Search results for: drug–drug interactions

Authors: S. T. Kumbhar, M. S. Bhatia, R. C. Khairate

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An effective nanodrug delivery system was developed by using chitosan for increased encapsulation efficiency and retarded release of curcumin. Potential ionotropic gelation method was used for the development of chitosan nanoparticles with TPP as cross-linker. The characterization was done for analysis of size, structure, surface morphology, and thermal behavior of synthesized chitosan nanoparticles. The encapsulation efficiency was more than 80%, with improved drug loading capacity. The in-vitro drug release study showed that curcumin release rate was decreased significantly. These chitosan nanoparticles could be a suitable platform for co-delivery of curcumin and anticancer agent for enhanced cytotoxic effect on tumor cells.

Keywords: Curcumin, chitosan, nanoparticles, anticancer activity

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Authors: Daria Zabolotnaya, Svetlana Degtyareva, Veronika Kanestri, Danila Konnov

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An adequate choice of the initial antiretroviral treatment determines the treatment efficacy. In the clinical guidelines in Russia non-nucleoside reverse transcriptase inhibitors (NNRTIs) are still considered to be an option for first-line treatment while pretreatment drug resistance (PDR) testing is not routinely performed. We conducted a cohort retrospective study in HIV-positive treatment naïve patients of the H-clinic (Moscow, Russia) who performed PDR testing from July 2017 to November 2021. All the information was obtained from the medical records anonymously. We analyzed the mutations in reverse transcriptase and protease genes. RT-sequences were obtained by AmpliSens HIV-Resist-Seq kit. Drug resistance was defined using the HIVdb Program v. 8.9-1. PDR was estimated using the Stanford algorithm. Descriptive statistics were performed in Excel (Microsoft Office, 2019). A total of 261 HIV-1 infected patients were enrolled in the study including 197 (75.5%) male and 64 (24.5%) female. The mean age was 34.6±8.3 years. The median CD4 count – 521 cells/µl (IQR 367-687 cells/µl). Data on risk factors of HIV-infection were scarce. The total quantity of strains containing mutations in the reverse transcriptase gene was 75 (28.7%). From these 5 (1.9%) mutations were associated with PDR to nucleoside reverse transcriptase inhibitors (NRTIs) and 30 (11.5%) – with PDR to NNRTIs. The number of strains with mutations in protease gene was 43 (16.5%), from these only 3 (1.1%) mutations were associated with resistance to protease inhibitors. For NNRTIs the most prevalent PDR mutations were E138A, V106I. Most of the HIV variants exhibited a single PDR mutation, 2 were found in 3 samples. Most of HIV variants with PDR mutation displayed a single drug class resistance mutation. 2/37 (5.4%) strains had both NRTIs and NNRTIs mutations. There were no strains identified with PDR mutations to all three drug classes. Though earlier data demonstrated a lower level of PDR in HIV treatment naïve population in Russia and our cohort can be not fully representative as it is taken from the private clinic, it reflects the trend of increasing PDR especially to NNRTIs. Therefore, we consider either pretreatment testing or giving the priority to other drugs as first-line treatment necessary.

Keywords: HIV, resistance, mutations, treatment

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Authors: Ainoa Guinart, Maria Korpidou, Daniel Doellerer, Cornelia Palivan, Ben L. Feringa

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Stimuli responsive systems arise from the need to meet unsolved needs of current molecular drugs. Our study presents the design of a delivery system with high spatiotemporal control and tuneable release profiles. We study the incorporation of a hydrophobic synthetic molecular motor into PDMS-b-PMOXA block copolymer vesicles to create a self-assembled system. We prove their successful incorporation and selective activation by low powered visible light (λ 430 nm, 6.9 mW). We trigger the release of a fluorescent dye with high release efficiencies over sequential cycles (up to 75%) with the ability to turn on and off the release behaviour on demand by light irradiation. Low concentrations of photo-responsive units are proven to trigger release down to 1 mol% of molecular motor. Finally, we test our system in relevant physiological conditions using a lung cancer cell line and the encapsulation of an approved drug. Similar levels of cell viability are observed compared to the free-given drugshowing the potential of our platform to deliver functional drugs on demand with the same efficiency and lower toxicity.

Keywords: molecular motor, polymer, drug delivery, light-responsive, cancer, selfassembly

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Authors: Jianuo Sun, Jinghan Wang, Sirui Zhang, Chenhan Xu, Hongxia Hao, Hong Zhou

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In recent years, the diversification and industrialization of drug-related crimes have posed significant threats to public health and safety globally. The widespread and increasingly younger demographics of drug users and the persistence of drug-impaired driving incidents underscore the urgency of this issue. Drug detection, a specialized forensic activity, is pivotal in identifying and analyzing substances involved in drug crimes. It relies on pharmacological and chemical knowledge and employs analytical chemistry and modern detection techniques. However, current drug detection methods are limited by their inability to perform semi-quantitative, real-time field analyses. They require extensive, complex laboratory-based preprocessing, expensive equipment, and specialized personnel and are hindered by long processing times. This study introduces an alternative approach using nucleic acid aptamers and Aggregation-Induced Emission (AIE) technology. Nucleic acid aptamers, selected artificially for their specific binding to target molecules and stable spatial structures, represent a new generation of biosensors following antibodies. Rapid advancements in AIE technology, particularly in tetraphenyl ethene-based luminous, offer simplicity in synthesis and versatility in modifications, making them ideal for fluorescence analysis. This work successfully synthesized, isolated, and purified an AIE molecule and constructed a probe comprising the AIE molecule, nucleic acid aptamers, and exonuclease for cocaine detection. The probe demonstrated significant relative fluorescence intensity changes and selectivity towards cocaine over other drugs. Using 4-Butoxytriethylammonium Bromide Tetraphenylethene (TPE-TTA) as the fluorescent probe, the aptamer as the recognition unit, and Exo I as an auxiliary, the system achieved rapid detection of cocaine within 5 mins in aqueous and urine, with detection limits of 1.0 and 5.0 µmol/L respectively. The probe-maintained stability and interference resistance in urine, enabling quantitative cocaine detection within a certain concentration range. This fluorescent sensor significantly reduces sample preprocessing time, offers a basis for rapid onsite cocaine detection, and promises potential for miniaturized testing setups.

Keywords: drug detection, aggregation-induced emission (AIE), nucleic acid aptamer, exonuclease, cocaine

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Authors: Vatsal M. Patel, Navin B. Patel

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The present studies deal with the developing a series bearing a diphenyl ethers nucleus using structure-based drug design concept. A newer series of diphenyl ether based azetidinone namely N-(3-chloro-2-oxo-4-(3-phenoxyphenyl)azetidin-1-yl)-2-(substituted amino)acetamide (2a-j) have been synthesized by condensation of m-phenoxybenzaldehyde with 2-(substituted-phenylamino)acetohydrazide followed by the cyclisation of resulting Schiff base (1a-j) by conventional method as well as microwave heating approach as a part of an environmentally benign synthetic protocol. All the synthesized compounds were characterized by spectral analysis and were screened for in vitro antimicrobial, antitubercular and antiprotozoal activity. The compound 2f was found to be most active M. tuberculosis (6.25 µM) MIC value in the primary screening as well as this same derivative has been found potency against L. mexicana and T. cruzi with MIC value 2.09 and 6.69 µM comparable to the reference drug Miltefosina and Nifurtimox. To provide understandable evidence to predict binding mode and approximate binding energy of a compound to a target in the terms of ligand-protein interaction, all synthesized compounds were docked against an enoyl-[acyl-carrier-protein] reductase of M. tuberculosis (PDB ID: 4u0j). The computational studies revealed that azetidinone derivatives have a high affinity for the active site of enzyme which provides a strong platform for new structure-based design efforts. The Lipinski’s parameters showed good drug-like properties and can be developed as an oral drug candidate.

Keywords: antimycobacterial, antiprotozoal, azetidinone, diphenylether, docking, microwave

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Authors: Bharti Jain, Rajeev Jain, Abuzar Kabir, Torki Zughaibi, Shweta Sharma

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Drug-facilitated crimes (DFCs) entail the use of a single drug or a mixture of drugs to render a victim unable. Traditionally, biological samples have been gathered from victims and conducted analysis to establish evidence of drug administration. Nevertheless, the rapid metabolism of various drugs and delays in analysis can impede the identification of such substances. For this, the present article describes a rapid, sustainable, highly efficient and miniaturized protocol for the identification and quantification of three sedative-hypnotic drugs, namely diazepam, chlordiazepoxide and ketamine in alcoholic beverages and complex food samples (cream of biscuit, flavored milk, juice, cake, tea, sweets and chocolate). The methodology involves utilizing fabric phase sorptive extraction (FPSE) to extract diazepam (DZ), chlordiazepoxide (CDP), and ketamine (KET). Subsequently, the extracted samples are subjected to analysis using gas chromatography-mass spectrometry (GC-MS). Several parameters, including the type of membrane, pH, agitation time and speed, ionic strength, sample volume, elution volume and time, and type of elution solvent, were screened and thoroughly optimized. Sol-gel Carbowax 20M (CW-20M) has demonstrated the most effective extraction efficiency for the target analytes among all evaluated membranes. Under optimal conditions, the method displayed linearity within the range of 0.3–10 µg mL–¹ (or µg g–¹), exhibiting a coefficient of determination (R2) ranging from 0.996–0.999. The limits of detection (LODs) and limits of quantification (LOQs) for liquid samples range between 0.020-0.069 µg mL-¹ and 0.066-0.22 µg mL-¹, respectively. Correspondingly, the LODs for solid samples ranged from 0.056-0.090 µg g-¹, while the LOQs ranged from 0.18-0.29 µg g-¹. Notably, the method showcased better precision, with repeatability and reproducibility both below 5% and 10%, respectively. Furthermore, the FPSE-GC-MS method proved effective in determining diazepam (DZ) in forensic food samples connected to drug-facilitated crimes (DFCs). Additionally, the proposed method underwent evaluation for its whiteness using the RGB12 algorithm.

Keywords: drug facilitated crime, fabric phase sorptive extraction, food forensics, white analytical chemistry

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Authors: Anshu Gupta, Charu Gupta

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Background: Punjab, a border state in India has achieved notoriety world over for its drug abuse problem. People right from school kids to elderly are hooked to drugs. This pattern of substance abuse is prevalent in both cities and villages alike. Excess of younger population in India has further aggravated the situation. It is feared that the benefits of India’s economic growth may well be negated by the rising substance abuse especially in this part of the country. It is quite evident that the pattern of substance abuse tends to change over time which is an impediment in the formulation of effective strategies to tackle this issue. Aim: Purpose of the study was to ascertain the change in the pattern of drug abuse for two consecutive years in the out patient department (OPD) population. Method: The study population comprised of all the patients reporting for deaddiction to the psychiatry outpatient department over a period of twelve months for two consecutive years. All the patients were evaluated by the International Classification of Diseases; 10 criteria for substance abuse/dependence. Results: A considerably high prevalence of substance abuse was present in the Indian population. In general, there was an increase in prevalence from first to the second year, especially among the female population. Increase in prevalence of substance abuse appeared to be more prominent among the younger age group of both the sexes. A significant increase in intravenous drug abuse was observed. Peer pressure and parental imitation were the major factors fueling substance abuse. Precipitation or fear of withdrawal symptoms was the major factor preventing abstinence. Substance abuse had a significant effect on the health and interpersonal relations of these patients. Summary/Conclusion: Drug abuse and addiction are on the rise throughout India. Changing cultural values, increasing economic stress and dwindling supportive bonds appear to be leading to initiation of substance abuse. Need of the hour is to formulate a comprehensive strategy to bring about an overall reduction in the use of drugs.

Keywords: deaddiction, peer pressure, parental imitation, substance abuse/dependance

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Authors: Simona Dostalova, Dita Munzova, Ana Maria Jimenez Jimenez, Marketa Vaculovicova, Vojtech Adam, Rene Kizek

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The boom of nanomedicine in recent years has led to the development of numerous new nanomaterials that can be used as nanocarriers in the drug delivery. These nanocarriers can either be synthetic or natural-based. The disadvantage of many synthetic nanocarriers is their toxicity in patient’s body. Protein cages that can naturally be found in human body do not exhibit such disadvantage. However, the release of cargo from some protein cages in target cells can be problematic. As a special type of protein cages can serve the capsid of many viruses, including phage. Phages infect bacterial cells; therefore they are not harmful to human cells. The targeting of phage particles to cancer cells can be solved by producing of empty phage capsids during which the targeting moieties (e.g. peptides) can be cloned into genes of phage capsid to decorate its surface. Moreover, the produced capsids do not contain viral nucleic acid and are therefore not infectious to beneficial bacteria in the patient’s body. The protein cage composed of viral capsid is larger than other frequently used apoferritin cage but its size is still small enough to benefit from passive targeting by Enhanced Permeability and Retention effect. In this work, bacteriophage λ was used, both whole and its empty capsid for delivery of different cytotoxic drugs (cisplatin, carboplatin, oxaliplatin, etoposide and doxorubicin). Large quantities of phage λ were obtained from phage λ-producing strain of E. coli cultivated in medium with 0.2 % maltose. After killing of E. coli with chloroform and its removal by centrifugation, the phage was concentrated by ultracentrifugation at 130 000 g and 4 °C for 3 h. The encapsulation of the drugs was performed by infusion method and four different concentrations of the drugs were encapsulated (200; 100; 50; 25 µg/ml). Free molecules of drugs were removed by dialysis. The encapsulation was verified using spectrophotometric and electrochemical methods. The amount of encapsulated drug linearly increased with the amount of applied drug (determination coefficient R2=0.8013). 76% of applied drug was encapsulated in phage λ particles (concentration of 10 µg/ml), even with the highest applied concentration of drugs, 200 µg/ml. Only 1% of encapsulated drug was detected in phage DNA. Similar results were obtained with encapsulation in phage empty capsid. Therefore, it can be concluded that the encapsulation of drugs into phage particles is efficient and mostly occurs by interaction of drugs with protein capsid.

Keywords: cytostatics, drug delivery, nanocarriers, phage capsid

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Authors: Shahab Azimi, Siamak Arzanpour, Anahita Sayyar

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Asthma and Chronic obstructive pulmonary disease (COPD) are common lung diseases that have a significant global impact. Pressurized metered dose inhalers (pMDIs) are widely used for treatment, but they can have limitations such as high medication release speed resulting in drug deposition in the mouth or oral cavity and difficulty achieving proper synchronization with inhalation by users. Spacers are add-on devices that improve the efficiency of pMDIs by reducing the release speed and providing space for aerosol particle breakup to have finer and medically effective medication. The aim of this study is to optimize the size and cylindrical shape of spacers to enhance their drug delivery performance. The study was based on fluid dynamics theory and employed Ansys software for simulation and optimization. Results showed that optimization of the spacer's geometry greatly influenced its performance and improved drug delivery. This study provides a foundation for future research on enhancing the efficiency of inhalation therapy for lung diseases.

Keywords: asthma, COPD, pressurized metered dose inhalers, spacers, CFD, shape optimization

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Authors: M. Helen

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Chemical graph serves as a convenient model for any real or abstract chemical system. Dendrimers are novel three dimensional hyper branched globular nanopolymeric architectures. Drug delivery scientists are especially enthusiastic about possible utility of dendrimers as drug delivery tool. Dendrimers like poly L lysine (PLL), poly-propylene imine (PPI) and poly-amidoamine (PAMAM), etc., are used as gene carrier in drug delivery system because of their chemical characteristics. These characteristics of chemical compounds are analysed using topological indices (invariants under graph isomorphism) such as Wiener index, Zagreb index, etc., Prof. V. R. Kulli motivated by the application of Zagreb indices in finding the total π energy and derived Gourava indices which is an improved version over Zagreb indices. In this paper, we study the structure of PLL-Dendrimer that has the following applications: reduction in toxicity, colon delivery, and topical delivery. Also, we determine first and second Gourava indices, first and second hyper Gourava indices, product and sum connectivity Gourava indices for PLL-Dendrimer. Gourava Indices have found applications in Quantitative Structure-Property Relationship (QSPR)/ Quantitative Structure-Activity Relationship (QSAR) studies.

Keywords: connectivity Gourava indices, dendrimer, Gourava indices, hyper GouravaG indices

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Authors: Rajni Kant Panik

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The aim of the present study was to develop and evaluate mupirocin loaded nanoparticle incorporated into hydrogel as an infected wound healer. Incorporated Nanoparticle in hydrogel provides a barrier that effectively prevents the contamination of the wound and further progression of infection to deeper tissues. Hydrogel creates moist healing environment on wound space with good fluid absorbance. Nanoparticles were prepared by double emulsion solvent evaporation method using different ratios of PLGA polymer and the hydrogels was developed using sodium alginate and gelatin. Further prepared nanoparticles were then incorporated into the hydrogels. The formulations were characterized by FT-IR and DSC for drug and polymer compatibility and surface morphology was studied by TEM. Nanoparticle hydrogel were evaluated for their size, shape, encapsulation efficiency and for in vitro studies. The FT-IR and DSC confirmed the absence of any drug polymer interaction. The average size of Nanoparticle was found to be in range of 208.21-412.33 nm and shape was found to be spherical. The maximum encapsulation efficiency was found to be 69.03%. The in vitro release profile of Nanoparticle incorporated hydrogel formulation was found to give sustained release of drug. Antimicrobial activity testing confirmed that encapsulated drug preserve its effectiveness. The stability study confirmed that the formulation prepared were stable. Present study complements our finding that mupirocin loaded Nanoparticle incorporated into hydrogel has the potential to be an effective and safe novel addition for the release of mupirocin in sustained manner, which may be a better option for the management of wound. These finding also supports the progression of antibiotic via hydrogel delivery system is a novel topical dosage form for the management of wound.

Keywords: hydrogel, nanoparticle, PLGA, wound healing

Procedia PDF Downloads 289

Authors: Kai-Cheng Hsu, Tzu-Ying Sung, Jinn-Moon Yang

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Colorectal cancer (CRC) is one of the main causes of cancer death in the world. Although several drugs have been developed to treat colorectal cancer, such as Regorafenib and 5-FU, their efficacy is often limited by the development of drug resistance. Therefore, development of new drugs with new scaffolds is necessary to treat CRC. Here, we used site-moiety maps to identify inhibitors against PIM1, LIMK1, SRC, and mTOR, which are often overexpressed in CRC. A site-moiety map represents physicochemical properties and moiety preferences of a binding site through anchors. An anchor contains three elements: (1) conserved interacting residues of a binding pocket; (2) moiety preference of the binding pocket; and (3) the type (e.g., hydrogen-bonding or van der Waals interactions) of interaction between the moieties and the binding pocket. Then, we performed a structure-based virtual screening of ~260,000 compounds and selected compound candidates with high site-moiety map scores for bioassays. Among these candidates, compound 1 and compound 2 inhibited the growth of CRC cells with IC50 values of <10 μM. The experimental result of enzyme-based assays indicated that compound 1 is a dual inhibitor against PIM1 (IC50 6 μM) and LIMK1(IC50 11 μM). Compound 2 was predicted as a SRC inhibitor and will be further validated. The compounds inhibited different protein targets compared to the current drugs. We believe that the compounds provide a starting point to design new drugs for CRC treatment.

Keywords: colorectal cancer, drug discovery, site-moiety map, virtual screening, PIM1, LIMK1

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Authors: Swapnila V. Vanshiv, Hemant P. Joshi, Atul B. Aware

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Current study illustrates the formulation of floating microspheres for purpose of gastroretention of Dipyridamole which shows pH dependent solubility, with the highest solubility in acidic pH. The formulation involved hollow microsphere preparation by using solvent evaporation technique. Concentrations of rate controlling polymer, hydrophilic polymer, internal phase ratio, stirring speed were optimized to get desired responses, namely release of Dipyridamole, buoyancy of microspheres, entrapment efficiency of microspheres. In the formulation, the floating microspheres were prepared by using ethyl cellulose as release retardant and HPMC as a low density hydrophilic swellable polymer. Formulated microspheres were evaluated for their physical properties such as particle size and surface morphology by optical microscopy and SEM. Entrapment efficiency, floating behavior and drug release study as well the formulation was evaluated for in vivo gastroretention in rabbits using gamma scintigraphy. Formulation showed 75% drug release up to 10 hr with entrapment efficiency of 91% and 88% buoyancy till 10 hr. Gamma scintigraphic studies revealed that the optimized system was retained in the gastric region (stomach) for a prolonged period i.e. more than 5 hr.

Keywords: Dipyridamole microspheres, gastroretention, HPMC, optimization method

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Authors: Norma Binti Alias, Che Rahim Che The, Norfarizan Mohd Said, Sakinah Abdul Hanan, Akhtar Ali

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This paper discusses on the transportation of magnetic drug targeting through blood within vessels, tissues and cells. There are three integrated mathematical models to be discussed and analyze the concentration of drug and blood flow through magnetic nanoparticles. The cell therapy brought advancement in the field of nanotechnology to fight against the tumors. The systematic therapeutic effect of Single Cells can reduce the growth of cancer tissue. The process of this nanoscale phenomena system is able to measure and to model, by identifying some parameters and applying fundamental principles of mathematical modeling and simulation. The mathematical modeling of single cell growth depends on three types of cell densities such as proliferative, quiescent and necrotic cells. The aim of this paper is to enhance the simulation of three types of models. The first model represents the transport of drugs by coupled partial differential equations (PDEs) with 3D parabolic type in a cylindrical coordinate system. This model is integrated by Non-Newtonian flow equations, leading to blood liquid flow as the medium for transportation system and the magnetic force on the magnetic nanoparticles. The interaction between the magnetic force on drug with magnetic properties produces induced currents and the applied magnetic field yields forces with tend to move slowly the movement of blood and bring the drug to the cancer cells. The devices of nanoscale allow the drug to discharge the blood vessels and even spread out through the tissue and access to the cancer cells. The second model is the transport of drug nanoparticles from the vascular system to a single cell. The treatment of the vascular system encounters some parameter identification such as magnetic nanoparticle targeted delivery, blood flow, momentum transport, density and viscosity for drug and blood medium, intensity of magnetic fields and the radius of the capillary. Based on two discretization techniques, finite difference method (FDM) and finite element method (FEM), the set of integrated models are transformed into a series of grid points to get a large system of equations. The third model is a single cell density model involving the three sets of first order PDEs equations for proliferating, quiescent and necrotic cells change over time and space in Cartesian coordinate which regulates under different rates of nutrients consumptions. The model presents the proliferative and quiescent cell growth depends on some parameter changes and the necrotic cells emerged as the tumor core. Some numerical schemes for solving the system of equations are compared and analyzed. Simulation and computation of the discretized model are supported by Matlab and C programming languages on a single processing unit. Some numerical results and analysis of the algorithms are presented in terms of informative presentation of tables, multiple graph and multidimensional visualization. As a conclusion, the integrated of three types mathematical modeling and the comparison of numerical performance indicates that the superior tool and analysis for solving the complete set of magnetic drug delivery system which give significant effects on the growth of the targeted cancer cell.

Keywords: mathematical modeling, visualization, PDE models, magnetic nanoparticle drug delivery model, drug release model, single cell effects, avascular tumor growth, numerical analysis

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Authors: Anushka Naidoo, Veron Ramsuran, Maxwell Chirehwa, Paolo Denti, Kogieleum Naidoo, Helen McIlleron, Nonhlanhla Yende-Zuma, Ravesh Singh, Sinaye Ngcapu, Nesri Padayatachi

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Background: Despite efforts to introduce new drugs and shorter drug regimens for drug-susceptible tuberculosis (TB), the standard first-line treatment has not changed in over 50 years. Rifampicin, isoniazid, and pyrazinamide are critical components of the current standard treatment regimens. Some studies suggest that microbiologic failure and acquired drug resistance are primarily driven by low drug concentrations that result from pharmacokinetic (PK) variability independent of adherence to treatment. Wide between-patient pharmacokinetic variability for rifampin, isoniazid, and pyrazinamide has been reported in prior studies. There may be several reasons for this variability. However, genetic variability in genes coding for drug metabolizing and transporter enzymes have been shown to be a contributing factor for variable tuberculosis drug exposures. Objective: We describe the pharmacokinetics of first-line TB drugs rifampicin, isoniazid, and pyrazinamide and assess the effect of genetic variability in relevant selected drug metabolizing and transporter enzymes on pharmacokinetic parameters of isoniazid and rifampicin. Methods: We conducted the randomized-controlled Improving retreatment success TB trial in Durban, South Africa. The drug regimen included rifampicin, isoniazid, and pyrazinamide. Drug concentrations were measured in plasma, and concentration-time data were analysed using nonlinear-mixed-effects models to quantify the effects of relevant covariates and single nucleotide polymorphisms (SNP’s) of drug metabolizing and transporter genes on rifampicin, isoniazid and pyrazinamide exposure. A total of 25 SNP’s: four NAT2 (used to determine acetylator status), four SLCO1B1, three Pregnane X receptor (NR1), six ABCB1 and eight UGT1A, were selected for analysis in this study. Genotypes were determined for each of the SNP’s using a TaqMan® Genotyping OpenArray™. Results: Among fifty-eight patients studied; 41 (70.7%) were male, 97% black African, 42 (72.4%) HIV co-infected and 40 (95%) on efavirenz-based ART. Median weight, fat-free mass (FFM), and age at baseline were 56.9 kg (interquartile range, IQR: 51.1-65.2), 46.8 kg (IQR: 42.5-50.3) and 37 years (IQR: 31-42), respectively. The pharmacokinetics of rifampicin and pyrazinamide was best described using one-compartment models with first-order absorption and elimination, while for isoniazid two-compartment disposition was used. The median (interquartile range: IQR) AUC (h·mg/L) and Cmax (mg/L) for rifampicin, isoniazid, and pyrazinamide were; 25.62 (23.01-28.53) and 4.85 (4.36-5.40), 10.62 (9.20-12.25) and 2.79 (2.61-2.97), 345.74 (312.03-383.10) and 28.06 (25.01-31.52), respectively. Eighteen percent of patients were classified as rapid acetylators, and 34% and 43% as slow and intermediate acetylators, respectively. Rapid and intermediate acetylator status based on NAT 2 genotype resulted in 2.3 and 1.6 times higher isoniazid clearance than slow acetylators. We found no effects of the SLCO1B1 genotypes on rifampicin pharmacokinetics. Conclusion: Plasma concentrations of rifampicin, isoniazid, and pyrazinamide were low overall in our patients. Isoniazid clearance was high overall and as expected higher in rapid and intermediate acetylators resulting in lower drug exposures. In contrast to reports from previous South African or Ugandan studies, we did not find any effects of the SLCO1B1 or other genotypes tested on rifampicin PK. However, our findings are in keeping with more recent studies from Malawi and India emphasizing the need for geographically diverse and adequately powered studies. The clinical relevance of the low tuberculosis drug concentrations warrants further investigation.

Keywords: rifampicin, isoniazid pharmacokinetics, genetics, NAT2, SLCO1B1, tuberculosis

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Authors: Saurabh B. Ganorkar, Atul A. Shirkhedkar

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The need for investigations protecting against toxic impurities though seems to be a primary requirement; the impurities which may prove non - toxic can be explored for their therapeutic potential if any to assist advanced drug discovery. The essential role of pharmaceutical analysis can thus be extended effectively to achieve it. The present study successfully achieved these objectives with characterization of major degradation products as impurities for Zileuton which has been used for to treat asthma since years. The forced degradation studies were performed to identify the potential degradation products using Ultra-fine Liquid-chromatography. Liquid-chromatography-Mass spectrometry (Time of Flight) and Proton Nuclear Magnetic Resonance Studies were utilized effectively to characterize the drug along with five major oxidative and hydrolytic degradation products (DP’s). The mass fragments were identified for Zileuton and path for the degradation was investigated. The characterized DP’s were subjected to In-Silico studies as XP Molecular Docking to compare the gain or loss in binding affinity with 5-Lipooxygenase enzyme. One of the impurity of was found to have the binding affinity more than the drug itself indicating for its potential to be more bioactive as better Antiasthmatic. The close structural resemblance has the ability to potentiate or reduce bioactivity and or toxicity. The chances of being active biologically at other sites cannot be denied and the same is achieved to some extent by predictions for probability of being active with Prediction of Activity Spectrum for Substances (PASS) The impurities found to be bio-active as Antineoplastic, Antiallergic, and inhibitors of Complement Factor D. The toxicological abilities as Ames-Mutagenicity, Carcinogenicity, Developmental Toxicity and Skin Irritancy were evaluated using Toxicity Prediction by Komputer Assisted Technology (TOPKAT). Two of the impurities were found to be non-toxic as compared to original drug Zileuton. As the drugs are purposed and repurposed effectively the impurities can also be; as they can have more binding affinity; less toxicity and better ability to be bio-active at other biological targets.

Keywords: UFLC, LC-MS-TOF, NMR, Zileuton, impurities, toxicity, bio-activity

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Authors: Yogeeta O. Agrawal, Hitendra S. Mahajan, Sanjay J. Surana

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Methotrexate is effective in controlling recalcitrant psoriasis when administered by the oral or parenteral route long-term. However, the systematic use of this drug may provoke any of a number of side effects, notably hepatotoxic effects. To reduce these effects, clinical studies have been done with topical MTx. It is useful in treating a number of cutaneous conditions, including psoriasis. A major problem in topical administration of MTx currently available in market is that the drug is hydrosoluble and is mostly in the dissociated form at physiological pH. Its capacity for passive diffusion is thus limited. Localization of MTx in effected layers of skin is likely to improve the role of topical dosage form of the drug as a supplementary to oral therapy for treatment of psoriasis. One of the possibilities for increasing the penetration of drugs through the skin is the use of Nanostructured lipid Carriers. The objective of the present study was to formulate and characterize Methotrexate loaded Nanostructured Lipid Carriers (MtxNLCs), to understand in vitro drug release and evaluate the role of the developed gel in the topical treatment of psoriasis. MtxNLCs were prepared by solvent diffusion technique using 3(2) full factorial design.The mean diameter and surface morphology of MtxNLC was evaluated. MtxNLCs were lyophilized and crystallinity of NLC was characterized by Differential Scanning Calorimtery (DSC) and powder X-Ray Diffraction (XRD). The NLCs were incorporated in 1% w/w Carbopol 934 P gel base and in vitro skin deposition studies in Human Cadaver Skin were conducted. The optimized MtxNLCs were spherical in shape, with average particle size of 253(±9.92)nm, zeta potential of -30.4 (±0.86) mV and EE of 53.12(±1.54)%. DSC and XRD data confirmed the formation of NLCs. Significantly higher deposition of Methotrexate was found in human cadaver skin from MtxNLC gel (71.52 ±1.23%) as compared to Mtx plain gel (54.28±1.02%). Findings of the studies suggest that there is significant improvement in therapeutic index in treatment of psoriasis by MTx-NLCs incorporated gel base developed in this investigation over plain drug gel currently available in the market.

Keywords: methotrexate, psoriasis, NLCs, hepatotoxic effects

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Authors: Mandy Wilson, Emma Vieira, Jocelyn Jones, Alice V. Brown, Lindey Andrews, Louise Southalan, Jackie Oakley, Dorothy Bagshaw, Patrick Egan, Laura Dent, Duc Dau, Lucy Spanswick

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Alcohol and drug dependency are pertinent issues for those experiencing homelessness. This includes Aboriginal and Torres Strait Islander people, Australia’s traditional owners, living in Perth, Western Australia (WA). Societal narratives around the drivers behind drug and alcohol dependency in Aboriginal communities, particularly those experiencing homelessness, have been biased and unchanging, with little regard for complexity. This can include the idea that Aboriginal people have ‘chosen’ to use alcohol or other drugs without consideration for intergenerational trauma and the trauma of homelessness that may influence their choices. These narratives have flow-on impacts on policies and services that directly impact Aboriginal people experiencing homelessness. In 2021, we commenced a project which aimed to listen to and elevate the voices of 70-90 Aboriginal people experiencing homelessness in Perth. The project is community-driven, led by an Aboriginal Community Controlled Organisation in partnership with a university research institute. A community-ownership group of Aboriginal Elders endorsed the project’s methods, chosen to ensure their suitability for the Aboriginal community. In this paper, we detail these methods, including semi-structured interviews influenced by an Aboriginal yarning approach – an important style of conversation for Aboriginal people which follows cultural protocols; and photovoice – supporting people to share their stories through photography. Through these engagements, we detail the reasons Aboriginal people in Perth shared for using alcohol or other drugs while experiencing homelessness. These included supporting their survival on the streets, managing their mental health, and coping while on the journey to finding support. We also detail why they sought to discontinue alcohol and other drug use, including wanting to reconnect with family and changing priorities. Finally, we share how Aboriginal people experiencing homelessness have said they are impacted by their family’s alcohol and other drug use, including feeling uncomfortable living with a family who is drug and alcohol-dependent and having to care for grandchildren despite their own homelessness. These findings provide a richer understanding of alcohol and drug use for Aboriginal people experiencing homelessness in Perth, shedding light on potential changes to targeted policy and service approaches.

Keywords: Aboriginal and Torres Strait Islander peoples, alcohol and other drugs, homelessness, community-led research

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Authors: Janneth Gonzalez, Marco Avila, George Barreto

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GRP78 participates in multiple functions in the cell during normal and pathological conditions, controlling calcium homeostasis, protein folding and unfolded protein response. GRP78 is located in the endoplasmic reticulum, but it can change its location under stress, hypoxic and apoptotic conditions. NF-κB represents the keystone of the inflammatory process and regulates the transcription of several genes related with apoptosis, differentiation, and cell growth. The possible relationship between GRP78-NF-κB could support and explain several mechanisms that may regulate a variety of cell functions, especially following brain injuries. Although several reports show interactions between NF-κB and heat shock proteins family members, there is a lack of information on how GRP78 may be interacting with NF-κB, and possibly regulating its downstream activation. Therefore, we assessed the computational predictions of the GRP78 (Chain A) and NF-κB complex (IkB alpha and p65) protein-protein interactions. The interaction interface of the docking model showed that the amino acids ASN 47, GLU 215, GLY 403 of GRP78 and THR 54, ASN 182 and HIS 184 of NF-κB are key residues involved in the docking. The electrostatic field between GRP78-NF-κB interfaces and molecular dynamic simulations support the possible interaction between the proteins. In conclusion, this work shed some light in the possible GRP78-NF-κB complex indicating key residues in this crosstalk, which may be used as an input for better drug design strategy targeting NF-κB downstream signaling as a new therapeutic approach following brain injuries.

Keywords: computational biology, protein interactions, Grp78, bioinformatics, molecular dynamics

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Authors: P. Behera, K. K. Singh, D. K. Saini, M. De

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Implementation of 2D materials in the detection of bio analytes is highly advantageous in the field of sensing because of its high surface to volume ratio. We have designed our sensor array with different cationic two-dimensional MoS₂, where surface modification was achieved by cationic thiol ligands with different functionality. Green fluorescent protein (GFP) was chosen as signal transducers for its biocompatibility and anionic nature, which can bind to the cationic MoS₂ surface easily, followed by fluorescence quenching. The addition of bio-analyte to the sensor can decomplex the cationic MoS₂ and GFP conjugates, followed by the regeneration of GFP fluorescence. The fluorescence response pattern belongs to various analytes collected and transformed to linear discriminant analysis (LDA) for classification. At first, 15 different proteins having wide range of molecular weight and isoelectric points were successfully discriminated at 50 nM with detection limit of 1 nM. The sensor system was also executed in biofluids such as serum, where 10 different proteins at 2.5 μM were well separated. After successful discrimination of protein analytes, the sensor array was implemented for bacteria sensing. Six different bacteria were successfully classified at OD = 0.05 with a detection limit corresponding to OD = 0.005. The optimized sensor array was able to classify uropathogens from non-uropathogens in urine medium. Further, the technique was applied for discrimination of bacteria possessing resistance to different types and amounts of drugs. We found out the mechanism of sensing through optical and electrodynamic studies, which indicates the interaction between bacteria with the sensor system was mainly due to electrostatic force of interactions, but the separation of native bacteria from their drug resistant variant was due to Van der Waals forces. There are two ways bacteria can be detected, i.e., through bacterial cells and lysates. The bacterial lysates contain intracellular information and also safe to analysis as it does not contain live cells. Lysates of different drug resistant bacteria were patterned effectively from the native strain. From unknown sample analysis, we found that discrimination of bacterial cells is more sensitive than that of lysates. But the analyst can prefer bacterial lysates over live cells for safer analysis.

Keywords: array-based sensing, drug resistant bacteria, linear discriminant analysis, two-dimensional MoS₂

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Authors: Abdul Matin, Muhammad Ajmal, Uzma Yunus, Noaman-ul Haq, Hafiz M. Shohaib, Ambreen G. Muazzam

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Carbon nanoparticles (CNPs) have unique properties that are useful for the diagnosis and treatment of cancer due to their precise properties like small size (ideal for delivery within the body) stability in solvent and tunable surface chemistry for targeted delivery. Here, highly fluorescent, monodispersed and water-soluble CNPs were synthesized directly from a suitable carbohydrate source (glucose and sucrose) by one-step acid assisted ultrasonic treatment at 35 KHz for 4 hours. This method is green, simple, rapid and economical and can be used for large scale production and applications. The average particle sizes of CNPs are less than 10nm and they emit bright and colorful green-blue fluorescence under the irradiation of UV-light at 365nm. The CNPs were characterized by scanning electron microscopy, fluorescent spectrophotometry, Fourier transform infrared spectrophotometry, ultraviolet-visible spectrophotometry and TGA analysis. Fluorescent CNPs were used as fluorescent probe and nano-carriers for anticancer drug. Functionalized CNPs (with ethylene diamine) were attached with anticancer drug-Methotrexate. In vitro bioactivity and biocompatibility of CNPs-drug conjugates was evaluated by LDH assay and Sulforhodamine B assay using human lung carcinoma cell lines (H157). Our results reveled that CNPs showed biocompatibility and CNPs-anticancer drug conjugates have shown potent cytotoxic effects and high antitumor activities in lung cancer cell lines. CNPs are proved to be excellent substitute for conventional drug delivery cargo systems and anticancer therapeutics in vitro. Our future studies will be more focused on using the same nanoparticles in vivo model system.

Keywords: carbon nanoparticles, carbon nanoparticles-methotrexate conjugates, human lung carcinoma cell lines, lactate dehydrogenase, methotrexate

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Authors: Abdulaziz Alakeel, Roaa Alamri, Abdulrahman Alomair, Mohammed Fouda

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Introduction: Ibrutinib is a selective, potent, and irreversible small-molecule inhibitor of Bruton's tyrosine kinase (BTK). It forms a covalent bond with a cysteine residue (CYS-481) at the active site of Btk, leading to inhibition of Btk enzymatic activity. The drug is indicated to treat certain type of cancers such as mantle cell lymphoma (MCL), chronic lymphocytic leukaemia and Waldenström's macroglobulinaemia (WM). Cardiac failure is a condition referred to inability of heart muscle to pump adequate blood to human body organs. There are multiple types of cardiac failure including left and right-sided heart failure, systolic and diastolic heart failures. The aim of this review is to evaluate the risk of cardiac failure associated with the use of ibrutinib and to suggest regulatory recommendations if required. Methodology: Signal Detection team at the National Pharmacovigilance Center (NPC) of Saudi Food and Drug Authority (SFDA) performed a comprehensive signal review using its national database as well as the World Health Organization (WHO) database (VigiBase), to retrieve related information for assessing the causality between cardiac failure and ibrutinib. We used the WHO- Uppsala Monitoring Centre (UMC) criteria as standard for assessing the causality of the reported cases. Results: Case Review: The number of resulted cases for the combined drug/adverse drug reaction are 212 global ICSRs as of July 2020. The reviewers have selected and assessed the causality for the well-documented ICSRs with completeness scores of 0.9 and above (35 ICSRs); the value 1.0 presents the highest score for best-written ICSRs. Among the reviewed cases, more than half of them provides supportive association (four probable and 15 possible cases). Data Mining: The disproportionality of the observed and the expected reporting rate for drug/adverse drug reaction pair is estimated using information component (IC), a tool developed by WHO-UMC to measure the reporting ratio. Positive IC reflects higher statistical association while negative values indicates less statistical association, considering the null value equal to zero. The results of (IC=1.5) revealed a positive statistical association for the drug/ADR combination, which means “Ibrutinib” with “Cardiac Failure” have been observed more than expected when compared to other medications available in WHO database. Conclusion: Health regulators and health care professionals must be aware for the potential risk of cardiac failure associated with ibrutinib and the monitoring of any signs or symptoms in treated patients is essential. The weighted cumulative evidences identified from causality assessment of the reported cases and data mining are sufficient to support a causal association between ibrutinib and cardiac failure.

Keywords: cardiac failure, drug safety, ibrutinib, pharmacovigilance, signal detection

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Authors: Jillian M. Hagel, Joseph E. Tucker, Peter J. Facchini

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With the aim of establishing a holistic approach for the treatment of central nervous system (CNS) disorders, we are pursuing a drug development program rapidly progressing through discovery and characterization phases. The drug candidates identified in this program are referred to as neuroplastogens owing to their ability to mediate neuroplasticity, which can be beneficial to patients suffering from anxiety, depression, or posttraumatic stress disorder. These and other related neuropsychiatric conditions are associated with the onset of neuronal atrophy, which is defined as a reduction in the number and/or productivity of neurons. The stimulation of neuroplasticity results in an increase in the connectivity between neurons and promotes the restoration of healthy brain function. We have synthesized a substantial catalogue of proprietary indolethylamine derivatives based on the general structures of serotonin (5-hydroxytryptamine) and psychedelic molecules such as N,N-dimethyltryptamine (DMT) and psilocin (4-hydroxy-DMT) that function as neuroplastogens. A primary objective in our screening protocol is the identification of derivatives associated with a significant reduction in hallucination, which will allow administration of the drug at a dose that induces neuroplasticity and triggers other efficacious outcomes in the treatment of targeted CNS disorders but which does not cause a psychedelic response in the patient. Both neuroplasticity and hallucination are associated with engagement of the 5HT2A receptor, requiring drug candidates differentially coupled to these two outcomes at a molecular level. We use novel and proprietary artificial intelligence algorithms to predict the mode of binding to the 5HT2A receptor, which has been shown to correlate with the hallucinogenic response. Hallucination is tested using the mouse head-twitch response model, whereas mouse marble-burying and sucrose preference assays are used to evaluate anxiolytic and anti-depressive potential. Neuroplasticity is assays using dendritic outgrowth assays and cell-based ELISA analysis. Pharmacokinetics and additional receptor-binding analyses also contribute the selection of lead candidates. A summary of the program is presented.

Keywords: neuroplastogen, non-hallucinogenic, drug development, anxiety, depression, PTSD, indolethylamine derivatives, psychedelic-inspired, 5-HT2A receptor, computational chemistry, head-twitch response behavioural model, neurite outgrowth assay

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Authors: V. Naga Sravan Kumar Varma, H. G. Shivakumar

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The aim of the study was to develop dual sensitive poly (N-isopropylacrylamide-co-acrylic acid) (PNA) nanogels(NGs) and studying its applications for Anti-Cancer therapy. NGs were fabricated by free radical polymerization using different amount of N-isopropylacrylamide and acrylic acid. A study for polymer composition over the effect on LCST in different pH was evaluated by measuring the absorbance at 500nm using UV spectrophotometer. Further selected NG’s were evaluated for change in hydrodynamic diameters in response to pH and temperature. NGs which could sharply respond to low pH value of cancer cells at body temperature were loaded with Fluorouracil (5-FU) using equilibrium swelling method and studied for drug release behaviour in different pH. A significant influence of NGs polymer composition over pH dependent LCST was observed. NGs which were spherical with an average particle size of 268nm at room temperature, shrinked forming an irregular shape when heated above to their respective LCST. 5FU loaded NGs did not intervene any difference in pH depended LCST behaviour of NGs. The in vitro drug release of NGs exhibited a pH and thermo-dependent control release. The cytoxicity study of blank carrier to MCF7 cell line showed no cytotoxicity. The results indicated that PNA NGs could be used as a potential drug carrier for anti-cancer therapy.

Keywords: pH and thermo-sensitive, nanogels, P(NIPAM-co-AAc), anti-cancer, 5-FU

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Authors: Swanand Pathak, Kiran R. Giri, Reena R. Giri, Kamlesh Palandurkar, Sangita Totade, Rajesh Jha, S. S. Patel

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Background: Population burden, illiteracy, availability of few doctors for larger group of population leads to many unanswered questions left in a patient’s mind. Incomplete information results into noncompliance, therapeutic failure, and adverse drug reactions (ADR). It is very important to establish a system which will provide noncommercial, independent, unbiased source of medicine information. Medicines Info OPD is a concept and step towards safe and appropriate use of medicines. Objective: (1) to assess the present status of knowledge about the medicines in the patients and its correlation with education; (2) to assess the medicine information dispensing modalities, their use and sufficiency from the patients view point; (3) to assess the overall need for Medicines Information OPD in present scenario. Materials and Methods: A pre-validated questionnaire based study was conducted amongst 500 patients of tertiary health care hospital. The questionnaire consisted of specific questions regarding understanding of prescription, knowledge about adverse drug reaction, view about self-medication and opinion regarding the need of Medicines Info OPD. Results: Significantly large proportion of patients opined that doctors do not have sufficient time in current Indian healthcare to explain the prescription and they are not aware of adverse drug reactions, expiry date or use the package inserts etc. Conclusion: Clinically relevant, up to date, user specific, independent, objective and unbiased Medicines Info OPD is essential for appropriate drug use and can help in a big way to common public to address many problems faced by them.

Keywords: information, prescription, unbiased, clinically relevant

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Authors: Giancarlo La Marca, Engy Shokry, Fabio Villanelli

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Epilepsy is one of the most common neurological disorders, with an estimated prevalence of 50 million people worldwide. Twenty five percent of the epilepsy population is represented in children under the age of 15 years. For antiepileptic drugs (AED), there is a poor correlation between plasma concentration and dose especially in children. This was attributed to greater pharmacokinetic variability than adults. Hence, therapeutic drug monitoring (TDM) is recommended in controlling toxicity while drug exposure is maintained. Carbamazepine (CBZ) is a first-line AED and the drug of first choice in trigeminal neuralgia. CBZ is metabolised in the liver into carbamazepine-10,11-epoxide (CBZE), its major metabolite which is equipotent. This develops the need for an assay able to monitor the levels of both CBZ and CBZE. The aim of the present study was to develop and validate a LC-MS/MS method for simultaneous quantification of CBZ and CBZE in dried blood spots (DBS). DBS technique overcomes many logistical problems, ethical issues and technical challenges faced by classical plasma sampling. LC-MS/MS has been regarded as superior technique over immunoassays and HPLC/UV methods owing to its better specificity and sensitivity, lack of interference or matrix effects. Our method combines advantages of DBS technique and LC-MS/MS in clinical practice. The extraction process was done using methanol-water-formic acid (80:20:0.1, v/v/v). The chromatographic elution was achieved by using a linear gradient with a mobile phase consisting of acetonitrile-water-0.1% formic acid at a flow rate of 0.50 mL/min. The method was linear over the range 1-40 mg/L and 0.25-20 mg/L for CBZ and CBZE respectively. The limit of quantification was 1.00 mg/L and 0.25 mg/L for CBZ and CBZE, respectively. Intra-day and inter-day assay precisions were found to be less than 6.5% and 11.8%. An evaluation of DBS technique was performed, including effect of extraction solvent, spot homogeneity and stability in DBS. Results from a comparison with the plasma assay are also presented. The novelty of the present work lies in being the first to quantify CBZ and its metabolite from only one 3.2 mm DBS disc finger-prick sample (3.3-3.4 µl blood) by LC-MS/MS in a 10 min. chromatographic run.

Keywords: carbamazepine, carbamazepine-10, 11-epoxide, dried blood spots, LC-MS/MS, therapeutic drug monitoring

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Authors: Subrata Kar, Banani Kundu, Papiya Nandy, Ruma Basu, Sukhen Das

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Natural montmorilollite clay is a common ingredient in pharmaceutical products, both as excipients and active support; hence considered as suitable candidate for Drug Delivery System. In this work, cationic detergent CTAB is used to increase the interlayer spacing of Na+-Montmoriollite clay to intercalate curcumin and methotrexate. Methotrexate is a folic acid antagonist, anti-proliferative and immunosuppressive agent; while curcumin is a bioactive constituent of rhizomes of Curcuma longa, possessing remarkable chemo-preventive and anti-inflammatory properties. The resultant inorganic-organic hybrids are characterized by X-ray diffraction (XRD), Infrared spectroscopy (FTIR) and Thermo Gravimetric Analysis (TGA) to confirm successful intercalation of curcumin and Methotrexate within clay layers. Pharmaceutical investigation of the hybrids is explored by studying the drug loading (%), encapsulation efficiency and release kinetics. Finally in-vitro studies are performed using cancer cells to find the effect of released curcumin to improve the sensitivity of clay bound methotrexate to ameliorate cell death compared to their effectiveness when used without the inorganic aluminosilicate vehicle.

Keywords: montmorillonite, methotrexate, curcumin, loading efficiency, release kinetics, anticancer activity

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Authors: Sarah P. Wuebbolt, Ashlee N. Sawyer-Mays

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Non-medical prescription and other drug (NMPOD) use has been a significant public health issue for the last few decades, with problematic use increasing among university students more recently. The current study focused on associations between NMPOD use and mental health, well-being, and world beliefs among young adults. Young adults (N=513) completed online questionnaires assessing stress, demographic characteristics, self-esteem, NMPOD use, coping mechanisms, and anxiety. A substantial portion of participants reported using cannabis (48.5%, n=249), while smaller portions of participants reported using stimulants (26.7%, n = 137), sedatives (17.2%, n=88), opioids (10.8%, n=55), and hallucinogens (14.4%, n=74). Five hierarchical logistic regressions were performed to determine the independent relationships between mental health, well-being, and world belief factors and NMPOD use for the five classes of substances. After controlling for demographic factors (age, gender, race/ethnicity, sexual orientation, and religious affiliation), depression was associated with increased non-medical stimulant, opioid, and cannabis use; coping self-efficacy was associated with increased hallucinogen use, and attendance of worship services was associated with decreased non-medical cannabis and hallucinogen use. Results suggest that depression was strongly associated with non-medical stimulant, opioid, and cannabis use, and attendance of worship services was protective against cannabis and hallucinogen use. To the best of our knowledge, this is one of the first studies to investigate the relationships between mental health, well-being, world beliefs, and NMPOD use among young adults. The present study illuminates future targets for intervention, such as increased access to mental health diagnosis and treatment and the exploration of the roles of religion and shared community in the prevention of drug use among young adults.

Keywords: cannabis, mental health, non-medical prescription and other drug use, world beliefs

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Authors: Krutika K. Sawant, Anil Solanki

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The present study deals with the preparation and optimization of ethyl cellulose-containing disopyramide phosphate loaded microspheres using solvent evaporation technique. A central composite design consisting of a two-level full factorial design superimposed on a star design was employed for optimizing the preparation microspheres. The drug:polymer ratio (X1) and speed of the stirrer (X2) were chosen as the independent variables. The cumulative release of the drug at a different time (2, 6, 10, 14, and 18 hr) was selected as the dependent variable. An optimum polynomial equation was generated for the prediction of the response variable at time 10 hr. Based on the results of multiple linear regression analysis and F statistics, it was concluded that sustained action can be obtained when X1 and X2 are kept at high levels. The X1X2 interaction was found to be statistically significant. The drug release pattern fitted the Higuchi model well. The data of a selected batch were subjected to an optimization study using Box-Behnken design, and an optimal formulation was fabricated. Good agreement was observed between the predicted and the observed dissolution profiles of the optimal formulation.

Keywords: disopyramide phosphate, ethyl cellulose, microspheres, controlled release, Box-Behnken design, factorial design

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Authors: Chee Wee Gan, Anthony Herr Cheun Ng, Yee Shan Wong, Subbu Venkatraman, Lynne Hsueh Yee Lim

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Otitis media with effusion (OME) is the leading cause of hearing loss in children worldwide. Surgery to insert grommet tube into the eardrum is usually indicated for OME unresponsive to antimicrobial therapy. It is the most common surgery for children. However, current commercially available grommet tubes are non-bioresorbable, not drug-treated, with unpredictable duration of retention on the eardrum to ventilate middle ear. Their functionality is impaired when clogged or chronically infected, requiring additional surgery to remove/reinsert grommet tubes. We envisaged that a novel fully bioresorbable grommet tube with sustained antibiotic release technology could address these drawbacks. In this study, drug-loaded bioresorbable poly(L-lactide-co-ε-caprolactone)(PLC) copolymer grommet tubes were fabricated by microinjection moulding technique. In vitro drug release and degradation model of PLC tubes were studied. Antibacterial property was evaluated by incubating PLC tubes with P. aeruginosa broth. Surface morphology was analyzed using scanning electron microscopy. A preliminary animal study was conducted using guinea pigs as an in vivo model to evaluate PLC tubes with and without drug, with commercial Mini Shah grommet tube as comparison. Our in vitro data showed sustained drug release over 3 months. All PLC tubes revealed exponential degradation profiles over time. Modeling predicted loss of tube functionality in water to be approximately 14 weeks and 17 weeks for PLC with and without drug, respectively. Generally, PLC tubes had less bacteria adherence, which were attributed to the much smoother tube surfaces compared to Mini Shah. Antibiotic from PLC tube further made bacteria adherence on surface negligible. They showed neither inflammation nor otorrhea after 18 weeks post-insertion in the eardrums of guinea pigs, but had demonstrated severe degree of bioresorption. Histology confirmed the new PLC tubes were biocompatible. Analyses on the PLC tubes in the eardrums showed bioresorption profiles close to our in vitro degradation models. The bioresorbable antibiotic-loaded grommet tubes showed good predictability in functionality. The smooth surface and sustained release technology reduced the risk of tube infection. Tube functional duration of 18 weeks allowed sufficient ventilation period to treat OME. Our ongoing studies include modifying the surface properties with protein coating, optimizing the drug dosage in the tubes to enhance their performances, evaluating their functional outcome on hearing after full resoption of grommet tube and healing of eardrums, and developing animal model with OME to further validate our in vitro models.

Keywords: bioresorbable polymer, drug release, grommet tube, guinea pigs, otitis media with effusion

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