blood constituents

BackgroundMany studies mentioned that using medicinal herbs and plants as feed additives to ruminants seems to be a recent trend depending on the availability and their cost but using them with monogastric animals and birds, as pharmaceutical tool, is available. As an example, the importance of garlic or onion in recent years, thanks to a wide range of useful properties, has been increasingly used as an additive in nutrition and protection of farm animals. Their action was manifested in a reduced expanding range of pathogenic microorganisms in the digestive tract, which resulted in the rapid growth of poultry, efficient digestion, and increased immunity and health of poultry.MethodsOne hundred and eight 30-week-old laying hens were randomly divided into six dietary treatment groups {G1 control, G2 contained 0.5% garlic powder (GP), G3 contained 1% GP, G4 contained 1% onion powder (OP), G5 contained 1% OP + 0.5% GP, and G6 contained 1% OP + 1% GP}. Each group included 18 hens in six replicates (3 birds/each). So, this work carried out to investigate the impact of incorporating garlic powder (GP) and/or onion powder (OP) in laying hens’ diets on their performance, egg quality, and some blood constituents.ResultsIncorporating GP, OP, and the mixture of them in laying hen diets had no significant effect on the average egg weight and consumption/hen/day throughout the three stages of egg collection, but had a significant improvement in the number of eggs/hen, percentage of egg production, egg mass/hen, and feed conversion. Inclusion of GP, OP, or the mixture of them in laying hen diets had no significant effect on the shape index, Haugh unit, albumin, and shell percentages; also, an insignificant increase for shell thickness was observed, but egg weight increases (P < 0.05). Incorporation of GP, OP, and the mixture of them significantly decreased (P < 0.05) total cholesterol concentration. Also, an inclusion of 0.5% GP, 1% GP, and 1% OP + 1% GP decreased (P < 0.05) high-density lipoprotein. Inclusion of only 1% OP + 1% GP (G6) decreased (P < 0.05) glutamic oxaloacetic transaminase; meanwhile, supplementation of 1% OP, 1% OP + 0.5% GP, or 1% OP + 1% GP increased (P < 0.05) creatinine.ConclusionFrom the results obtained and under conditions suitable for this study, it can be mentioned that the incorporation of garlic or onion powder or the mixture of them can be safely used with improvement in the general health of hens, egg weight, and feed conversion and decrease in the blood cholesterol.

DRUG REPOSITION OF NON-CANCER DRUGS FOR CANCER TREATMENTS VIA PHARMACOVIGILANCE APPROACH - REPURPOSING DRUGS IN ONCOLOGY

This study for drug repositioning has been performed for the drugs which are in the market since more than a decade and they are approved with their well-established efficacy and safety in human being. Objective of this study was to reposition the existing non-cancer drug therapy for cancer treatment, which is having well characterized pharmacologic profile with more efficacy and least toxicity as anti-neoplastic agent. We have retrieved the source data from FDA Adverse Event Reporting System (FAERS) for the last 13 years covering duration from 2004 to 2016 and analysed those using pharmacovigilance approach ‘a proposed future novel pharmaceutical tool for drug reposition’. Signal management activity was performed for statistical analysis. Result of statistical analysis derived that propranolol; metformin; pioglitazone; dabigatran and nitroglycerin are the existing non-cancer drugs which deserved for their direct / indirect reposition for cancer treatment and anti-neoplastic activity. Further studies retrieving the source data from other regulatory database (e.g. Eudravigilance of EMA and VigiFlow of WHO) and post-marketing surveillance study with the same objective may adjuvant our results for the reposition of existing drugs by pharmacovigilance approach.

Gas-phase structures of protonated arabino nucleosides

Nucleoside modification plays an important role in the native function of DNA and RNA and is also an important synthetic tool for pharmaceuticals. The gas-phase structures of several protonated arabino nucleosides, an important family of modified nucleoside pharmaceuticals, are examined in this work. Infrared multiple photon dissociation action spectra are collected for the protonated forms of the adenine, cytosine, guanine, and uracil arabinosides ([araAdo+H]+, [araCyd+H]+, [araGuo+H]+, and [araUrd+H]+) in the IR fingerprint and hydrogen-stretching regions. Electronic structure calculations are performed to determine low-energy conformers of [araAdo+H]+, [araCyd+H]+, [araGuo+H]+, and [araUrd+H]+, and generate predicted IR spectra for comparison to experiments. Conformers displaying a unique O2′H⋯O5′ hydrogen-bonding interaction are populated in each of these systems. Conformers exhibiting hydrogen-bonding interactions between the nucleobase and O5′ are also found to display good agreement with the measured spectra. Competition between sugar–sugar, and nucleobase–sugar hydrogen bonding reveals a preference for [araCyd+H]+, [araGuo+H]+, and [araUrd+H]+ to stabilize the sugar ring pucker over the nucleobase rotation. N3 protonation of [araAdo+H]+ provides a very strong N3H+⋯O5′ hydrogen-bonding interaction, such that nucleobase–sugar hydrogen-bonding takes energetic preference over stabilization of the sugar puckering. However, conformers exhibiting each mode of hydrogen bonding contribute to the measured spectrum of [araAdo+H]+.

Pharmaceutical Promotion Tools Effect on Physician&amp;#39;s Adoption of Medicine Prescribing: Evidence from Jordan

The study aims to investigate the effect of pharmaceutical promotion tools on physician&amp;#39;s adoption of medicine prescribing in Jordan. Medical representative detailing visit, promotional medicine price, external medical conference sponsorship, and free sampling were the main promotional tools investigated in this study. Researcher collected primary data using a questionnaire from a judgment sample of 150 practicing physicians in the private sector (non-probability sampling), who responded to the study questionnaire. Multiple regression analysis was used to analyze the data. The results indicated that there were a high level of acceptance and effect for the previously mentioned promotional tools on physicians&amp;rsquo; adoption; the most influential independent variable was promotional medicine price followed by free sampling, while external medical conference sponsors and medical representative detailing visit were the lowest influential medical promotional tools. Managers and decision makers who are working in pharmaceutical companies in Jordan were recommended to focus on scientific detailing and free sampling and to decrease budget allocated for External medical conferences sponsorship.

The Role of PI3K in Met Driven Cancer: A Recap.

The Receptor Tyrosine Kinase (RTK) Met, overexpressed or mutated in cancer, plays a major role in cancer progression and represents an attractive target for cancer therapy. However RTK inhibitors can lead to drug resistance, explaining the necessity to develop therapies that target downstream signaling. Phosphatidylinositide 3-kinase (PI3K) is one of the most deregulated pathways in cancer and implicated in various types of cancer. PI3K signaling is also a major signaling pathway downstream of RTK, including Met. PI3K major effectors include Akt and “mechanistic Target of Rapamycin” (mTOR), which each play key roles in numerous and various cell functions. Advancements made due to the development of molecular and pharmaceutical tools now allow us to delve into the roles of each independently. In this review, we summarize the current understanding we possess of the activation and role of PI3K/Akt/mTOR, downstream of Met, in cancer.