Search results for: tuberculosis drugs

Authors: Ananya Gupta, Sangeeta Bhaskar

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Mycobacterium indicus pranii (MIP) is a saprophytic mycobacterium. It is a predecessor of M. avium complex (MAC). Whole genome analysis and growth kinetics studies have placed MIP in between pathogenic and non-pathogenic species. It shares significant antigenic repertoire with M. tuberculosis and have unique immunomodulatory properties. MIP provides better protection than BCG against pulmonary tuberculosis in animal models. Immunization with MIP by aerosol route provides significantly higher protection as compared to immunization by subcutaneous (s.c.) route. However, mechanism behind differential protection has not been studied. In this study, using mice model we have evaluated and compared the M.tb specific immune response in lung compartments (airway lumen / lung interstitium) as well as spleen following MIP immunization via nasal (i.n.) and s.c. route. MIP i.n. vaccination resulted in increased seeding of memory T cells (CD4+ and CD8+ T-cells) in the airway lumen. Frequency of CD4+ T cells expressing Th1 migratory marker (CXCR3) and activation marker (CD69) were also high in airway lumen of MIP i.n. group. Significantly high ex vivo secretion of cytokines- IFN-, IL-12, IL-17 and TNF- from cells of airway luminal spaces provides evidence of antigen-specific lung immune response, besides generating systemic immunity comparable to MIP s.c. group. Analysis of T cell response on per cell basis revealed that antigen specific T-cells of MIP i.n. group were functionally superior as higher percentage of these cells simultaneously secreted IFN-gamma, IL-2 and TNF-alpha cytokines as compared to MIP s.c. group. T-cells secreting more than one of the cytokines simultaneously are believed to have robust effector response and crucial for protection, compared with single cytokine secreting T-cells. Adoptive transfer of airway luminal T-cells from MIP i.n. group into trachea of naive B6 mice revealed that MIP induced CD8 T-cells play crucial role in providing long term protection. Thus the study demonstrates that MIP intranasal vaccination induces M.tb specific memory T-cells in the airway lumen that results in an early and robust recall response against M.tb infection.

Keywords: airway lumen, Mycobacterium indicus pranii, Th1 migratory markers, vaccination

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Authors: Hui-Hsin Huang, Sheng-Tung Huang, Chi-Ming Lee, Chiao-Han Yen, Chun-Mao Lin

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At initiation stage, there are no symptoms at initiation stage; however, at late stage, patients suffer symptoms as soon as ovarian cancer metastasis. Moreover, ovarian cancer cells are resistant to some anti-ovarian cancer drugs in clinical. Thus, it is very important to find an effective treatment for resistant ovarian cancer. Anthraquinone derivatives are able to induce DNA damage and lead to cell apoptosis, so several derivatives have been used for clinical application. Therefore, to explore more effective anti-ovarian cancer drugs, this study investigates the mechanism of three new anthraquinone compounds bearing different functional groups to camptothecin-resistance ovarian cell line A2780R2000. Cell viability was determined by MTT assay after treating A2780R2000 with the three new anthraquinone compounds. The results indicated that IC50 values are 33.44μM (Compound I), 25.77μM (Compound II) and 24.59μM (Compound III). Next, through cell cycle analysis, the results demonstrated that three new anthraquinone compounds not only induced A2780R2000 cell cycle arrest at early stage but also apoptosis at late stage. Besides, through apoptosis assay, the results indicated new anthraquinone compound induced apoptosis at late stage. Furthermore, the results of western blot show that the three new anthraquinone compounds lead to A2780R2000 apoptosis through intrinsic pathway. Theses results suggested that three new anthraquinone compounds may be potential new drugs for clinical cancer treatment in the future.

Keywords: anthraquinone, camptothecin, resistance, ovarian cancer

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Authors: Kinga Mylkie, Pawel Nowak, Marta Z. Borowska

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The most important proteins in human serum responsible for drug binding are human serum albumin (HSA) and α1-acid glycoprotein (AGP). The AGP molecule is a glycoconjugate containing a single polypeptide chain composed of 183 amino acids (the core of the protein), and five glycan branched chains (sugar part) covalently linked by an N-glycosidic bond with aspartyl residues (Asp(N) -15, -38, -54, -75, - 85) of polypeptide chain. This protein plays an important role in binding alkaline drugs, a large group of drugs used in psychiatry, some acid drugs (e.g., coumarin anticoagulants), and neutral drugs (steroid hormones). The main goal of the research was to obtain magnetic nanoparticles coated with biopolymers in a chemically modified form, which will have highly reactive functional groups able to effectively immobilize the glycoprotein (acid α1-glycoprotein) without losing the ability to bind active substances. The first phase of the project involved the chemical modification of biopolymer starch. Modification of starch was carried out by methods of organic synthesis, leading to the preparation of a polymer enriched on its surface with aldehyde groups, which in the next step was coupled with 3-aminophenylboronic acid. Magnetite nanoparticles coated with starch were prepared by in situ co-precipitation and then oxidized with a 1 M sodium periodate solution to form a dialdehyde starch coating. Afterward, the reaction between the magnetite nanoparticles coated with dialdehyde starch and 3-aminophenylboronic acid was carried out. The obtained materials consist of a magnetite core surrounded by a layer of modified polymer, which contains on its surface dihydroxyboryl groups of boronic acids which are capable of binding glycoproteins. Magnetic nanoparticles obtained as carriers for plasma protein immobilization were fully characterized by ATR-FTIR, TEM, SEM, and DLS. The glycoprotein was immobilized on the obtained nanoparticles. The amount of mobilized protein was determined by the Bradford method.

Keywords: glycoproteins, immobilization, magnetic nanoparticles, polysaccharides

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Authors: Jakub Młoźniak, Adam Szymański, Gabriela Stondzik, Dagny Krankowska, Tomasz Mikuła

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Nontuberculous mycobacteria (NTM) are bacterial species that cause diversely manifesting diseases mainly in immunocompromised patients. In people with HIV, NTM infection is an AIDS-defining disease and usually appears when the lymphocyte T CD4 count is below 50 cells/μl. The usage of antiretroviral therapy has decreased the prevalence of NTM among people with HIV, but the disease can still be observed especially among patients with late HIV diagnosis. Common presence in environment, human colonization, clinical similarity with tuberculosis and slow growth on culture makes NTM especially hard to diagnose. The study aimed to analyze the epidemiology and clinical course of NTM among patients with HIV. This study included patients with NTM and HIV admitted to our department between 2017 and 2023. Medical records of patients were analyzed and data on age, sex, median time from HIV diagnosis to identification of NTM infection, median CD4 count at NTM diagnosis, methods of determining NTM infection, type of species of mycobacteria identified, clinical symptoms and treatment course were gathered. Twenty-four patients (20 men, 4 women) with identified NTM were included in this study. Among them, 20 were HIV late presenters. The patients' median age was 40. The main symptoms which patients presented were fever, weight loss and cough. Pulmonary disease confirmed with positive cultures from sputum/bronchoalveolar lavage was present in 18 patients. M. avium was the most common species identified. M. marinum caused disseminated skin lesions in 1 patient. Out of all, 5 people were not treated for NTM caused by lack of symptoms and suspicion of colonization with mycobacterium. Concomitant tuberculosis was present in 6 patients. The median diagnostic time from HIV to NTM infections was 3.5 months. The median CD4 count at NTM identification was 69.5 cells/μl. Median NTM treatment time was 16 months but 7 patients haven’t finished their treatment yet. The most commonly used medications were ethambutol and clarithromycin. Among analyzed patients, 4 of them have died. NTM infections are still an important disease among patients who are HIV late presenters. This disease should be taken into consideration during the differential diagnosis of fever, weight loss and cough in people with HIV with lymphocyte T CD4 count <100 cells/μl. Presence of tuberculosis does not exclude nontuberculous mycobacterium coinfection.

Keywords: mycobacteriosis, HIV, late presenter, epidemiology

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Authors: Tansel Comoglu

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Orally fast disintegrating tablets (FDTs or ODTs) have become popular during the last decade, and manufacturing of ODTs is getting a rapidly growing area in the pharmaceutical industry. The concept of ODTs has emerged from the desire to provide patients with more conventional means of taking their medication. Drugs, that have satisfactory absorption from the oral mucosa or aimed for immediate therapeutic activity can be formulated in ODTs. After placing the ODT into the mouth, these tablets dissolve or disintegrate in the mouth usullay less than a minute, in the absence of additional water. Even though the ODT technology has taken an important path, as proved by a large group of commercial products on the drug market, there are so many problems to be solved in ODT formulations such as; formulation of hydrophobic drugs is stil a challenge, especially when the amount of drug is high. As these tablets dissolve or disintegrate in the mouth without the need of additional water, taste masking of active ingredients becomes essential in these systems because the drug is entirely released in the mouth. In ODT technology, coping with the taste of drugs is still a challenge. Resins or sweeteners or other techniques are also used in the formulation to aid taste-masking of the API. Another important factor to consider is whether they can be manufactured using conventional equipment and processes, as this will have a positive influence on manufacturing costs. Some products, however, may require a more costly, special unitdose packaging if the dosage form is fragile. In this overview, benefits, various formulation technologies, clinical studies and some future research trends of ODTs will be discussed.

Keywords: orally fast disintegrating tablets, benefits, formulation technologies, future research trends

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Authors: Samson F. Agberotimi, Rachel B. Asagba, Choja Oduaran

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Disturbing rate of use of different substances such as cannabis, alcohol, as well as pharmaceutical drugs among Nigerian youth in recent times has been affirmed in the literature. There is, however, a paucity of literature addressing the pattern of usage of such drugs, especially for clinical relevance and intervention planning. The present study investigated the prevalence and pattern of drug usage among youth in Ogbomoso, Nigeria. A cross-sectional survey involving 92 purposively selected participants comprising of 82 males and 10 females aged between 15 and 24 years was conducted. A measure of drug involvement and demographic characteristics was administered to the participants. Descriptive analysis was done using the SPSS v.21. Cannabis (79.4%), alcohol (77.2%), codeine (70.7%), tobacco (65.2%) and tramadol (47.8%) are the five most frequently used substances. However, the majority of the users of tobacco (68.3%) and alcohol (62.0%) are casual users indicating a mild level of use of the substances among the participants. On the other hand, 49.2% of the codeine users, 27.3% of the tramadol users, and 21.9% of the cannabis users reported harmful/intensive levels of use. Furthermore, the results revealed individuals at the pathological level of use as 28.8% for cannabis, 25.0% for tramadol, and 21.6% for codeine, and thus require clinical/therapeutic intervention. In conclusion, cannabis remains the most frequently used substance among youths. However, there appears to be a shift from the use of conventional psychoactive substances to pharmaceutical/prescription drugs such as codeine and tramadol. The findings of this study raised the need for both preventive and therapeutic interventions addressing the problem of substance use disorder among youth in contemporary society.

Keywords: Ogbomoso, pattern of drug use, prevalence of drug use, youth

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Authors: Ocsana Opris, Ildiko Lung, Maria L. Soran, Alexandra Ciorita, Lucian Copolovici

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The effects assessment of environmental stress factors on both crop and wild plants of nutritional value are a very important research topic. Continuously worldwide consumption of drugs leads to significant environmental pollution, thus generating environmental stress. Understanding the effects of the important drugs on plant composition and ultrastructural modification is still limited, especially at environmentally relevant concentrations. The aim of the present work was to investigate the influence of three non-steroidal anti-inflammatory drugs (NSAIDs) on chlorophylls content, carotenoids content, total polyphenols content, antioxidant capacity, and ultrastructure of orache (Atriplex patula L.) and spinach (Spinacia oleracea L.). All green leafy vegetables selected for this study were grown in controlled conditions and treated with solutions of different concentrations (0.1‒1 mg L⁻¹) of diclofenac, ibuprofen, and naproxen. After eight weeks of exposure of the plants to NSAIDs, the chlorophylls and carotenoids content were analyzed by high-performance liquid chromatography coupled with photodiode array and mass spectrometer detectors, total polyphenols and antioxidant capacity by ultraviolet-visible spectroscopy. Also, the ultrastructural analyses of the vegetables were performed using transmission electron microscopy in order to assess the influence of the selected NSAIDs on cellular organisms, mainly photosynthetic organisms (chloroplasts), energy supply organisms (mitochondria) and nucleus as a cellular metabolism coordinator. In comparison with the control plants, decreases in the content of chlorophylls were observed in the case of the Atriplex patula L. plants treated with ibuprofen (11-34%) and naproxen (25-52%). Also, the chlorophylls content from Spinacia oleracea L. was affected, the lowest decrease (34%) being obtained in the case of the treatment with naproxen (1 mg L⁻¹). Diclofenac (1 mg L⁻¹) affected the total polyphenols content (a decrease of 45%) of Atriplex patula L. and ibuprofen (1 mg L⁻¹) affected the total polyphenols content (a decrease of 20%) of Spinacia oleracea L. The results obtained also indicate a moderate reduction of carotenoids and antioxidant capacity in the treated plants, in comparison with the controls. The investigations by transmission electron microscopy demonstrated that the green leafy vegetables were affected by the selected NSAIDs. Thus, this research contributes to a better understanding of the adverse effects of these drugs on studied plants. Important to mention is that the dietary intake of these drugs contaminated plants, plants with important nutritional value, may also presume a risk to human health, but currently little is known about the fate of the drugs in plants and their effect on or risk to the ecosystem.

Keywords: abiotic stress, green leafy vegetables, pigments content, ultra structure

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Authors: Senthil Rajan Dharmalingam, Shamala Nadaraju, Srinivasan Ramamurthy

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Doxorubicin is the most widely used anticancer drugs in chemotherapy treatment. However, problems related to the development of multidrug resistance (MDR) and acute cardiotoxicity have led researchers to investigate alternative forms of administering doxorubicin for cancer therapy. Several methods have been attempted to overcome MDR, including the co-administration of a chemosensitizer inhibiting the efflux caused by ATP binding cassette transporters with anticancer drugs, and the bypass of the efflux mechanism. Co encapsulation of doxorubicin (Dox) and cyclosporine A (CSA) into poly (DL-lactide-co-glycolide) nanoparticles was emulsification-solvent evaporation method using polyvinyl alcohol as emulsion stabilizers. The Dox-CSA loaded nanoparticles were evaluated for particle size, zeta potential and PDI by light scattering analysis and thermal characterizations by differential scanning calorimetry (DSC). Loading efficiency (LE %) and in-vitro dissolution samples were evaluated by developed and validated HPLC method. The optimum particle size obtained is 298.6.8±39.4 nm and polydispersity index (PDI) is 0.098±0.092. Zeta potential is found to be -29.9±4.23. Optimum pH to increase Dox LE% was found 7.1 which gave 42.5% and 58.9% increase of LE% for pH 6.6 and pH 8.6 compared respectively. LE% achieved for Dox is 0.07±0.01 % and CSA is 0.09±0.03%. Increased volume of PVA and weight of PLGA shows increase in size of nanoparticles. DSC thermograms showed shift in the melting peak for the nanoparticles compared to Dox and CSA indicating encapsulation of drugs. In conclusion, these preliminary studies showed the feasibility of PLGA nanoparticles to entrap Dox and CSA and require future in-vivo studies to be performed to establish its potential.

Keywords: doxorubicin, cyclosporine, PLGA, nanoparticles

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Authors: Polina Prokopovich

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Disease-modifying osteoarthritis drugs (DMOADs) are a new therapeutic class for OA, preventing or inhibiting OA development. Unfortunately, none of the DMOADs have been clinically approved due to their poor therapeutic effects in clinical trials. The joint environment has played a role in the poor clinical performance of these drugs by limiting the amount of drug effectively delivered as well as the time that the drug spends within the joint space. The current study aims to enhance the cartilage uptake and retention time of the DMOADs-model (licofelone), which showed a significant therapeutic effect against OA progression and is currently in phase III. Licofelone will be covalently conjugated to the hydrolysable, cytocompatible, and cationic poly beta-amino ester polymers (PBAE). The cationic polymers (A16 and A87) can be electrostatically attached to the negatively charged cartilage component (glycosaminoglycan), which will increase the drug penetration through the cartilage and extend the drug time within the cartilage. In the cartilage uptake and retention time studies, an increase of 18 to 37 times of the total conjugated licofelone to A87 and A16 was observed when compared to the free licofelone. Furthermore, the conjugated licofelone to A87 was detectable within the cartilage at 120 minutes, while the free licofelone was not detectable after 60 minutes. Additionally, the A87-licofelone conjugate showed no effect on the chondrocyte viability. In conclusion, the cationic A87 and A16 polymers increased the percentage of licofelone within the cartilage, which could potentially enhance the therapeutic effect and pharmacokinetic performance of licofelone or other DMOADs clinically.

Keywords: PBAE, cartilage., osteoarthritis, injectable biomaterials, drug delivery

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Authors: Aarushi Baloria, Joshina Jamwal

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The paper attempts to understand the genesis of the Kashmir conflict, the LoC trade, and the various challenges which impede LoC trade. The paper further understands how this trade assists in mitigating tension between the countries and act as a conference building measure (CBM). The paper discusses later on the positive aspects of LoC trade with the help of statistical data like increase in state's economy along with negatives like smuggling of arms, drugs, swapping and interchanging of Hawala money and other unconstitutional activities like terrorism that took place on trade points across LoC. Moreover, the paper also mentioned in the international context; the episodes of Ireland of Europe, Palestine of Middle East, Uganda of Africa not only as transaction step but also as a peace channel between the fragmented parts. Thus, the paper, in a nutshell, reflects how the trade across LoC benefited in various psychological, economic, and political reasons, and it is worth taking risk, taking its overall positive things into consideration.

Keywords: drugs, economy, international, peace, psychological, trade

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Authors: Recep Keşli, Hayriye Tokay, Cengiz Demir, İsmail Ceyhan

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Objective: In many countries, tuberculosis (TB) is still one of the most important diseases. Tuberculosis is among top 10 causes of death worldwide. The early diagnosis of active tuberculosis still depends on the presence of acid resistant bacilli (ARB) in stained smears. In this study, we aimed to investigate the diagnostic performances of Erlich Ziehl Neelsen (EZN), Kinyoun and two different fluorescent stains. Methods: The specimens were obtained from the patients who applied to Chest Diseases Departments of Ankara Atatürk Chest Diseases and Thoracic Surgery Training and Research Hospital, and Afyon Kocatepe University, ANS Research and Practice Hospital. The study was carried out in the Medical Microbiology Laboratory, School of Medicine, Afyon Kocatepe University. All the non-sterile specimens were homogenized and decontaminated according to the EUCAST instructions. Samples were inoculated onto the Löwenstein-Jensen agars (bio-Merieux Marcy l'Etoile, France) and then incubated at 37˚C, for 40 days. Four smears were prepared from each specimen. Slides were stained with commercial EZN (BD, Sparks, USA), Kinyoun (SALUBRIS Istanbul, Turkey), Auramine (SALUBRIS Istanbul, Turkey) and Rhodamine (SALUBRIS Istanbul, Turkey) kit. While EZN and Kinyoun stainings were examined by light microscope, Auramine and Rhodamine slides were examined by fluorescence microscopy. Results: A total of 158 respiratory system samples (sputum, broncho alveolar lavage fluid…etc) were enrolled into the study. A hundred and two of the samples that processed were found as culture positive. The sensitivity, specificity, positive predictive, and negative predictive values were detected as 100%, 67.5%, 73.5%, and 100% for EZN, 100%, 70.9%, 77.4%, and 100% for Kinyoun, 100%,77.8%, 84.3%, 100% for Auramine, and 100%, 80% , 86.3%, and 100% for Rhodamine respectively. Conclusions: According to our study auramine and rhodamine staining methods showed the best diagnostic performance among the four investigated staining methods. In conclusion, the fluorochrome staining method may be accepted as the most reliable, rapid and useful method for diagnosis of the mycobacterial infections truly.

Keywords: acid resistant bacilli (ARB), auramine, Ehrlich-Ziehl-Neelsen (EZN), Kinyoun, Rhodamine

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Authors: Blessing Atim Aderibigbe

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A series of amine/ester-linked hybrid compounds containing pharmacophores, such as ursolic acid, oleanolic acid, ferrocene and bisphosphonates, were synthesized in an attempt to develop potent antibacterial and anticancer agents. Their structures were analyzed and confirmed using Nuclear Magnetic Resonance, Fourier Transform Infrared Spectroscopy, and mass spectroscopy. All the synthesized hybrid compounds were evaluated for their antibacterial activities against eleven selected bacterial strains using a serial dilution method. Some of the compounds displayed significant antibacterial activity against most of the bacterial and fungal strains. In addition, the in vitro cytotoxicity of these compounds was also performed against selected cancer cell lines. Some of the compounds were also found to be more active than their parent compounds, revealing the efficacy of designing hybrid molecules using plant-based bioactive agents.

Keywords: ursolic acid, hybrid drugs, oleanolic acid, bisphosphonates

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Authors: M. Kumpugdee-Vollrath, T. G. D. Phu, M. Helmis

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A suitable model membrane to study the pharmacological effect of pharmaceutical products is human stratum corneum because this layer of human skin is the outermost layer and it is an important barrier to be passed through. Other model membranes which were also used are for example skins from pig, mouse, reptile or fish. We are interested in fish skins in this project. The advantages of the fish skins are, that they can be obtained from the supermarket or fish shop. However, the fish skins should be freshly prepared and used directly without storage. In order to understand the effect of different model drugs e.g. lidocaine HCl, resveratrol, paracetamol, ibuprofen, acetyl salicylic acid on the properties of the model membrane from various types of fishes e.g. trout, salmon, cod, plaice permeation tests were performed and differential scanning calorimetry was applied.

Keywords: fish skin, model membrane, permeation, DSC, lidocaine HCl, resveratrol, paracetamol, ibuprofen, acetyl salicylic acid

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Authors: A. J. S. P. Nileema, S. Kulatunga , S. H. Palihawadana

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Computer aided detection (CAD) system was developed for the diagnosis of pulmonary tuberculosis using digital chest X-rays with MATLAB image processing techniques using a statistical approach. The study comprised of 200 digital chest radiographs collected from the National Hospital for Respiratory Diseases - Welisara, Sri Lanka. Pre-processing was done to remove identification details. Lung fields were segmented and then divided into four quadrants; right upper quadrant, left upper quadrant, right lower quadrant, and left lower quadrant using the image processing techniques in MATLAB. Contrast, correlation, homogeneity, energy, entropy, and maximum probability texture features were extracted using the gray level co-occurrence matrix method. Descriptive statistics and normal distribution analysis were performed using SPSS. Depending on the radiologists’ interpretation, chest radiographs were classified manually into PTB - positive (PTBP) and PTB - negative (PTBN) classes. Features with standard normal distribution were analyzed using an independent sample T-test for PTBP and PTBN chest radiographs. Among the six features tested, contrast, correlation, energy, entropy, and maximum probability features showed a statistically significant difference between the two classes at 95% confidence interval; therefore, could be used in the classification of chest radiograph for PTB diagnosis. With the resulting value ranges of the five texture features with normal distribution, a classification algorithm was then defined to recognize and classify the quadrant images; if the texture feature values of the quadrant image being tested falls within the defined region, it will be identified as a PTBP – abnormal quadrant and will be labeled as ‘Abnormal’ in red color with its border being highlighted in red color whereas if the texture feature values of the quadrant image being tested falls outside of the defined value range, it will be identified as PTBN–normal and labeled as ‘Normal’ in blue color but there will be no changes to the image outline. The developed classification algorithm has shown a high sensitivity of 92% which makes it an efficient CAD system and with a modest specificity of 70%.

Keywords: chest radiographs, computer aided detection, image processing, pulmonary tuberculosis

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Authors: A. A. Agbor, Jean Joel R. Bigna, Serges Clotaire Billong, Mathurin Cyrille Tejiokem, Gabriel L. Ekali, Claudia S. Plottel, Jean Jacques N. Noubiap, Hortence Abessolo, Roselyne Toby, Sinata Koulla-Shiro

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Background: Contributors to fatal outcomes in patients undergoing tuberculosis (TB) treatment in the setting of HIV co-infection are poorly characterized, especially in sub-Saharan Africa. Our study’s aim was to assess factors associated with death in TB/HIV co-infected patients during the first 6 months their TB treatment. Methods: We conducted a tertiary-care hospital-based retrospective cohort study from January 2006 to December 2013 at the Yaoundé Central Hospital, Cameroon. We reviewed medical records to identify hospitalized co-infected TB/HIV patients aged 15 years and older. Death was defined as any death occurring during TB treatment, as per the World Health Organization’s recommendations. Logistic regression analysis identified factors associated with death. Magnitudes of associations were expressed by adjusted odds ratio (aOR) with 95% confidence interval. A p value < 0.05 was considered statistically significant. Results: The 337 patients enrolled had a mean age of 39.3 (+/- 10.3) years and more (54.3%) were women. TB treatment outcomes included: treatment success in 60.8% (n=205), death in 29.4% (n=99), not evaluated in 5.3% (n=18), loss to follow-up in 5.3% (n=14), and failure in 0.3% (n=1) . After exclusion of patients lost to follow-up and not evaluated, death in TB/HIV co-infected patients during TB treatment was associated with: a TB diagnosis made before national implementation of guidelines regarding initiation of antiretroviral therapy (aOR = 2.50 [1.31-4.78]; p = 0.006), the presence of other AIDS-defining infections (aOR = 2.73 [1.27-5.86]; p = 0.010), non-AIDS comorbidities (aOR = 3.35 [1.37-8.21]; p = 0.008), not receiving co-trimoxazole prophylaxis (aOR = 3.61 [1.71-7.63]; p = 0.001), not receiving antiretroviral therapy (aOR = 2.45 [1.18-5.08]; p = 0.016), and CD4 cell counts < 50 cells/mm3 (aOR = 16.43 [1.05-258.04]; p = 0.047). Conclusions: The success rate of anti-tuberculosis treatment among hospitalized TB/HIV co-infected patients in our setting is low. Mortality in the first 6 months of treatment was high and strongly associated with specific clinical factors including states of greater immunosuppression, highlighting the urgent need for targeted interventions, including provision of anti-retroviral therapy and co-trimoxazole prophylaxis in order to enhance patient outcomes.

Keywords: TB/HIV co-infection, death, treatment outcomes, factors

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Authors: Monika Verma, Renuka Sharma, B. R. Gulati, Namita Singh

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In combination therapy, two chemotherapeutic agents work together in a collaborative action. It has appeared as one of the promising approaches to improve anti-cancer treatment efficacy. In the present investigation, piperine (P-NPS), paclitaxel (PTX NPS), and a combination of both, piperine-paclitaxel nanoparticle (Pip-PTX NPS), were made by the nanoprecipitation method and later characterized by PSA, DSC, SEM, TEM, and FTIR. All nanoparticles exhibited a monodispersed size distribution with a size of below 200 nm, zeta potential ranges from (-30-40mV) and a narrow polydispersity index (>0.3) of the drugs. The average encapsulation efficiency was found to be between 80 and 90%. In vitro release of drugs for nanoparticles was done spectrophotometrically. FTIR and DSC results confirmed the presence of the drug. The Pip-PTX NPS significantly inhibit cell proliferation as compared to the native drugs nanoparticles in the breast cancer cell line MCF-7. In addition, Pip-PTX NPS suppresses cells in colony formation and soft gel agar assay. Scratch migration and Transwell chamber invasion assays revealed that combined nanoparticles reduce the migration and invasion of breast cancer cells. Morphological studies showed that Pip-PTX NPS penetrates the cells and induces apoptosis, which was further confirmed by DNA fragmentation, SEM, and western blot analysis. Taken together, Pip-PTX NPS inhibits cell proliferation, anchorage dependent and anchorage independent cell growth, reduces migration and invasion, and induces apoptosis in cells. These findings support that combination therapy using Pip-PTX NPS represents a potential approach and could be helpful in the future for breast cancer therapy.

Keywords: piperine, paclitaxel, breast cancer, apoptosis

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Authors: Maki Mizogami, Hironori Tsuchiya, Yoshiroh Hayabuchi, Kenji Shigemi

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Since drugs exhibit significant structure-dependent differences in activity and toxicity, their differentiation based on the mechanism of action should have implications for comparative drug efficacy and safety. We aimed to differentiate drug stereoisomers by their stereostructure-selective membrane interactions underlying pharmacological and toxicological effects. Biomimetic lipid bilayer membranes were prepared with phospholipids and sterols (either cholesterol or epicholesterol) to mimic the lipid compositions of neuronal and cardiomyocyte membranes and to provide these membranes with the chirality. The membrane preparations were treated with different classes of stereoisomers at clinically- and pharmacologically-relevant concentrations (25-200 μM), followed by measuring fluorescence polarization to determine the membrane interactivity of drugs to change the physicochemical property of membranes. All the tested drugs acted on lipid bilayers to increase or decrease the membrane fluidity. Drug stereoisomers could not be differentiated when interacting with the membranes consisting of phospholipids alone. However, they stereostructure-selectively interacted with neuro-mimetic and cardio-mimetic membranes containing 40 mol% cholesterol ((3β)-cholest-5-en-3-ol) to show the relative potencies being local anesthetic R(+)-bupivacaine > rac-bupivacaine > S(‒)-bupivacaine, α2-adrenergic agonistic D-medetomidine > rac-medetomidine > L-medetomidine, β-adrenergic antagonistic R(+)-propranolol > rac-propranolol > S(–)-propranolol, NMDA receptor antagonistic S(+)-ketamine > rac-ketamine, analgesic monoterpenoid (+)-menthol > (‒)-menthol, non-steroidal anti-inflammatory S(+)-ibuprofen > rac-ibuprofen > R(‒)-ibuprofen, and bioactive flavonoid (+)-epicatechin > (‒)-epicatechin. All of the order of membrane interactivity were correlated to those of beneficial and adverse effects of the tested stereoisomers. In contrast, the membranes prepared with epicholesterol ((3α)-chotest-5-en-3-ol), an epimeric form of cholesterol, reversed the rank order of membrane interactivity to be S(‒)-enantiomeric > racemic > R(+)-enantiomeric bupivacaine, L-enantiomeric > racemic > D-enantiomeric medetomidine, S(–)-enantiomeric > racemic > R(+)-enantiomeric propranolol, racemic > S(+)-enantiomeric ketamine, (‒)-enantiomeric > (+)-enantiomeric menthol, R(‒)-enantiomeric > racemic > S(+)-enantiomeric ibuprofen, and (‒)-enantiomeric > (+)-enantiomeric epicatechin. The opposite configuration allows drug molecules to interact with chiral sterol membranes enantiomer-selectively. From the comparative results, it is speculated that a 3β-hydroxyl group in cholesterol is responsible for the enantioselective interactions of drugs. In conclusion, the differentiation of drug stereoisomers by their stereostructure-selective membrane interactions would be useful for designing and predicting drugs with higher activity and/or lower toxicity.

Keywords: chiral membrane, differentiation, drug stereoisomer, enantioselective membrane interaction

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Authors: O. Atli Eklioglu

Abstract:

Atypical antipsychotics such as quetiapine, olanzapine, and risperidone have been frequently and chronically used to treat psychiatric disorders accompanied by psychosis mainly schizophrenia. Since these drugs are commonly used in male patients of reproductive age, it is required to determine the possible effects of them on the reproductive system. In this study, it was aimed to evaluate the possible toxic effects of quetiapine, olanzapine and risperidone, which are the most frequently prescribed and chronically used psychiatric drugs, on sperm parameters. For this purpose, quetiapine (10, 20 and 40 mg/kg), olanzapine (2.5, 5 and 10 mg/kg), and risperidone (1.25, 2.5 and 3 mg/kg) were administered to male rats for 28 consecutive days. At the end of this period, sperm concentration, motility, and morphology were investigated by a computer-assisted sperm analysis system. According to the results, sperm parameters were negatively affected by antipsychotic use.

Keywords: quetiapine, olanzapine, risperidone, sperm count, motility, sperm morphology, computer-assisted sperm analysis

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Authors: Susan Scott, Dina Hanna, Bassel Zebian, Gary Ruiz, Sreena Das

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Although the number of cases of TB in England has fallen over the last 4 years, it remains an important public health burden with 1 in 20 cases dying annually. The vast majority of cases present in non-UK born individuals with social risk factors. We present a case of non-pulmonary TB presenting in a healthy child born in the UK to professional parents. We present a case of a healthy 10 year old boy who developed acute back pain during school PE. Over the next 5 months, he was seen by various health and allied professionals with worsening back pain and kyphosis. He became increasing unsteady and for the 10 days prior to admission to our hospital, he developed fevers. He was admitted to his local hospital for tonsillitis where he suffered two falls on account of his leg weakness. A spinal X-ray revealed a pathological fracture and gibbus formation. He was transferred to our unit for further management. On arrival, the patient had lower motor neurone signs of his left leg. He underwent spinal fixture, laminectomy and decompression. Microbiology samples taken intra-operatively confirmed Mycobacterium Tuberculosis. He had a positive Mantoux and T-spot and treatment were commenced. There was no evidence of immune compromise. The patient was born in the UK, had a BCG scar and his only travel history had been two years prior to presentation when he travelled to the Phillipines for a short holiday. The patient continues to have issues around neuropathic pain, mobility, pill burden and mild liver side effects from treatment. Discussion: There is a paucity of case reports on spinal TB in paediatrics and diagnosis is often difficult due to the non-specific symptomatology. Although prognosis on treatment is good, a delayed diagnosis can have devastating consequences. This case highlights the continued need for higher index of suspicion and diagnosis in a world with changing patterns of migration and increase global travel. Surgical intervention is limited to the most serious cases to minimise further neurological damage and improve prognosis. There remains the need for a multi-disciplinary approach to deal with challenges of treatment and rehabilitation.

Keywords: tuberculosis, non-pulmonary TB, public health burden, diagnostic challenge

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Authors: Fei Ye, Åsa Barrefelt, Manuchehr Abedi-Valugerdi, Khalid M. Abu-Salah, Salman A. Alrokayan, Mamoun Muhammed, Moustapha Hassan

Abstract:

With appropriate encapsulation in functional nanoparticles drugs are more stable in physiological environment and the kinetics of the drug can be more carefully controlled and monitored. Furthermore, targeted drug delivery can be developed to improve chemotherapy in cancer treatment, not only by enhancing intracellular uptake by target cells but also by reducing the adverse effects in non-target organs. Inorganic imaging agents, delivered together with anti-cancer drugs, enhance the local imaging contrast and provide precise diagnosis as well as evaluation of therapy efficacy. We have developed biodegradable polymeric vesicles as a nanocarrier system for multimodal bio-imaging and anticancer drug delivery. The poly (lactic-co-glycolic acid) PLGA) vesicles were fabricated by encapsulating inorganic imaging agents of superparamagnetic iron oxide nanoparticles (SPION), manganese-doped zinc sulfide (MN:ZnS) quantum dots (QDs) and the anticancer drug busulfan into PLGA nanoparticles via an emulsion-evaporation method. T2-weighted magnetic resonance imaging (MRI) of PLGA-SPION-Mn:ZnS phantoms exhibited enhanced negative contrast with r2 relaxivity of approximately 523 s-1 mM-1 Fe. Murine macrophage (J774A) cellular uptake of PLGA vesicles started fluorescence imaging at 2 h and reached maximum intensity at 24 h incubation. The drug delivery ability PLGA vesicles was demonstrated in vitro by release of busulfan. PLGA vesicles degradation was studied in vitro, showing that approximately 32% was degraded into lactic and glycolic acid over a period of 5 weeks. The biodistribution of PLGA vesicles was investigated in vivo by MRI in a rat model. Change of contrast in the liver could be visualized by MRI after 7 min and maximal signal loss detected after 4 h post-injection of PLGA vesicles. Histological studies showed that the presence of PLGA vesicles in organs was shifted from the lungs to the liver and spleen over time.

Keywords: biodegradable polymers, multifunctional nanoparticles, quantum dots, anticancer drugs

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Authors: Swati Gautam, Amita Jain, Shyampyari Jaiswar

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Objective: To elucidate the role of (ApaI&TaqI) VDR gene polymorphism in the pathogenesis of female genital tuberculosis (FGTB) cases. Background: Female genital TB represents about 15-20% of total extra-pulmonary TB (EPTB). Female subjects with vitamin D deficiency have been shown to be at higher risk of pulmonary TB as well as FGTB. In same context few functional polymorphism in vitamin D receptor (VDR) gene has been considered as an important genetic risk factor that modulate the development of FGTB. Therefore we aimed, to elucidate the role of (ApaI&TaqI) VDR gene polymorphism in the pathogenesis of FGTB. Study design: Case-Control study. Sample size: Cases (60) and Controls (60). Study site: Department of Obstetrics & Gynecology & Department of Microbiology, K.G.M.U. Lucknow, (UP). Inclusion criteria: Cases: Women with age group 20-35 years, premenstrual endometrial aspiration collected and included in the study, those were positive with acid-fast bacilli (AFB)/ TB-PCR/ LJ culture/ liquid culture. Controls: Women with age group 20-35 years having no history of ATT and all test negative for TB recruited as control. Exclusion criteria: -Women with endometriosis, polycystic ovaries (PCOD), positive on Chlamydia & gonorrhea, already on anti-tubercular therapy (ATT) excluded. Materials and Methods: Blood samples were collected in EDTA tubes from cases and controls stored at -20ºC. Genomic DNA extraction was carried out by salting-out method. Genotyping of VDR gene (ApaI&TaqI) polymorphism was performed by using single amplification refractory mutation system (ARMS) PCR technique. PCR products were analyzed by electrophoresis on 2% agarose gel. Statistical analysis was done by SPSS16.3 software & computing odds ratio (OR) with 95% CI. Results: Increased risk of female genital tuberculosis was observed in AA genotype (OR =1.1419-6.212 95% CI, P*<0.036) and A allele (OR =1.255-3.518, 95% CI, P* < 0.006) in FGTB as compared to controls. Moreover A allele was found more frequent in FGTB patients. No significant difference was observed in TaqI gene polymorphism of VDR gene. Conclusion: The ApaI polymorphism is significantly associated with etiology of FGTB and plays an important role as a genetic risk factor in FGTB women.

Keywords: ARMS, ATT, EPTB, FGTB, VDR

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Authors: Cesar Torres, Robert Briber, Nam Sun Wang

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Eye drops are the most commonly used treatment for short-term and long-term ophthalmic diseases. However, eye drops could deliver only about 5% of the functional ingredients contained in a burst dosage. To address the limitations of eye drops, the use of therapeutic contact lenses has been introduced. Drug-loaded contact lenses provide drugs a longer residence time in the tear film and hence, decrease the potential risk of side effects. Nevertheless, a major limitation of contact lenses as drug delivery devices is that most of the drug absorbed is released within the first few hours. This fact limits their use for extended release. The present study demonstrates the application of long-alkyl chain ionic surfactants on extending drug release kinetics from commercially available silicone hydrogel contact lenses. In vitro release experiments were carried by immersing drug-containing contact lenses in phosphate buffer saline at physiological pH. The drug concentration as a function of time was monitored using ultraviolet-visible spectroscopy. The results of the study demonstrate that release kinetics is dependent on the ionic surfactant weight percent in the contact lenses, and on the length of the hydrophobic alkyl chain of the ionic surfactants. The use of ionic surfactants in contact lenses can extend the delivery of drugs from a few hours to a few weeks, depending on the physicochemical properties of the drugs. Contact lenses embedded with ionic surfactants could be potential biomaterials to be used for extended drug delivery and in the treatment of ophthalmic diseases. However, ocular irritation and toxicity studies would be needed to evaluate the safety of the approach.

Keywords: contact lenses, drug delivery, controlled release, ionic surfactant

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Authors: Abbas Jafarizad, Duygu Ekinci

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In this work targeted drug delivery is proposed to decrease adverse effect of drugs with concomitant reduces in consumption and treatment outgoings. Nanoparticles (NPs) can be prepared from a variety of materials such as lipid, biodegradable polymer that prevent the drugs cytotoxicity in healthy cells, etc. One of the most important drugs used in chemotherapy is mitoxantrone (MTX) which prevents cell proliferation by inhibition of topoisomerase II and DNA repair; however, it is not selective and has some serious side effects. In this study, mentioned aim is achieved by using several nanocarriers like magnetite (Fe3O4) and their composites with magnetic graphene oxide (Fe3O4@GO). Also, cytotoxic potential of Fe3O4, Fe3O4-MTX, and Fe3O4@GO-MTX nanocomposite were evaluated on mesenchymal stem cells (MSCs). In this study, we reported the synthesis of monodisperse Fe3O4 NPs and Fe3O4@GO nanocomposite and their structures were investigated by using field emission scanning electron microscope (FESEM), Fourier transform infrared (FTIR) spectra, atomic force microscopy (AFM), Brauneur Emmet Teller (BET) isotherm and contact angle studies. Moreover, we used 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to evaluate cytotoxic effects of MTX, Fe3O4 NPs, Fe3O4-MTX and Fe3O4@GO-MTX nanocomposite on MSCs. The in-vitro MTT results indicated that all concentrations of MTX and Fe3O4@GO-MTX nanocomposites showed cytotoxic effects while all concentrations of Fe3O4 NPs and Fe3O4-MTX NPs did not show any cytotoxic effect on stem cells. The results from this study indicated that using Fe3O4 NPs as anticancer drug delivery systems could be a trustworthy method for cancer treatment. But for reaching excellent and accurate results, further investigation is necessary.

Keywords: mitoxantrone, magnetite, magnetic graphene oxide, MTT assay, mesenchymal stem cells

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Authors: Yasin I. Tayem, Jamil Ahmed, Mahmood Bahzad, Abdullah Alnama, Fahad Al Asfoor, Mahmood A. Jalil, Mohammed Radhi, Ahmed Alenezi, Khalid A. J. Al-Khaja

Abstract:

Drug-drug interactions (DDIs) represent a significant cause of patient’s morbidity and mortality. The rate of DDIs is rapidly increasing worldwide with the increasing proportion of ageing population and frequent requirement of polypharmacy-prescription of multiple drugs to treat comorbidities. Prescribing physicians are responsible for checking their prescriptions for the presence and severity of DDIs. However, since a large number of new drugs are approved and marketed every year, new interactions between medications are increasingly reported. Consequently, it is no longer practical for physicians to rely only upon their previous knowledge of medicine to avoid potential DDIs. The aim of this study was to explore the perceptions of physicians working at primary healthcare centers in Bahrain towards DDIs and how they manage them during their practice. Methodology: In this cross-sectional study, physicians working at all governmental primary healthcare centers in Bahrain were invited to voluntarily, privately and anonymously respond to a self-administered questionnaire. The questionnaire aims to assess their self-reported knowledge of DDIs and how they check for them in their practice. The participants were requested to provide socio demographic data and information related to their attitudes towards DDIs including strategies they employ for detecting and managing them, and their awareness of drugs which commonly cause DDIs. At the end of the questionnaire, an open-ended item was added to allow participants to further add any comment. Findings and Conclusions: The study is going on currently, and the results and conclusions will be presented at the conference.

Keywords: awareness, drug interactions, health centres, physicians

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Authors: Ellen Lagast, Melissa Ceuterick, Mark Leys

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Although adolescence is a stressful period with an increased risk for mental illnesses such as anxiety and depression, little in-depth knowledge is available on the determinants of the use of psychotropic drugs (BZD/SSRIs) and the effects. A qualitative research with adolescents in Flanders was performed. Based on indepth interviews, the interviewees indicate feelings of ambiguity towards their medication use because on the one hand the medication helps to manage their mental vulnerability and disrupted lives, but on the other hand they experience a loss of control of their self and their environment. Undesired side-effects and stigma led to a negative pharmaceutical self. The interviewed youngsters also express dissatisfaction about the prescription behavior with regard to psychotropic drugs of their general practitioner (GP). They wished to have received more information about alternative non-pharmaceutical treatment options. Notwithstanding these comments, the majority of the interviewees maintained trust in their GP to act in their best interest. This paper will relate the prescription behavior in primary care to the organization of mental health care to better understand the “phamaceuticalization” and medicalization of mental health problems in Belgium. Belgium implemented fundamental mental health care reforms to collaborate, to integrate care and to optimize continuity of care. Children and adolescents still are confronted with long waiting lists to access (non-medicalized) mental health services. This access to mental health care partly explains general practitioners’ prescription behavior of psychotropics. Moreover, multidisciplinary practices have not pervaded primary health care yet. Medicalization and pharmaceuticalization of mental health vulnerabilities of youth are both a structural and cultural problem.

Keywords: adolescents, antidepressants, benzodiazepines, mental health system, psychotropic drugs

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Authors: Ubaka Chukwuemeka Michael, Ukwe Chinwe Victoria

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Background: The use of antipsychotic monotherapy remains the standard for schizophrenic disorders so also a prescription switch from older typical to newer atypical classes of antipsychotics on the basis of better efficacy and tolerability. However, surveys on the quality of antipsychotic drug use and substitution in developing countries are very scarce. This study was intended to evaluate quality and factors that drive the prescription and substitution of antipsychotic drugs among schizophrenic patients visiting a regional psychiatric hospital. Methods: Case files of patients visiting a federal government funded Neuropsychiatric Hospital between July 2012 and July 2014 were systematically retrieved. Patient demographic characteristics, clinical details and drug management data were collected and subjected to descriptive and inferential data analysis to determine quality and predictors of utilization. Results: Of the 600 case files used, there were more male patients (55.3%) with an overall mean age of 33.7±14.4 years. Typical antipsychotic agents accounted for over 85% of prescriptions, with majority of the patients receiving more than 2 drugs in at least a visit (80.9%). Fluphenazine (25.2%) and Haloperidol (18.8%) were mostly given as antipsychotics for treatment initiation while Olazenpine (23.0%) and Benzhexol (18.3%) were the most currently prescribed antipsychotics. Nearly half (42%, 252/600) of these patients were switched from one class to another, with 34.5% (207/600) of them switched from typical to atypical drug classes. No demographic or clinical factors influenced drug substitutions but a younger age and being married influenced being prescribed a polypharmacy regimen (more than 2 drugs) and an injectable antipsychotic agent. Conclusion: The prevalence of antipsychotic polypharmacy and use of typical agents among these patients was high. However, only age and marital status affected the quality of antipsychotic prescriptions among these patients.

Keywords: antipsychotics, drug substitution, pharmacoepidemiology, polypharmacy

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Authors: S. Boulenouar, A. Boukli Hacene, S. Brahmi

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Quality is an old concept but which recently became omnipresent in the society. It is a pledge of the well done job and therefore the satisfaction of the customer. Now, dispensing pharmacies seem to be held away from this approach. Officinal staff is called to dispense drugs. However this essential function is rarely studied and taken into account. To contribute to the good use of medicines and to reduce the dangers, it is important to consider the dispensation of drugs practised in the pharmacies. It is a both descriptive and retrospective study .The descriptive part is to conduct a survey near to the dispensary pharmacists. The retrospective section concentrates on the analysis of medicine prescriptions dispensed to patients. Following the survey that we carried out near the pharmacists of dispensary of the town of Oran, it appears that in majority, they are not inclined, by themselves, to take up the challenge of quality at the dispensary. The approach requires time and a motivation that pharmacists do not have for the moment. Efforts are still needed on the part of pharmacists, but also of authorities and organizations in charge of quality in the dispensary. At the end of this work, it seems to us that the implementation of a quality approach is part of our reflection on the added value of the pharmacist of dispensary in the drug chain.

Keywords: customer satisfaction, dispensary, dispensing of the drug, quality approach

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Authors: Zhi Hao Chow, Cian Mulligan, Jack Walsh, Antonio Garzon Vico, Dimitar Krastev

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Drug development is resource-intensive, time-consuming, and increasingly expensive with each developmental stage. The success rates of drug development are also relatively low, and the resources committed are wasted with each failed candidate. As such, a reliable method of predicting the success of drug development is in demand. The hypothesis was that some examples of failed drug candidates are pushed through developmental pipelines based on false confidence and may possess common linguistic features identifiable through sentiment analysis. Here, the concept of using text analysis to discover such features in research publications and investor reports as predictors of success was explored. R studios were used to perform text mining and lexicon-based sentiment analysis to identify affective phrases and determine their frequency in each document, then using SPSS to determine the relationship between our defined variables and the accuracy of predicting outcomes. A total of 161 publications were collected and categorised into 4 groups: (i) Cancer treatment, (ii) Neurodegenerative disease treatment, (iii) Vaccines, and (iv) Others (containing all other drugs that do not fit into the 3 categories). Text analysis was then performed on each document using 2 separate datasets (BING and AFINN) in R within the category of drugs to determine the frequency of positive or negative phrases in each document. A relative positivity and negativity value were then calculated by dividing the frequency of phrases with the word count of each document. Regression analysis was then performed with SPSS statistical software on each dataset (values from using BING or AFINN dataset during text analysis) using a random selection of 61 documents to construct a model. The remaining documents were then used to determine the predictive power of the models. Model constructed from BING predicts the outcome of drug performance in clinical trials with an overall percentage of 65.3%. AFINN model had a lower accuracy at predicting outcomes compared to the BING model at 62.5% but was not effective at predicting the failure of drugs in clinical trials. Overall, the study did not show significant efficacy of the model at predicting outcomes of drugs in development. Many improvements may need to be made to later iterations of the model to sufficiently increase the accuracy.

Keywords: data analysis, drug development, sentiment analysis, text-mining

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Authors: A. Hilsana, Vinay U. Rao, M. Sudhakar

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Even though a number of non-steroidal anti-inflammatory drugs (NSAIDS) are available with different chemistries, they share a common solubility characteristic that is they are relatively more soluble in alkaline environment and practically insoluble in acidic environment. This work deals with developing a wax matrix drug delivery platform for controlled delivery of three model NSAIDS, Diclofenac sodium (DNa), Mefenamic acid (MA) and Naproxen (NPX) using the melt granulation technique. The aim of developing the platform was to have a general understanding on how an erodible matrix system modulates drug delivery rate and extent and how it can be optimized to give a delivery system which shall release the drug as per a common target product profile (TPP). Commonly used waxes like Cetostearyl alcohol and stearic acid were used singly an in combination to achieve a TPP of not 15 to 35% in 1 hour and not less than 80% Q in 24 hours. Full factorial design of experiments was followed for optimization of the formulation.

Keywords: NSAIDs, controlled delivery, target product profile, melt granulation

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Authors: Gabriela Wyszogrodzka, Przemyslaw Dorozynski, Barbara Gil, Maciej Strzempek, Bartosz Marszalek, Piotr Kulinowski, Wladyslaw Piotr Weglarz, Elzbieta Menaszek

Abstract:

MOFs (Metal-Organic Frameworks) belong to a new group of porous materials with a hybrid organic-inorganic construction. Their structure is a network consisting of metal cations or clusters (acting as metallic centers, nodes) and the organic linkers between nodes. The interest in MOFs is primarily associated with the use of their well-developed surface and large porous. Possibility to build MOFs of biocompatible components let to use them as potential drug carriers. Furthermore, forming MOFs structure from cations possessing paramagnetic properties (e.g. iron cations) allows to use them as MRI (Magnetic Resonance Imaging) contrast agents. The concept of formation of particles that combine the ability to transfer active substance with imaging properties has been called theranostic (from words combination therapy and diagnostics). By building MOF structure from iron cations it is possible to use them as theranostic agents and monitoring the distribution of the active substance after administration in real time. In the study iron-MOF: Fe-MIL-101-NH2 was chosen, consisting of iron cluster in nodes of the structure and amino-terephthalic acid as a linker. The aim of the study was to investigate the possibility of applying Fe-MIL-101-NH2 as inhalable theranostic particulate system for the first-line anti-tuberculosis antibiotic – isoniazid. The drug content incorporated into Fe-MIL-101-NH2 was evaluated by dissolution study using spectrophotometric method. Results showed isoniazid encapsulation efficiency – ca. 12.5% wt. Possibility of Fe-MIL-101-NH2 application as the MRI contrast agent was demonstrated by magnetic resonance tomography. FeMIL-101-NH2 effectively shortening T1 and T2 relaxation times (increasing R1 and R2 relaxation rates) linearly with the concentrations of suspended material. Images obtained using multi-echo magnetic resonance imaging sequence revealed possibility to use FeMIL-101-NH2 as positive and negative contrasts depending on applied repetition time. MOFs micronization via ultrasound was evaluated by XRD, nitrogen adsorption, FTIR, SEM imaging and did not influence their crystal shape and size. Ultrasonication let to break the aggregates and achieve very homogeneously looking SEM images. MOFs cytotoxicity was evaluated in in vitro test with a highly sensitive resazurin based reagent PrestoBlue™ on L929 fibroblast cell line. After 24h no inhibition of cell proliferation was observed. All results proved potential possibility of application of ironMOFs as an isoniazid carrier and as MRI contrast agent in inhalatory treatment of tuberculosis. Acknowledgments: Authors gratefully acknowledge the National Science Center Poland for providing financial support, grant no 2014/15/B/ST5/04498.

Keywords: imaging agents, metal-organic frameworks, theranostics, tuberculosis

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